# gene_set_details

description_brief: CDK Regulation of DNA Replication
systematic_name: M6682
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_mcmPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Initiation of DNA replication in eukaryotes is a highly conserved, multi-step process (replication licensing) designed to restrict initiation events to once per replication origin per S phase. Its control has been uncovered by the discovery of the cyclin dependent kinases (CDKs) as master regulators of the cell cycle and the initiator proteins of DNA replication, such as the Origin Recognition Complex (ORC), Cdc6/18, Cdt1 and the mini-chromosome maintenance complex (Mcm). The proteins and the sequence of events involved in this process are conserved throughout the eukaryotic kingdom. First, the ORC comprised of six proteins binds to replication origins in the chromosomal DNA. At the end of mitosis, ORC, Cdc6/18 and Cdt1 assist the binding of Mcm proteins 27 to chromatin, and chromatin becomes licensed for replication. The activated Mcm complex functions as a replicating helicase and moves along with the replication fork to bring the origins to the unlicensed state. The cycling of CDK activity in the cell cycle regulates the two states of replication origins, the licensed state in G1-phase and the unlicensed state for the rest of the cell cycle. The restriction on licensing is relieved when CDK falls off at the completion of mitosis to allow a new round of replication.


description_brief: Cell Cycle: G1/S Check Point
systematic_name: M648
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_g1Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The G1/S cell cycle checkpoint controls the passage of eukaryotic cells from the first 'gap' phase (G1) into the DNA synthesis phase (S). Two cell cycle kinases, CDK4/6-cyclin D and CDK2-cyclin E, and the transcription complex that includes Rb and E2F are pivotal in controlling this checkpoint. During G1 phase, the Rb-HDAC repressor complex binds to the E2F-DP1 transcription factors, inhibiting the downstream transcription. Phosphorylation of Rb by CDK4/6 and CDK2 dissociates the Rb-repressor complex, permitting transcription of S-phase genes encoding for proteins that amplify the G1 to S phase switch and that are required for DNA replication. Many different stimuli exert checkpoint control including TGFb, DNA damage, contact inhibition, replicative senescence, and growth factor withdrawal. The first four act by inducing members of the INK4 or Kip/Cip families of cell cycle kinase inhibitors. TGFb additionally inhibits the transcription of Cdc25A, a phosphatase that activates the cell cycle kinases. Growth factor withdrawal activates GSK3b, which phosphorylates cyclin D, leading to its rapid ubiquitination and proteosomal degradation. Ubiquitination, nuclear export, and degradation are mechanisms commonly used to rapidly reduce the concentration of cell-cycle control proteins.


description_brief: Cell Cycle: G2/M Checkpoint
systematic_name: M8560
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_g2Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The G2/M DNA damage checkpoint prevents the cell from entering mitosis (M phase) if the genome is damaged. The Cdc2-cyclin B kinase is pivotal in regulating this transition. During G2 phase, Cdc2 is maintained in an inactive state by the kinases Wee1 and Mt1. As cells approach M phase, the phosphatase Cdc25 is activated, perhaps by the polo-kinase Pik1. Cdc25 then activates Cdc2, establishing a feedback amplification loop that efficiently drives the cell into mitosis. DNA damage activates the DNA-PK/ATM/ATR kinases, initiating two parallel cascades that inactivate Cdc2-cyclin B. The first cascade rapidly inhibits progression into mitosis: the CHK kinases phosphorylate and inactivate Cdc25, which can no longer activate Cdc2. The second cascade is slower. Phosphorylation of p53 dissociates it from MDM2, activating its DNA binding activity. Acetylation by p300/PCAF further activates its transcriptional activity. The genes that are turned on by p53 constitute effectors of this second cascade. They include 14-3-3s, which binds to the phosphorylated Cdc2-cyclin B kinase and exports it from the nucleus; GADD45, which apparently binds to and dissociates the Cdc2-cyclin B kinase; and p21Cip1, an inhibitor of a subset of the cyclin-dependent kinases including Cdc2 (CDK1).


description_brief: Cell to Cell Adhesion Signaling
systematic_name: M12851
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_cell2cellPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Interactions between cells responsible for cell to cell adhesion also can communicate signals into the cellular interior, often involving interactions with cytoskeletal elements to produce changes in cell motility, migration, proliferation and shape. The cadherins are cell surface adhesion molecules that help form tight junctions between cells such as formation of epithelial cell layers. E-cadherin inactivation has been implicated in cancer development. In addition to mediating adhesion with other cells, cadherins transduce signals into cells through interactions with the catenins. Catenins probably affect actin cytoskeletal function through interactions with proteins like actinin and vinculin. Catenins also probably trigger changes in cell shape and motility with signals through the Rho small GTPases. Another important cell adhesion molecule is CD-31, or PECAM-1, involved in the formation of junctions between endothelial cells, cell migration, migration of lymphocytes, and regulation of lymphocyte activation. Src phosphorylates PECAM-1 on tyrosine residues causing SHP-2 association with PECAM-1. Paxillin acts as an adaptor protein between proteins involved in adhesion signaling like FAK and src and cytoskeletal elements. In addition to signals created by adhesion molecules to alter cellular responses, other signaling pathways can alter adhesion through components of the focal adhesion complex.


description_brief: Ceramide Signaling Pathway
systematic_name: M19943
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_ceramidePathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Over 1,000 papers and reviews have been written about the role of ceramide in the production of programmed cell death or apoptosis. Ceramide is a sphingosine-based lipid-signaling molecule involved in the regulation of cellular differentiation, proliferation, and apoptosis. This diagram represents some of the current understanding of the cascades that couple ceramide to specific signaling pathways. These cascades illustrate that ceramide can be a growth stimulus or proapototic signal. The ultimate ceramide action is determined within the context of other stimuli and by the subcellular topology of its production and is cell-type specific. There are 2 forms of sphingomyelinase, acid (acid-sphingomyelinase:A-SMase) and neutral (neutral-sphingomyelinase N-SMase), that can produce ceramide. TNF-alpha can stimulate either form of sphingomyelinase as can other death receptors. Different domanis of TNF-alpha stimulate the different Smases. N-SMase stimulation is enhanced by the receptor for activated-C kinase 1 (RACK1). The activity of each form is dependent on the local intracellular pH. In the illustration the forms are seperated to reduce confusion however ceramide produced by either method can stimulate either cascade depending on the presence of specific co-factors and activators. A-SMase has been recognized as one of the required molecules to mediate proapoptotic signalling in cell death induced by a diverse array of stresses such as H2O2, Heat, UV exposure and Radiation. ROS generation in mitochondria activates caspase-3 via cooperation of cytochrome c, Aif and caspase-9 and stimulates or increases ceramide generation through A-SMase in a proaptotic activation cycle. Caspase-3 further increases its own activation by proteolytically cleaving ceramide inhibited catalase which is an inhibitor of ROS generation. Ceramide-activated protein kinase(CARK) also known as Kinase Supressor of RAS (KSR) activity is in some cases the switch point in the balance between proapoptotic and antiapoptotic signals and is also cell-type specific. In endothelial cells for example the activation of KSR is required for apoptosis. In contrast in epithelial cells activation of KSR is required for cell proliferation. An additional switch point is the availability of Bad in the cell. Activation of KSR leads to further mitocondrial stimulation or association with RAS and activation of the Raf1 cascade leading to proliferation or differentiation.


description_brief: Chaperones modulate interferon Signaling Pathway
systematic_name: M9546
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_tidPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Signaling by interferon-gamma stimulates anti-viral responses and tumor suppression through the heterodimeric interferon-gamma receptor. Signaling is initiated by binding of interferon-gamma to its receptor, activating the receptor-associated JAK2 tyrosine kinase to phosphorylate STAT transcription factors that activate interferon responsive genes. Molecular chaperones that modulate or alter protein folding interact with different components of the interferon signaling pathway. One chaperone that modulates interferon signaling is hTid-1, a member of the DnaJ family of chaperones and a cochaperone for the heat shock protein Hsp70, another molecular chaperone. hTid-1 was found in a two-hybrid screen to bind to JAK2 and also to interact with the interferon-gamma receptor. In addition, hTid-1 and JAK2 also interact with Hsp70. Overexpression of hTid-1 represses transcriptional activation by interferon-gamma and Hsp70 dissociates from these proteins when interferon is added to cells, suggesting that Hsp70 holds Jak2 in an inactive conformation prior to ligand activation, and is released in the presence of agonist to allow the activation of Jak-2 and downstream pathways. hTid-1 and Hsp-70 interact with other signaling proteins as well. One of this is Tax, a protein encoded by the HTLV-1 virus that binds to hTid-1. hTid-1 also represses NF-kB activation by blocking the phosphorylation and inactivation of I-kappaB by the IkappaB kinase beta. Hsp70 plays a significant role in protein unfolding for entry into mitochondria and also interacts with tumor suppressor gene products to produce their anti-proliferative activity. One of the actions of interferon is to induce apoptosis of infected target cells, in part through a mitochondrial dependent mechanism. An interaction between interferon signaling and Hsp70 may alter this mitochondrial apoptosis pathway, perhaps playing a role in interferon-mediated apoptosis of infected or transformed cells. The HTLV-1 Tax protein that interacts with Hsp70 blocks mitochondrial induced apoptosis, providing a protection against interferon-mediated cellular defenses.


description_brief: Classical Complement Pathway
systematic_name: M7146
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_classicPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The complement system is part of the defense against invading cells and is composed of about twenty different proteins found in the plasma. When activated, complement proteins form a pathway of proteolytic reactions that culminates in the lysis of foreign cells. The complement system also stimulates phagocytosis of foreign cells and an inflammatory response. There are two different complement systems, the classical complement pathway initiated by antibody complexes on the cell surface, and an alternative complement pathway that is initiated without antibodies. The complement system proteins are named with a capital C followed by a number. A small letter after the number indicates that the protein is a smaller protein resulting from the cleavage of a larger precursor by a protease. In the classical pathway, the first step is the initiation of the pathway triggered by recognition by complement factor C1 of antigen-antibody complexes on the cell surface. When C1 complex interacts with aggregates of IgG with antigen on a cell's surface, two C1-associated proteases, C1r and C1s, are activated. Other factors like lipopolysaccharide also activate C1s. Once C1s is activated, it cleaves C4 to form C4b that then binds to the cell membrane of the cell being attacked. The proteolytic complement cascade is then amplified on the cell membrane through sequential cleavage of complement factors and recruitment of new factors until a cell surface complex containing C5b, C6, C7, and C8 is formed. The addition of a multiple C9 proteins creates the membrane attack complex results in a large pore that spans the membrane of the cell being attacked, allowing ions to flow freely between the cellular interior and exterior. Ions flow out, but large molecules stay in, causing water to flood into the cell and ultimately burst the cell from osmotic pressure.


description_brief: Complement Pathway
systematic_name: M917
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_compPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The complement pathway consists of a series of over thirty proteins in plasma that are part of the immune response. Activation of the complement system lyses bacterial cells, forms chemotactic peptides (C3a and C5a) attracting immune cells, and increases phagocytotic clearance of infecting cells. Complement can also increase the permeability of vascular walls and cause inflammation. Most complement proteins exist in plasma as inactive precursors that cleave and activate each other in a proteolytic cascade in response to three different mechanisms by which the complement system is activated, the classical pathway, the alternative pathway and the lectin-induced pathway. These three systems are distinct in the initiation of the proteolytic cascade but share most of their components and all three converge in the creation of a C3 convertase that cleaves the C3 complement protein, leading ultimately to the formation of the membrane attack complex, MAC, a pore causing lysis of cells. The classical pathway is activated by the recognition of foreign cells by antibodies bound to the surface of the cells. The alternative and lectin-induced pathways are both antibody independent. Proteolysis is triggered in the alternative pathway by the spontaneous activation of C3 convertase from C3 and is triggered in the lectin-induced pathway by the recognition of carbohydrates on the bacterial cell surface by mannan-binding protein, Mbp. In addition to providing a key part of the response to bacterial infection, the complement system can be involved in the response to fungi, viruses and protists. While activation of the complement system is a key part of the immune system, it must also be kept in check to prevent inappropriate or exaggerated responses. Twelve different proteins have been identified that inhibit complement activation to control the system, including Factor H, Factor I and C1 inhibitor. Deficiencies in components of the complement system have been identified in humans that cause a variety of immune related disorders. C3 deficiency is associated with recurrent bacterial infections, while a lack of C2 can cause antibody-antigen complexes to accumulate and cause the autoimmune disorder systemic lupus erythematosus. People lacking C1 inhibitor have also been identified and found to be prone to uncontrolled complement activation and dangerous swelling through production of C3a and C5a anaphylotoxins.


description_brief: Control of skeletal myogenesis by HDAC & calcium/calmodulin-dependent kinase (CaMK)
systematic_name: M1547
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_hdacPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The differentiation of muscle cells is transcriptionally regulated, in part by the myocyte enhancer factor-2, MEF2. During myogenesis MEF2 binds to MyoD and other basic helix-loop-helix factors to activate transcription of genes involved in muscle cell differentiation. Transcriptional activation by MEF2 is blocked by interaction with HDAC5 and other histone deacetylases. In undifferentiated myoblasts, HDAC5 is present in the nucleus where it binds to MEF2 to block activation of muscle genes. When activated by IGF-1 signaling, CaM kinase phosphorylates HDAC proteins, causing them to be exported from the nucleus, releasing the block on MEF2 transcriptional activation and allowing differentiation to proceed. Transcription cofactors also interact with MEF2 to contribute to gene regulation and myogenesis. The transcriptional regulator NFAT, for example, acts as a cofactor for MEF2 when calcium and calcineurin signaling activate it. There are four members of the Mef2 gene family, Mef2a-2d. Mef2a is expressed in brain, heart and skeletal muscle. Mef2c is involved in myogenesis in cardiac and skeletal muscle. Mef2d is widely expressed, and may be involved in the regulation of T cell function as well as muscle. Several factors regulate Mef2 transcription factors, including Map kinases and histone deacetylase (HDAC) enzymes. Mef2 is phosphorylated by p38 map kinase, and phosphorylation of Mef2c by p38 contributes to skeletal muscle differentiation. BMK-1 (also called Erk5) is another member of the Map kinase family that regulates the activity of Mef2 family members and is unique in that it appears itself to possess a transcriptional activation domain and act as a transcriptional coactivator. Mekk3 disruption prevented normal cardiovascular development in mice and appears to signal through p38 and Mef2c in normal cardiovascular development.


description_brief: Corticosteroids and cardioprotection
systematic_name: M10066
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_gcrpathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Myocardial infarction damages heart tissue both during the initial ischemia and the subsequent reperfusion of tissues with oxygen. Corticosteroids can protect cardiac tissue from damage following a heart attack, but the mechanisms by which corticosteroids are cardioprotective have not been clear and negative side effects such as reduced wound healing may result from their use. Corticosteroids exert a variety of actions through binding to the glucocorticoid receptor (GR), a member of the steroid hormone receptor gene family. GR acts as a ligand-dependent transcription factor, but some of the cardioprotective effects mediated by GR-bound corticosteroids are non-transcriptional in nature. Glucocorticoids are commonly used as anti-inflammatory drugs in a variety of conditions, and some of their effects in the heart result from inhibition of the inflammatory response of heart tissue to ischemia and reperfusion. NF-kB is a transcription factor involved in signaling by inflammatory factors such as TNF, and is repressed by glucocorticoids. Annexin-1 is a calcium-dependent phospholipid binding protein whose expression is induced by corticosteroids and inhibits the infiltration of neutrophils into tissue, blocking reperfusion-induced inflammatory heart damage. A non-transcriptional cardioprotective effect of glucocorticoids is activation of NO production by endothelial nitric oxide synthase (eNOS). Glucocorticoids activate eNOS through activation of PI3 kinase and AKT and increased NO produced by eNOS can diffuse into surrounding tissues to prevent clotting and cause vasodilation. The beta-2 adrenergic receptor can also activate PI3 kinase and may synergize with glucocorticoids in this pathway. The atrial natriuretic factor (ANF) is a peptide secreted by the atrial wall in response to increased atrial pressure such as occurs during cardiac failure and to be decreased by myocardial infarction. Glucocorticoids increase the secretion of ANF by acting at the transcriptional level to increase expression of the pro-ANF peptide, perhaps inducing increased water excretion in the kidneys to reduce blood volume and reduce atrial pressure. The exploration of glucorticoid responses may allow the identification of compounds that retain the cardioprotective activities but do not inhibit wound healing. Alternative mechanisms of eNOS activation may also provide a route to identify cardioprotective drugs.


description_brief: CTCF: First Multivalent Nuclear Factor
systematic_name: M11420
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_ctcfPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  CTCF is central to signaling pathways in immature B cells elicited by cross-linking the Ig BCR and stimulation with TGF. Both stimuli result in induction of cell cycle arrest and apoptosis. BCR ligation stimulates a transient induction of MYC that leads to high level CTCF expression and feedback suppression of MYC transcription. BCR ligation also activates PTEN opposing PI3K activation of MYC. Pharmacologic inactivation of PI3K or mTOR/FRAP results in suppression of S6K resulting in activation of CTCF and suppression of MYC. CTCF activation induces transcriptional activation of p19ARF, with its downstream consequences, and of p27. Growth arrest is occasioned by co-expression of p21 and p27 and inhibition of MYC. CTCF, is bona fide multivalent DNA-sequence binder which specificity is mediated by different sets of zinc fingers (ZFs). For three different DNA target sites, particular groups of ZFs which cannot be deleted from the 11 ZF domain without loosing binding to a given site, are shown by a rainbow in the box on the left.


description_brief: CTL mediated immune response against target cells
systematic_name: M1462
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_ctlPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Cytotoxic T lymphocytes (CTLs), also known as killer T cells, provide a cell-mediated response to specific foreign antigens associated with cells. CTLs only respond to foreign antigen when it is presented bound to the MHC-1 expressed on the surface of all cells. CTLs do not respond to soluble antigen, but induce apoptosis in viral-infected cells and in cancer cells. When the complex of antigen bound to MHC-1 is bound to antigen-specific T cell receptor, the cytotoxic T cell induces apoptosis in the target cell primarily by two pathways, one involving perforin-mediated apoptosis and the other involving Fas/Fas-ligand interaction. When CTLs are activated by recognition of specific antigen on a cell, they release perforin proteins that integrate into the membrane of the target cell and organize to form a membrane pore. This allows the protease granzyme to enter the cell and activate the apoptotic caspase proteolytic cascade , and also allows other molecules to cross the cell membrane and trigger osmotic lysis of the membrane. The interaction of T-cell Fas ligand with the Fas receptor in the target cell can also activate the caspase cascade and other pathways involved in apoptosis. The interaction of a CTL with antigen-MHC I complex activates the CTL to proliferate and amplify the clone of T cells that respond to that antigen, amplifying the immune response against that specific antigen.


description_brief: CXCR4 Signaling Pathway
systematic_name: M882
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_cxcr4Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  CXCR4 is a chemokine receptor in the GPCR gene family, and is expressed by cells in the immune system and the central nervous system. In response to binding its ligand SDF-1 (stromal cell-derived factor-1), CXCR4 triggers the migration and recruitment of immune cells. This ligand-receptor pair may also play a role in development of the nervous system. In addition to acting as a chemokine receptor, CXCR4 is a co-receptor for entry of HIV into T cells and ligands of CXCR4, including SDF-1 may help to block HIV infection. Early in the infection of an individual, HIV viruses often are tropic for the CCR5 coreceptor that provides for macrophage entry, then later in infection are tropic for CXCR4 and T cell entry. Viruses that are tropic for CXCR4 are generally syncitium forming, causing T cells to aggregate and be destroyed at a rapid rate. CXCR4 induces downstream signaling by several different pathways. As a GPCR, CXCR4 binding of SDF-1 activates G-protein mediated signaling, including downstream pathways such as ras, and PI3 kinase. PI3 kinase activated by SDF-1 and CXCR4 plays a role in lymphocyte chemotaxis in response to these signals. One endpoint of CXCR4 signaling is the activation of transcription factors such as AP-1 and chemokine regulated genes. JAK/STAT signaling pathways also appear to play a role in SDF-1/CXCR4 signaling. Delineation of the signaling mechanisms utilized by CXCR4 may assist in determining the role of CXCR4 in HIV infection and in the immune response.


description_brief: Cyclins and Cell Cycle Regulation
systematic_name: M17770
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_cellcyclePathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The cell cycle is regulated by the interplay of many molecules. Key among these are the cyclins which are expressed and then degraded in a concerted fashion to drive the stages of the cell cycle. Cyclins combine with cyclin dependent kinases (cdks) to form activated kinases that phosphorylate targets leading to cell cycle regulation. A breakdown in the regulation of this cycle can lead to out of control growth and contribute to tumor formation. Defects in many of the molecules that regulate the cell cycle have been implicated in cancer. Key among these are p53, the cdk inhibitors (p15, p16, p18, p19, p21, p27), and Rb, all of which act to keep the cell cycle from progressing until all repairs to damaged DNA have been completed.


systematic_name: M12399
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_cftrPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_brief:
  Cystic fibrosis transmembrane conductance regulator (CFTR) and beta 2 adrenergic receptor (b2AR) pathway

description_full:
  The defects in cAMP-regulated chloride channel CTFR are believed to be the major cause for cystic fibrosis. Regulation of CFTR protein by the surface receptor beta adrenergic receptor is mediated through the ezrin/radixin/moesin binding phosphoprotein 50 (EBP50), which binds both the C-termini CFTR and b2AR through their PDZ binding motifs. In the resting state, CFTR, b2AR, and EBP50 exist as a macromolecular complex on the apical surface of epithelial cells. Upon agonist activation of the b2AR, the adenulate cyclase is stimulated through the G protein pathway, leading to an increase in cAMP. The elevated concentration of cAMP activates PKA, which is anchored near CFTR via interaction with Ezrin. The phosphorylation of CFTR by PKA disrupts the complex and leads to compartmentalized and specific signaling of the channel.


description_brief: Cytokine Network
systematic_name: M17406
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_cytokinePathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Several different cell types coordinate their efforts as part of the immune system, including B cells, T cells, macrophages, neutrophils, basophils and eosinophils. Each of these cell types has a distinct role in the immune system, and communicates with other immune cells using secreted factors called cytokines, including interleukins, TNF, and the interferons. Macrophages phagocytose foreign bodies and are antigen-presenting cells, using cytokines to stimulate specific antigen dependent responses by B and T cells and non-specific responses by other cell types. T cells secrete a variety of factors to coordinate and stimulate immune responses to specific antigen, such as the role of helper T cells in B cell activation in response to antigen. The proliferation and activation of eosinophils, neutrophils and basophils respond to cytokines as well. Cytokine communication is often local, within a tissue or between cells in close proximity. Each of the cytokines is secreted by one set of cells and provokes a response in another target set of cells, often including the cell that secretes the cytokine. Some cytokines, like IL-1, interferons and TNF, stimulate a broad inflammatory response in response to infection or injury. Other cytokines have more specific functions such the following examples. IL-2 stimulates the proliferation and activation of B and T cells. IL-4 plays a role in the differentiation of Th2 cells, in allergic responses, and in the switching of antibody types. IL-5 stimulates the production and maturation of eosinophils during inflammation. IL-8 is a chemokine, a chemotactic factor that attracts neutrophils, basophils and T cells to sites of inflammation. IL-12 and IL-18 are involved in helper T cell differentiation. IL-10 apparently acts to repress secretion of proinflammatory cytokines. The complex interplay of these different cytokine functions with immune cells is essential for correct immune function.


description_brief: Cytokines and Inflammatory Response
systematic_name: M6910
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_inflamPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Inflammation is a protective response to infection by the immune system that requires communication between different classes of immune cells to coordinate their actions. Acute inflammation is an important part of the immune response, but chronic inappropriate inflammation can lead to destruction of tissues in autoimmune disorders and perhaps neurodegenerative or cardiovascular disease. Secreted cytokine proteins provide signals between immune cells to coordinate the inflammatory response. Some cytokines such as IL-1, IL-6 and TNF act to broadly provoke the inflammatory response while others act on specific types of immune cells. Macrophages and other phagocytotic cells provide a front-line defense against bacterial infection. Macrophages stimulate the inflammatory responses of neutrophils, fibroblasts, and endothelial cells in response infection by secreting IL-1 and TNF. IL-1 and TNF cause fever through alteration of the body temperature set-point in the hypothalamus. Fibroblasts and endothelial cells respond to IL-1 and TNF by recruiting more immune cells to the site of inflammation. Secreted IL-8 is a chemokine that attracts neutrophils to sites of infection. Macrophages also present antigen to T helper cells that play a central role in coordinating immune responses. T helper cells induce clonal expansion of T cells that respond to antigen, with IL-2 as a key mediator of T cell proliferation and activation. TGF-beta is a negative regulator of proliferation in many cells, have anti-inflammatory actions in some settings. The cytotoxic activity of Natural Killer cells (NK cells) and lymphokine activated killer cells (LAK cells) toward viral infected or tumor cells is stimulated by IL-2 and other cytokines. T helpers secrete IL-3 and IL-5 to stimulate eosinophil proliferation and activation. Eosinophils are involved in the immune response to parasitic infection. T helper cells are required to stimulate B cell responses as well, with the cytokines IL-10, IL-4 and other cytokines regulating the clonal selection and differentiation of antigen-specific B cells to form antibody-secreting plasma B cells and memory cells. In addition to inducing activation and proliferation of specific differentiated immune cells, cytokines act on hematopoeitic stem cells, causing their proliferation and differentiation into the full range of immune cells.


description_brief: D4-GDI Signaling Pathway
systematic_name: M15513
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_d4gdiPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  D4-GDI (GDP dissociation inhibitor) is a negative regulator of the ras related Rho Family of GTPases. Since the rho GTPases promote cytoskeletal and membrane changes associated with apoptotic cell death, the removal of the D4-GDI block through its cleavage is important for inducing apoptosis. Caspase-3 cleaves the 28 kDa mature form of D4-GDI to give a 5 kDa and 23 kDa Size fragment. The 23 kDa fragment then translocates to the nucleus. The mechanisms involving cleavage of D4-GDI with apoptosis are not presently known. Activation of the Jun N-Terminal kinase, a regulator of apoptosis, may be one of the mechanisms.


description_brief: Dendritic cells in regulating TH1 and TH2 Development
systematic_name: M9177
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_dcPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  While T cells and B cells carry out the actions of antigen-specific immune responses, antigen-presenting cells called dendritic cells are required for this to happen. The name of dendritic cells is based on their shape, with activated dendritic cells displaying long processes on their surface. When immature dendritic cells found throughout the body internalize and present antigen, they express markers that stimulate the activation of lymphocytes, and migrate to lymphocyte rich tissues like the spleen and lymph nodes to initiate immune responses. In addition to stimulating responses against antigens, dendritic cells also produce tolerance to self antigens. Dendritic cells can be derived from either myeloid or lymphoid lineages. Monocyte derived lineages (pDC1) stimulate Th1 cell differentiation while plasmacytoid (lymphoid) dendritic cells (pDC2) induce Th2 cell differentiation. Factors that stimulate the maturation of monocytes derived dendritic cells include GM-CSF, and IL-4. IL-3 stimulates the differentiation of pDC2 cells into DC2 cells. A variety of factors are involved in antigen-recognition and processing by immature dendritic cells and in the maturation of these cells. The transition to mature dendritic cells down-regulates the factors involved in antigen internalization, and increases the expression of MHC, costimulatory molecules involved in lymphocyte activation, adhesion molecules, and specific cytokines and chemokines. Toll-like receptors on the surface of immature dendritic cells recognize microbial components to induce dendritic cell maturation. In addition to stimulating B cell responses, dendritic cells are potent activators of T cells. IL-12 secretion by dendritic cells stimulates T cell responses, particularly differentiation of Th1 cells that produce interferon-gamma and other pro-inflammatory cytokines. While IL-4 generally stimulates Th2 differentiation, the stimulation of Th2 cell formation by DC2 cells does not appear to involve IL-4. The stimulation of Th1 and Th2 cell formation by dendritic cells appears to be balanced by counter-regulation of each pathway by the other. Interferon-gamma produced by Th1 cells blocks the further stimulation of Th1 differentiation by DC1 cells. The IL-4 produced by Th2 cells kills dendritic cell precursors that contribute to Th2 cell creation. Direct interactions between T cells and dendritic cells are enhanced through the expression of adhesion molecules and costimulatory receptors CD80 and CD86 expressed by mature dendritic cells activate T cells in concert with the recognition of antigen/MHC by the T cell receptor. The central role of dendritic cells as modulators of immune responses makes them an important focus of studies about autoimmune disease, transplant rejection, allergies, responses to infections, and other alterations of the immune response.


description_brief: Deregulation of CDK5 in Alzheimers Disease
systematic_name: M12718
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_p35AlzheimersPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Cyclin-dependent kinase 5 (cdk5), a multi-functional kinase, and its neuron-specific activator p35 are required for neurite outgrowth and cortical lamination. Proteolytic cleavage of p35 produces p25, which accumulates in the brains of patients with Alzheimer's disease. Conversion of p35 to p25 causes prolonged activation and mislocalization of cdk5 and the hyperphosphorylates tau, leading to the formation of paired helical filaments and promotes apoptosis. In cultured primary cortical neurons, excitotoxins, hypoxic stress and calcium influx induce the production of p25. In fresh brain lysates, addition of calcium can stimulate cleavage of p35 to p25. Specific inhibitors of calpain1, effectively inhibit the calcium-induced cleavage of p35. In vitro, calpain1 directly cleaves p35 to release a fragment with relative molecular mass 25,000. Application of the amyloid beta-peptide A beta induces the conversion of p35 to p25 in primary cortical neurons. Inhibition of cdk5 or calpain activity reduces cell death in A beta-treated cortical neurons. These observations indicate that cleavage of p35 to p25 by calpain may be involved in the pathogenesis of Alzheimer's disease. GSK3B also phosphoryklates tau but does not induce hyperphosphorylation in response to calpain activating stimuli. Additionally down-regulation or inhibition of PP2A increases the hyper-phosphorylation of tau.


description_brief: Double Stranded RNA Induced Gene Expression
systematic_name: M10570
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_rnaPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  One defense against viral infection is provided by PKR, double-stranded RNA activated protein kinase. When PKR interacts with dsRNA found in cells during viral infection, PKR phosphorylates itself and cellular proteins including the translation factor elF2a and the transcription factor NF-kB. The repression of translation caused by phosphorylation of elF2a prevents cells from producing viral proteins and creating infectious viral particles. PKR phosphorylation of I-kB kinase activates NF-kB to induce transcription of inflammatory factors and stimulate an immune response that impedes viral infection. The PKR kinase is induced by interferon and some of the anti-viral activity of interferon may be mediated by PKR. Some viruses have evolved mechanisms to inactivate PKR to promote successful infection. Another substrate of PKR, the tumor suppressor p53, may be involved in potential PKR regulation of the cell cycle and apoptosis.


description_brief: E2F1 Destruction Pathway
systematic_name: M6031
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_skp2e2fPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  E2F-1 is a transcription factor that regulates the expression of genes involved in the cell cycle and that is involved in progression of the cell cycle from G1 into S phase. Over-expression of E2F-1 can induce cellular transformation and its under-expression can repress apoptosis. Association with the tumor suppressor Rb represses E2F-1 activity, and this repression is relieved when the cdk2/cyclin E complex at the G1 to S phase transition phosphorylates Rb. Like many cell cycle regulators, E2F-1 is regulated through phosphorylation by a cyclin-dependent protein kinase, cdk2/cyclin A, and by proteolytic degradation. Phosphorylation of E2F-1 by cdk2/cyclin A leads to E2F-1 inactivation, blocking DNA binding. E2F-1 is also regulated through degradation in the proteosome at the S/G2 transition. The F box complex that degrades E2F-1 contains components shared with the complexes that target other cell cycle factors for degradation. The F box protein that specifically recruits E2F for ubiquitination and degradation is Skp2. Other components of the SCF complex include Skp1, Cul1, and cdc34. Skp2 expression is cyclical, increasing in the S/G2 transition as E2F-1 is degraded. Knowledge of E2F-1 activity and its regulation form part of the complex set of interactions regulating the cell cycle and potential targets for the treatment of cancer.


description_brief: Effects of calcineurin in Keratinocyte Differentiation
systematic_name: M3430
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_calcineurinPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The differentiation of keratinocytes constantly replenishes the upper layers of human skin we lose each day. One factor that contributes to terminal keratinocyte differentiation is increased levels of intracellular calcium. Adding calcium to the medium of cultured keratinocytes elevates intracellular calcium and triggers differentiation. Intracellular calcium levels are also increased in response to phospholipase C activation, producing IP3 and releasing calcium from stores in the ER. Intracellular calcium alters multiple signaling pathways, one of which is binding to calmodulin to activate the serine-threonine protein phosphatase calcineurin. Calcineurin dephosphorylates and activates the transcription factor NFAT and both calcineurin and NFAT are expressed in differentiating keratinocytes. Activated NFAT can regulate transcription through binding its own cognate DNA binding site. One marker of keratinocyte differentiation, the p21 gene, is activated by NFAT by a different mechanism, with NFAT activating the p21 promoter by acting as a coactivator for the transcription factors Sp1 and Sp3. Another protein activated by calcium that may be involved in keratinocyte differentiation is protein kinase C (PKC). One substrate of activated PKC is MARCKS (myristoylated alanine-rich kinase C substrate). Phosphorylation of MARCKS by PKC in intact keratinocytes is not induced during calcium-induced differentiation, but does increase when tested in vitro. PKC activity is increased by calcium during keratinocyte differentiation but PKC MARCKS phosphorylation is blocked by the formation of a complex between calmodulin and MARCKS. The immunosuppressants cyclosporin-A (CsA) and FK506 inhibit T cell activation through indirect inhibition of NFAT activation and have several side effects including changes in the skin, suggesting that calcineurin activity may play a role in normal skin physiology. CsA is used to treat psoriasis, a disease involving abnormal proliferation of skin cells. The activity of CsA in treating psoriasis may involve inhibition of immune cells, but may also directly involve inhibition of calcineurin activity in keratinocytes.


description_brief: EGF Signaling Pathway
systematic_name: M1909
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_egfPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The epidermal growth factor (EGF) peptide induces cellular proliferation through the EGF receptor, which has a tyrosine kinase cytoplasmic domain, a single transmembrane domain and an extracellular domain involved in EGF binding and receptor dimerization. Inhibitors of the EGF receptor are being pursued as potential cancer therapies and EGF may stimulate wound healing. Mutation of the EGF receptor has been associated with cancer in humans. The proliferative effects of EGF are signaled through several pathways. Binding of EGF results in EGF receptor dimerization, autophosphorylation of the receptor, and tyrosine phosphorylation of other proteins. The EGF receptor activates ras and the MAP kinase pathway, ultimately causing phosphorylation of transcription factors such as c-Fos to create AP-1 and ELK-1 that contribute to proliferation. Activation of STAT-1 and STAT-3 transcription factors by JAK kinases in response to EGF contributes to proliferative signaling. Phosphatidylinositol signaling and calcium release induced by EGF activate protein kinase C, another component of EGF signaling. Crosstalk of EGF signaling with other pathways make the EGF receptor a junction point between signaling systems.


description_brief: Electron Transport Reaction in Mitochondria
systematic_name: M15371
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_etcPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The body gets energy through the oxidation of food such as glucose and fatty acids. The chemical energy contained in these foods is extracted and converted until it reaches a common form, the high-energy phosphate bonds of ATP. The hydrolysis of ATP is highly favorable and is coupled to a variety of energetically unfavorable processes to drive them forward. How is the energy of glucose captured and converted to make ATP? Most of the energy of glucose or fatty acids is extracted through oxidation to produce the reduced high-energy electron carriers NADH and FADH2. From there, the energy is transferred next to the electron transport system associated with the mitochondrial inner membrane. This chain includes a series of protein complexes and non-membrane cofactors that transfer the electrons from NADH and FADH2 in a series of redox reactions from carrier to carrier. Oxygen is the final electron acceptor at the end of the chain, resulting in the production of water. The oxygen we breath, and which is transported by hemoglobin in the blood to all of the tissues, serves this purpose and allows electron transport to occur. As the electrons pass through the chain, they transfer their energy to the complexes, which use the energy to pump protons out of the mitochondrial matrix, creating a proton gradient across the inner mitochondrial membrane. The chemical energy that started with glucose, and was transferred to NADH and FADH2, is then converted to the energy of a concentration gradient. The inner mitochondrial membrane is impermeable to protons on its own, so the energy of the proton gradient is stable, waiting to be recaptured. The energy is recaptured by ATP synthase in the inner mitochondrial membrane. This enzyme allows protons to flow back down their concentration gradient across the membrane, and in the process uses the energy of the gradient to drive ATP synthesis. The movement of the electrons through electron transport, the proton gradient and ATP synthesis are all coupled processes that require each other to occur. The cell does not store energy as ATP, but only has enough ATP on hand for its immediate energy needs. If electron transport ceases or is inhibited, then ATP synthesis also rapidly halts. This regulation ensures that ATP production closely matches the needs of the cell. Glycolysis and the Krebs cycle are also closely linked to the energy needs of the cell. The abundance of ATP, NADH and pathway intermediates regulates key steps in these pathways so that are activated when energy is required to feed the electron transport system and they are inhibited when not needed to save metabolic energy. If oxygen is absent, electron transport and the Kreb's cycle rapidly halt, leaving glycolysis and fermentation as the main means of energy production. During aerobic exercise, the rapid consumption of ATP leads to use of the proton gradient to make more ATP, increased electron transport to regenerate the proton gradient, increased oxygen consumption, and increased activity of the Kreb's cycle and glycolysis to supply high energy electrons to drive electron transport. Uncoupling agents allow protons to flow across the mitochondrial membrane without producing ATP. The chemical compound dinitrophenol (DNP), for example, can transport protons to flow across the inner mitochondrial membrane without ATP synthase. In the presence of dinitrophenol, energy is consumed to pump protons out of mitochondria, but this energy is not recaptured in chemical form in ATP. Instead, this energy is released as heat. Dinitrophenol was once used as diet remedy to lose weight without exercise or diet, but this compound is a metabolic poison and resulted in deaths in when purposefully given to humans. Proteins also can act as uncoupling agents in the mitochondria. A mitochondrial uncoupling protein is found in brown adipose tissue. An increase in the activity of uncoupling proteins increases heat production by allowing protons to flow down their gradient without making ATP and may serve as protection against cold, as well as a potential means of obesity control.


description_brief: Endocytotic role of NDK, Phosphins and Dynamin
systematic_name: M5940
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_ndkDynaminPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Reliable neurotransmitter release requires the presence of sufficent numbers of synaptic vesicles. The process of synaptic vesicle endocytosis (SVE) is coordinated by a group of proteins called dephosphins. The current set of seven known dephosphins are nerve treminal proteins with little or no structural hoimology but satisfy two essential criteria: they are essential for SVE and they are rapidly and coordinately dephosphorlyated in response to a calcium influx through voltage-dependent calicium channels. The calicium signal is mediated by calmodulin (CaM) and calcineurin. Each dephosphin plays an essential role in overlapping phases or segments of the cycle. The four phases of SVE are nucleation, invagination, fission and uncoating. In this diagram the internalization of the vesicle is the uncoating step. In order to illustrate the complexity of this process the initial display of the protein is labelled with a name and a number. This number is then used at the decloaking or uncoating step to show the release and seperation of the various factors. Each step in the process has a different set of complex components. The components are shown in highlighted boxes above. The nucleation phase initiates with the activation of CaM/Calcineurin and the subsequent dephosphorylation of AP180. AP180 and clathrin are then recruited to the membrane by AP2 and PtdIns(4,5)P2 (comma shaped molecule in the diagram). Nucleation is completed by the addition of epsin and eps15. Invagination proceeds with the formation of the amphiphysin1/2 heterodimer and its addition to the maturing vesicle surface complexes. The final components, dynamin and synaptojanin, are recruited to the budding vesicle by the amphiphysin1/2 heterodimer. Dynamin forms a complete ring around the vesicle neck and completes fission via its PtdIns(4,5)P2 stimulated GTPase activity. After internalization the vesicle is quickly uncoated, in a process believed to be mediated by synaptojanin, and is accompnied by the disassembly of clathrin.


description_brief: Eph Kinases and ephrins support platelet aggregation
systematic_name: M16334
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_ephA4Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Eph kinases are a family of receptor tyrosine kinases with an extracellular domain that binds their ligand, the ephrins, and an intracellular kinase domain. The ephrins are also expressed on the cell surface, so that interaction between Eph kinases and ephrins occurs at the interface between neighboring cells. Binding of ephrins to Eph kinases stimulates signaling in both directions across the interface between cells, in both the receptor expressing and the ligand expressing cells. Eph kinases and ephrins are involved in several biological processes, and their role in neuronal development has been extensively examined. Both Eph kinases (EphA4 and EphB1) and ephrins (ephrinB1) are expressed on platelets, suggesting activation of eph kinases by ephrins may play a role in clotting when platelets are brought into close proximity in the developing clot. Platelet activation progresses in stages with an early stage that is stimulated by soluble factors like ADP acting through GPCRs and is reversible and later stages with stronger interaction between platelets that may require interact between Eph kinases and ephrins. One of the molecular targets of signaling by Eph kinases and ephrins is the actin cytoskeleton, which also plays a role in platelet activation. Clustering Eph kinases or ephrins in platelets stimulated cytoskeletal changes as well as other markers of platelet activation during clotting such as secretion of alpha-granules to release clotting factors. Clustering ephrins together activated Rap1b, a ras gene family member that may regulate integrins. Platelet activation caused Eph kinases to bind to src family members Fyn and Lyn and also with the cell adhesion molecule L1. Failure of the ephrins/Eph kinase pathway to function normally in platelets may result in loosely associated platelets and improper clot formation. Eph kinases and ephrins are also expressed on the vascular wall by endothelial cells, suggesting that signaling by these proteins may also play a role in the interaction of platelets with the vascular wall and clot formation in the vasculature.


description_brief: EPO Signaling Pathway
systematic_name: M12836
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_epoPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Erythropoietin functions to increase the number of red blood cells. Thus, it has found utility as a drug for those needing to replenish erythrocytes for a number of reasons. The signaling mechanism includes multimerization of the receptor upon ligand binding, activation of MAPK cascade, and phosphorylation and activation of Stat5.


description_brief: Erk and PI-3 Kinase Are Necessary for Collagen Binding in Corneal Epithelia
systematic_name: M6355
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_ecmPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Activation of the MAPK kinase pathway has been identified as a mechanism that integrins use to regulate gene expression leading to cell shape changes during cell spreading or migration Epithelial cells respond to extracellular matrix (ECM) cause integrin-mediated FAK phosphorylation that in turn phosphorylates the surrounding proteins (paxillin, Fyn/shc, and src) and leads to signal amplification. FAK also binds PI-3 kinase and is upstream of the MAP kinase pathway. When MAPkinase or PI-3 kinase was inhibited, actin reorganization was blocked. Src phosphorylates p190RhoGAP, inactivating its GAP function that may allow RhoGTP to stay active longer, promoting further signal amplification. Activated RhoGTP binds to downstream kinases such as Rho-associated coiled coil-containing protein kinase (p160ROCK) and p140 diaphanous (p140Dia) to increase actin polymerization and contraction. Actin reorganization assists integrin clustering, allowing more ECM binding that increase FAK phosphorylation and other signal transduction events.


description_brief: Erk1/Erk2 Mapk Signaling pathway
systematic_name: M287
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_erkPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The p44/42 MAP Kinase pathway consists of a protein kinase cascade linking growth and differentiation signals with transcription in the nucleus. Growth factor receptors and tyrosine kinases activate Ras which in turn activates c-Raf, MEK, and MAP kinase. Activated p44/42 MAP Kinase translocates to the nucleus and activates transcription by phosphorylation of kinases such as p90 RSK, MSK, and transcription factors such as ELK-1 and Stat3. The importance of this pathway in both growth control and development has been demonstrated via the transforming properties of various mutant forms of Ras, Raf, MEK and by their effects on development. Signal amplification and the potential for crosstalk appear to be important features of this regulatory network.


description_brief: Erythrocyte Differentiation Pathway
systematic_name: M9367
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_erythPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Stem cells in the bone marrow produce a variety of hematopoietic cell types from common progenitor cells under the influence of cytokines and growth factors. CFU-GEMM cells are a key intermediate in the differentiation of granulocytes, erythrocytes, monocytes and megakaryocytes. Erythropoietin (EPO) is a cytokine produced in the kidneys that, along with other cytokines, induces red blood cell (erythrocyte) differentiation in the bone marrow from CFU-GEMM cells. As the erythrocyte lineage progresses, cells lose their nuclei, and move out of the bone marrow into circulation. The ability of EPO to selectively induce red blood cell differentiation has allowed extensive therapeutic use of the recombinant form of this cytokine to treat anemias.


description_brief: Erythropoietin mediated neuroprotection through NF-kB
systematic_name: M6917
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_eponfkbPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Erythropoietin (Epo) is most commonly known as the cytokine secreted by the kidneys that stimulates red blood cell production and is used as a drug for the treatment of anemias. Epo is also secreted in the brain in response to hypoxia, such as ischemic stroke. Epo production in the brain is stimulated by the hypoxia-inducible transcription factor HIF-1. Administration of Epo to the brain in rodents before hypoxic stress or other neuronal stresses is neuroprotective, preventing neuronal apoptosis. The erythropoietin receptor (EpoR) is known to associate with JAK kinases that phosphorylate and activate the STAT family of transcription factors. The neuroprotection by Epo involves cross-talk between Epo receptor and anti-apoptotic pathways through activation of NF-kB by the JAK2 kinase. Epo stimulates JAK2 phosphorylation of I-kB, releasing NF-kB to translocate into the nucleus and activate transcription of neuroprotective genes. Neuroprotective genes activated by NF-kB include the anti-oxidant enzyme manganese superoxide dismutase and calbindin-D(28k). The erythropoietin receptor is also essential for proper brain development in mice. The absence of EpoR causes high levels of neuronal apoptosis in the developing mouse brain, further confirming the important role of Epo as a neuroprotective agent.


description_brief: Eukaryotic protein translation
systematic_name: M7721
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_eifPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The scanning translation initiation model suggests that 40S ribosomal subunit preloaded with factors bind to the 5 end of the mRNA near the cap. The 48S subunit moves along the mRNA until it finds the initiation triplet and in complex with tRNA and 60S subunit formed the first peptide bond. Translation control is mostly regulated at the protein initiation step through translation initiation factors such as eIF2 or eIF4.


description_brief: Extrinsic Prothrombin Activation Pathway
systematic_name: M4470
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_extrinsicPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Blood coagulation or clotting takes place in 3 essential phases. The first phase is the activation of a prothrombin activator complex. The second phase is the activation of prothrombin. The third stage is clot formation as a result of fibrinogen cleavage by activated thrombin. The prothrombin activation complex is formed by two pathways each of which results in a different form of the prothrombin activator. The extrinsic mechanism of prothrombin activator formation begins with trauma to vascular walls or extravascular tissues. The damaged tissue releases tissue thromboplastin also known as tissue factor (TF). The formation of a clot by this mechanism usually takes as little as 15 seconds. This cascade is initiated by the activation of factor X by TF and factor VII. Activated factor X combined with factor V, factor VII and TF constitutes the prothrombin activator. Calcium (Ca++) is required for each of these steps. The prothrombin activator in the extrinsic pathway is very similar to the activator in the intrinsic pathway. Antithrombin III inhibits the activity of thrombin and also the step leading to the activation of factor X. Antithrombin III is a hundred to a thousand times more effective when bound by heparin. Protein C is activated by thrombin and with the Protein S cofactor provides a strong negative feedback in this phase of clot formation. Disease Significance: Most of the clotting factors are formed in the liver. Diseases of the liver or damage to the liver can depress the levels of these factors in the blood resulting in excessive bleeding. Vitamin K deficiency can also result in a similar condition since Vitamin K is essential for the formation of factor VII, IX, X and prothrombin. Vitamin K is synthesized in the intestinal tract by bacteria.


description_brief: FAS signaling pathway ( CD95 )
systematic_name: M9503
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_fasPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Receptors in the TNF receptor family are associated with the induction of apoptosis, as well as inflammatory signaling. The Fas receptor (CD95) mediates apoptotic signaling by Fas-ligand expressed on the surface of other cells. The Fas-FasL interaction plays an important role in the immune system and lack of this system leads to autoimmunity, indicating that Fas-mediated apoptosis removes self-reactive lymphocytes. Fas signaling is also involved in immune surveillance to remove transformed cells and virus infected cells. Binding of FAS to oligimerized FasL on another cell activates apoptotic signaling through a cytoplasmic domain termed the death domain that interacts with signaling adaptors including FAF, FADD and DAX to activate the caspase proteolytic cascade. Caspase-8 and caspase-10 are first activated, to then cleave and activate downstream caspases, and a variety of cellular substrates that lead to cell death. Caspases cleave nuclear lamins, causing the nucleus to break down and lose its normal structure and another caspase substrate is DFF, inducing cleavage and degradation of the genome. Other caspase substrates are involved in cytoskeletal structure, cell cycle regulation and signaling pathways. Activation of JNK kinase, activation of Jun, and production of ceramide may also play roles in Fas-mediated apoptosis. Activation of fas-mediated apoptosis is opposed by I-FLICE and FAP. Viruses and tumors may escape immune surveillance in part through suppression of fas-mediated apoptosis using similar mechanisms.


description_brief: Fc Epsilon Receptor I Signaling in Mast Cells
systematic_name: M1908
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_fcer1Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The Fc Epsilon Receptor 1 signaling pathway in mast cells uses multiple core signal path to achieve its necessary ends. Through the BTK protein and PKC Mast cells are able to degranulate, through the PKC and MAPK paths the cells are able to alter cytokine expression and arachidonic acid release.


description_brief: Fibrinolysis Pathway
systematic_name: M2842
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_fibrinolysisPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Clot formation and fibrinolysis is a balance of plasmin activation/inhibition and thrombin-thrombomodulin activity that regulates fibrin polymer formation and degradation. Active thrombin is produced by the cleavage of prothrombin in the intrinsic thrombin activation pathway or the extrinsic thrombin activation pathway. Cleavage of fibrinogen by thrombin releases the fibrin monomers that auto-polymerize within seconds into fibrin threads or fibers. The coagulation cascade has many feedback loops. One example is the binding of thrombin to the fibrin polymers resulting in a reduction in soluble thrombin. The fibers form a more stable clot as a result of the covalent bonds formed by activated factor XIII enzyme (also known as Fibrin stabilizing factor). These fibers form a mesh the traps platelets, blood cells and plasma to form a clot. The removal of the clot is caused by plasmin cleavage of the fibrin monomers into soluble fibrin degradation products. Plasmin is formed by the cleavage of plasminogen between Arg561 and Val562. Plasmin is a two-chain trypsin-like serine protease. Plasminogen activator inhibitor 1 (PAI1) and plasminogen activator inhibitor 2 (PAI2) inhibit cleavage of plasminogen by tissue-type plasminogen activator (tPA) or urokinase plasminogen activator (uPA). The presence of fibrin fibers and fibrin degradation products exert a two-fold stimulation of tPA and uPA. Plasmin activity is also inhibited by alpha2-antiplasmin. Thrombin activatable fibrinolysis inhibitor (TAFI) is a carboxy-peptidase B-like proenzyme activated by the thrombin-thrombomodulin dimer. TAFI cleaves (DD)E2 to separate DD and E fragments which do not enhance the activation of tPA or uPA and results in a reduced feedback signal. Disease Significance: Overabundance or increased activity of the plamsminogen activator inhibitors or reduced presence or function of tPA or uPA can result in atherosclerotic disease and venous thrombosis due to an increase in fibrin deposition or formation of a thrombus. Thrombosis can also result from plasminogen deficiency caused by a lack of protein or lack of functional protein. Reduced or depleted levels of alpha2-antiplamin can result in severe bleeding disorders.


description_brief: fMLP induced chemokine gene expression in HMC-1 cells
systematic_name: M10287
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_fmlpPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Neutrophils respond to bacterial infection by releasing reactive oxygen species that kill bacteria and by expressing chemokines that attract other immune cells to the site of infection. The multisubunit enzyme NADPH oxidase expressed by neutrophils produces reactive oxygen species rapidly released in what is known as the respiratory burst. Activity of the NADPH oxidase is induced by fMLP receptor ligands, formylated peptides from bacteria. The fMLP receptor is a G-protein coupled receptor, FPR-1, that activates Map kinase pathways and phospholipase C. Phospholipase C activation releases IP3 and calcium, activating protein kinase C and also activating the transcription factor NFAT, which contributes to activation of chemokine genes. One of the components of the NADPH oxidase is p47phox. PKC activation phosphorylates p47phox to activate NADPH oxidase activity. Activation of Map kinase cascades leads to Erk1/Erk2 dependent p47phox phosphorylation as well as activation of the Elk-1 transcription factor and chemokine gene expression. Inhibition of p38 did not affect p47phox phosphorylation, indicating that p38 is not involved in Erk1/2 activation of the NADPH oxidase. Inhibition of p38 did inhibit NADPH oxidase though, indicating that other pathways contribute to activation of this enzyme. The pathways involved in neutrophils activation are important to understand innate immune responses to bacterial infection.


description_brief: Free Radical Induced Apoptosis
systematic_name: M96
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_freePathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Oxidative stress is one factor that can trigger programmed cell death. Activated neutrophils responding to inflammatory stimulation produce reactive oxygen species like superoxide free radicals to kill invading bacteria, but these reactive oxygen species can also attack endothelial cells lining the vascular wall and trigger apoptosis. Endothelial cells also produce reactive oxygen species inside the cell that can contribute to oxidative stress and apoptosis, such as during reperfusion injury following ischemia. Superoxide dismutase (SOD) converts highly reactive and damaging superoxide free radicals to peroxides that are less reactive than superoxide but stimulate apoptosis. The glutathione (GSH) peptide reducing agent removes toxic metabolites and repairs damage created by reactive oxygen species. Glutathione peroxidase (GPx), for example, removes peroxides using glutathione as a reducing agent, and glutathione reductase (GSR) regenerates reduced glutathione. Inside the endothelial cell peroxide can be converted to hydroxyl ions in the presence of iron. Peroxides and hydroxyl radicals activate NF-kB and activate expression of inflammatory genes including adhesion molecules, TNF and IL-8. The apoptotic response of endothelial cells to oxidative stress may be involved in the development and progression of atherosclerosis.


description_brief: GATA3 participate in activating the Th2 cytokine genes expression
systematic_name: M1394
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_gata3Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  CD4+ helper T cells differentiate into distinct subtypes, Th1 and Th2 cells. Th2 cells are involved in the response to extracellular helminthe parasites and allergic responses and secrete a distinct set of cytokines including IL-4, IL-5 and IL-13. The development and differentiation of T cells is influenced by many factors, including transcription factors such as GATA-3, a transcription factor associated with induction of Th2 cells. Factors that increase cAMP levels in Th2 cells activate p38 kinase, which phosphorylates and activates GATA-3 independently of PKA. Cells expressing GATA-3 develop the profile of Th2 cells, secreting IL-4, IL-5 and IL-13. These cytokines are found in a gene cluster together and are regulated coordinately by GATA-3. Binding of GATA-3 in the regulatory regions of these genes alters chromatin structure, increasing accessibility to other transcription factors. Activation of the T cell receptor through interaction with antigen on antigen presenting cells activates NFAT and other transcription factors that cooperate with GATA-3 in inducing Th2 cell differentiation. Dominant negative GATA-3 can repress the secretion of these cytokines and block the airway inflammation that causes asthma. Blocking GATA-3 action such as through antisense treatment has been suggested as a therapeutic strategy to treat asthma. GATA-3 has also been implicated in developmental processes such as the development of the inner ear.


description_brief: Granzyme A mediated Apoptosis Pathway
systematic_name: M3075
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_setPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  One mechanism used by cytotoxic T cells to kill tumor cells and virus-infected cells is the release of perforin and granzyme proteins. Perforin proteins form pores in the membranes of the attacked cell, allowing the entry of Granzyme A and Granzyme B. Granzyme B induces caspase activation and cleavage of factors like ICAD, releasing DFF40 to fragment DNA, one of the hallmarks of apoptotic cell death. Granzyme A is also an abundant granzyme released by cytotoxic T cells and is important in cytotoxic T cell induced apoptosis, activating caspase independent pathways. Once in a cell, Granzyme A activates DNA nicking by the recently identified DNAse NM23-H1, a tumor suppressor gene product whose expression is reduced in transformed, metastatic cells. The previous identification of NM23-H1 as a tumor suppressor indicates that its DNAse activity plays an important role in immune surveillance to prevent cancer through the induction of tumor cell apoptosis. The activation of NM23-H1 occurs indirectly, through the cleavage of proteins that inhibit NM23-H1 in the SET complex, which includes SET, Ape1, pp32 and HMG2. SET is a substrate for the Granzyme A protease, and SET cleavage relieves NM23-H1 inhibition to cause apoptotic DNA degradation. In addition to inhibiting NM23-H1, SET has nucleosome assembly activity and also may help the interaction of transcriptional regulation with chromatin structure by interacting with the transcriptional coactivator CBP. The targets of Granzyme A found in the SET complex also have other important functions. Ape1 repairs oxidative DNA damage, reduces transcription factors involved in immediate early responses, and its cleavage by Granzyme A may contribute to DNA degradation and apoptosis. HMG2 is an acidic chromatin-associated protein that bends DNA, alters chromatin structure and alters the accessibility of genes for transcription. In addition to acting as a nucleosome assembly factor and an inhibitor of NM23-H1, SET inhibits DNA and histone methylation by the CBP transcriptional coactivator. The tumor suppressor pp32 is not cleaved by Granzyme A but is part of the SET complex. Other targets of Granzyme A include nuclear lamins responsible for maintaining nuclear structure and histones, the basic building blocks of chromatin structure. The common involvement of the proteins of the SET complex in chromatin structure and DNA repair suggest that they work together to protect chromatin and DNA structure and that inactivation of the complex contributes to apoptosis by blocking the maintenance of DNA and chromatin structural integrity.


description_brief: Growth Hormone Signaling Pathway
systematic_name: M9043
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_ghPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Growth hormone plays a major role in regulating growth during childhood and adolescence and also regulates metabolism. Defects in growth hormone signaling can result in dwarfism and decreases in growth hormone levels with age have been suggested to play a role in the reduced function of some physiological systems. Growth hormone signals a response in cells through the growth hormone receptor, a member of the cytokine receptor gene family. Growth hormone causes the receptor to dimerize, activating the JAK2 protein kinase. The activity of JAK2 mediates many of the downstream responses to growth hormone through phosphorylation of STAT transcription factors, MAP kinases, other kinase cascades and molecules involved in metabolism like IRS-1. Factors like SOCS and SHP-1 appear to play a role in the down regulation of signaling by growth hormone and cytokines.


description_brief: Hemoglobin's Chaperone
systematic_name: M19553
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_ahspPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The function of hemoglobin in oxygen transport by red blood cells requires precise assembly of a tetramer of two beta-subunits and two alpha-units. If too many beta-subunits are present, then all tetramers of beta-subunits are formed that bind oxygen but do not release it when needed. When alpha-subunits are in excess they form precipitates with oxidized heme that damage red blood cells. Red blood cells require a precise coregulation of alpha and beta subunit expression to maintain the proper ratio of the subunits and normal red blood cell function. Generally red blood cells express slightly more alpha than beta-subunits to avoid forming unproductive beta-tetramers (HbH). The slight excess of alpha units are blocked from precipitation by a molecular chaperone, AHSP, alpha-hemoglobin stabilizing protein. Expression of the AHSP gene is coordinately activated with the globin genes and heme biosynthesis genes by the GATA-1 gene involved in erythrocyte differentiation. AHSP blocks precipitation of alpha-units, and promotes the formation of normal productive alpha-beta tetramers (HbA). People with mutation or deletion of the beta-subunit gene have Beta-thalassemias resulting from an over-abundance of alpha subunits and their precipitation. The severity of the phenotype may depend on the AHSP genotype of these individuals and elevating AHSP levels through gene therapy may provide a treatment strategy for beta-thalassemia.


description_brief: HIV Induced T Cell Apoptosis
systematic_name: M16519
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_tcapoptosisPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  HIV infection is associated with immunosuppression caused by a dramatic reduction in the helper T cell population. The loss of helper T cells may be caused by HIV-induced apoptosis of both infected and uninfected helper T cells. HIV uses the CCR5 chemokine receptor as a coreceptor for macrophage cell entry and upregulates fas-ligand on these cells. CD4 on helper T cells is essential for viral cell entry and infection. Cross-linking of CD4 on the T cell surface may be involved in upregulation of Fas and sensitization of T cells to apoptosis induced by the Fas/Fas-ligand interaction.


description_brief: HIV-I Nef: negative effector of Fas and TNF
systematic_name: M13968
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_hivnefPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  HIV infection leads to drastic declines in CD4 T helper cells, in part through apoptosis of uninfected cells. Apoptosis of uninfected cells may be induced through the expression of Fas ligand on the surface of HIV-infected cells, stimulating the Fas-dependent apoptotic pathway in cells that come in contact with infected cells. The NEF protein expressed by HIV may play induce the expression of Fas-ligand by infected cells. If this is the case, then a question that arises is how infected cells themselves escape Fas-mediated apoptosis. The NEF protein appears to play a role in this process as well. NEF interacts with the ASK1 kinase (apoptosis signal-regulating kinase) involved in apoptotic signaling by TNF and Fas-ligand. Interaction of NEF with ASK1 prevents phosphorylation of downstream MAP kinases and JNK kinases involved in apoptotic signaling.


description_brief: How does salmonella hijack a cell
systematic_name: M16120
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_salmonellaPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Pathogenic Salmonella enter cells such as those of the intestinal epithelium by altering cellular cytoskeletal structure and inducing membrane ruffling of the infected cell. Salmonella is able to alter the cytoskeleton and membrane through the action of secreted bacterial Sip proteins, SopE, SopB, and SptP that are inserted into the cytosol of the infected cell. Sip proteins encoded by Salmonella are required for the action of SopE and for the invasion of epithelial cells. SipA stabilizes actin filaments, inducing membrane ruffling and perhaps focusing membrane changes where bacteria are localized to allow their entry. SipC produces a similar effect on actin filaments and cytoskeletal structure. SopE acts as an exchange factor on Rac1 and Cdc42, two GTPases in the Rho family that regulate actin cytoskeleton. The activation of Rac2 and Cdc42 by Salmonella SopE induces changes in cytoskeleton structure that allow bacterial entry into the cell. SopB is another salmonella protein that acts as an inositol polyphosphate phosphatase and also stimulates Cdc42 and Rac1. One of the cellular targets of both Cdc42 and Rac1 that affects actin structure is the Arp2/3 complex. Cdc42 and Rac1 activate Wasp, which activates Arp2/3. Activated Arp2/3 induces the formation of actin Y branches, which in combination with changes in actin caused by SipA and SipC help to form lamellipodia, and causes membrane ruffling, leading to entry of Salmonella into the affected cell. After the initial infection, cells quickly return to their normal morphology, a process that depends on the action of the bacterial protein SptP. While SopE acts as an exchange factor, SptP acts as a GTPase activating protein to inactivate Rac1 and Cdc42 once again. This inactivation of the original entry mechanism provides an example of the delicate balance between infectious organisms and their host.


description_brief: How Progesterone Initiates the Oocyte Maturation
systematic_name: M13883
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_mPRPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Progesterone (Pg) binds to both intracellular iPR and plasma membrane- bound mPR. (Right Top) After binding to Pg, iPR is recruited to the membrane associated protein tyrosine kinase p60c- src, which induces activation of the MAPK signaling pathway. This results in activation of p90Rsk and the subsequent phosphorylation and inactivation of Myt1, which favors formation of the activated cell cycle complex cyclin B-Cdc2. Activation of cyclin B-Cdc2 causes breakdown of the germinal vesicle and the initiation of oocyte maturation. (Left). In contrast, binding of Pg to mPR leads to inhibition of adenylyl cyclase (AC) through activation of Gi or inhibition of Gs. This leads to a decrease in the cAMPdependent kinase PKA, which relieves inhibition of Cdc25C (the phosphatase that dephosphorylates and activates cyclin B-Cdc2) and also indirectly promotes the activation of MAPK signaling. PKA also regulates the initiation of oocyte maturation through other effects that are independent of PKA activity.


description_brief: Human Cytomegalovirus and Map Kinase Pathways
systematic_name: M8353
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_hcmvPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  To replicate in the host cell, viruses commandeer cellular signaling pathways. Cytomegalovirus (CMV) is a DNA virus with that is widespread in the population but usually causes disease only in immunocompromised individuals and is also a viral cause of birth defects. One of the actions of CMV in the host cell is to stimulate MAP kinase pathways. Both p38 and ERK kinases are activated by CMV infection through activation map kinase kinases and inhibition of phosphatases. One result of Map kinase activation by CMV is activation of transcription of viral genes, increasing the production of viral gene products. Both p38 and ERK kinases contribute to the activation of viral genes by cellular transcription factors acting through the viral UL4 promoter at upstream and basal transcription elements. Another target of prolonged p38 activation during infection is Rb, contributing to viral replication. Activation of MKK1 and MKK2 leads to Erk1 and Erk2 activation, and phosphorylation of downstream targets. The MEKK1 kinase regulates the immediate early promoter indirectly through downstream kinase signaling and perhaps more directly through activation of NF-kB. Map kinase pathways activated by CMV converge on increased transcription of viral genes and increased replication of the viral genome. Better understanding of the mechanisms involved in the interaction of CMV with cellular signaling machinery will provide improved ways to treat CMV-mediated disease.


description_brief: Hypoxia and p53 in the Cardiovascular system
systematic_name: M5202
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_p53hypoxiaPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Hypoxic stress, like DNA damage, induces p53 protein accumulation and p53-dependent apoptosis in oncogenically transformed cells. Unlike DNA damage, hypoxia does not induce p53-dependent cell cycle arrest, suggesting that p53 activity is differentially regulated by these two stresses. Hypoxia induces p53 protein accumulation, but in contrast to DNA damage, hypoxia fails to induce endogenous downstream p53 effector mRNAs and proteins, such as p21, Bax, CIP1, WAF1 etc. Hypoxia does not inhibit the induction of p53 target genes by ionizing radiation, indicating that p53-dependent transactivation requires a DNA damage-inducible signal that is lacking under hypoxic treatment alone. The phosphatidylinositol 3-OH-kinase-Akt pathway inhibits p53-mediated transcription and apoptosis. Mdm2, a ubiquitin ligase for p53, plays a central role in regulation of the stability of p53 and serves as a good substrate for Akt. Mdm-2 targets the p53 tumor suppressor for ubiquitin-dependent degradation by the proteasome, but, in addition, the p53 transcription factor induces Mdm-2, thus, establishing a feedback loop. Hypoxia or DNA damage by abrogating binding of HIF-1 with VHL and p53 with Mdm-2, respectively, leads to stabilization and accumulation transcriptionally active HIF-1 and p53. At the molecular level, DNA damage induces the interaction of p53 with the transcriptional activator p300 as well as with the transcriptional corepressor mSin3A. In contrast, hypoxia primarily induces an interaction of p53 with mSin3A, but not with p300.


description_brief: Hypoxia-Inducible Factor in the Cardiovascular System
systematic_name: M13324
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_hifPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Hypoxia (or low O2 levels) affects various pathologies. First, tissue ischemia, a variation in O2 tension caused by hypoxia/reoxygenation, can lead to endothelial cell changes. For example, long periods of ischemia result in endothelial changes, such as vascular leakage, resulting in varicose veins. In more severe situations, ischemia can lead to myocardial or cerebral infarction and retinal vessel occlusion. Of interest, HIF-1 is stabilized prior to induction of vascular endothelial growth factor (VEGF) expression during acute ischemia in the human heart. Second, pulmonary hypertension associated with chronic respiratory disorders results from persistent vasoconstriction and vascular remodeling. Third, hypoxic gradients created in enlarging solid tumors trigger expression of genes containing hypoxia response element (HRE)s such as those involved in angiogenesis. This allows subsequent delivery of O2, nutrients, and further tumor growth. Vascular remodeling is an important component to tumorigenesis; without proper blood supply, delivery of oxygen may occur by diffusion, but becomes inefficient in tumors greater than 1 mm in diameter. Short-term hypoxia can also elevate platelet numbers, while prolonged exposure may cause some degree of thrombocytopenia in response to increased levels of erythropoetin (EPO). Another disorder involving inadequate responses to hypoxia is preeclampsia, a pathology of pregnancy thought to be caused by improper differentiation of placental trophoblast cells due to poorly controlled O2 tension or improper hypoxia-inducible factor (HIF)-mediated responses. The primary molecular mechanism of gene activation during hypoxia is through HIF-1. Several genes involved in cellular differentiation are directly or indirectly regulated by hypoxia. These include EPO, LDH-A, ET-1, transferrin, transferrin receptor, VEGF, Flk-1, Flt-1, platelet-derived growth factor- (PDGF-), basic fibroblast growth factor (bFGF), and others genes affecting glycolysis. HIF-1 is a member of the basic helix-loop-helix (bHLH)-PAS family of transcription factors known to induce gene expression by binding to a ~50-bp HRE containing a core 5'-ACGTG-3' sequence. bHLH-PAS proteins heterodimerize to form transcription complexes that regulate O2 homeostasis, circadian rhythms, neurogenesis, and toxin metabolism. Three bHLH-PAS proteins in vertebrates respond to hypoxia: HIF-1 , EPAS (HIF-2 ), and HIF-3. These dimerize with ARNT (aryl hydrocarbon receptor nuclear translocator protein), ARNT-2, or ARNT-3. HIF-1 is ubiquitinated and subsequently degraded in less than 5 minutes under normoxic conditions. Although several candidate O2-sensing molecules have emerged in the literature, the molecular basis of how cells sense O2 levels is poorly characterized. pVHL, the protein product of a tumor-suppressor gene responsible for von Hippel Lindau disease, is implicated in this O2-sensing system by its association with HIF-1 , targeting it for ubiquitin-mediated degradation. Similarly, F-box-containing proteins recognize substrates of the ubiquitin ligases, targeting them for phosphorylation-dependent ubiquitination and proteosomal degradation. In addition to F-boxes, most of these proteins also contain a WD40 or a leucine-rich repeat (LLR) domain that presumably functions as a Ser/Thr binding module. A second family of proteins assisting the ubiquitin ligases share a region designated SOCS-box (originally from the suppressor of cytokine signaling proteins SOCS). Under low O2 (&lt;5% O2) HIF-1 is stabilized leading to the formation of a functional transcription factor complex with ARNT. This complex is the master regulator of O2 homeostasis and induces a network of genes involved in angiogenesis, erythropoiesis, and glucose metabolism.


description_brief: IGF-1 Signaling Pathway
systematic_name: M2623
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_igf1Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Insulin like growth factor 1 (IGF-1) and its receptor (IGF-1R) provide a potent proliferative signaling system that stimulates growth in many different cell types and blocks apoptosis. In vivo IGF-1 acts as an intermediate of many growth hormone responses, and may stimulate the growth of some types of cancer. IGF-1 also provides a mitogenic signal to act as a growth factor for many tissue culture cells. One component of IGF-1 mitogenic signaling is association of the receptor tyrosine kinase with Shc, Grb2, and Sos-1 to activate ras and the Map kinase cascade (raf, Mek, Erk). An endpoint of the Map kinase pathway is modification of transcription factor activity, such as activation of ELK transcription factors. Serum response factor (SRF) and AP-1 contribute to mitogenic signaling by many factors. Phosphorylation of IRS-1 and PI3 kinase activation are also involved in IGF-1 signaling, similar to insulin signaling.


description_brief: IL 17 Signaling Pathway
systematic_name: M19422
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_il17Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Inflammation is a complex response involving many different cells and signaling molecules, including the secretion of the cytokine IL-17 by activated T cells. IL-17 secretion is restricted to specific subsets of T cells but the receptor for IL-17 is widely expressed throughout the body, including fibroblasts and epithelial cells. Inflammatory responses involving IL-17 probably contribute to arthritis, asthma, skin immune reactions and autoimmune disorders. Fibroblasts and other cells stimulated by IL-17 are induced themselves to secrete inflammatory and hematopoietic cytokines, including IL-6, IL-8, G-CSF and Stem Cell Factor (SCF). These cytokines in turn provoke a range of activities, including the stimulation of neutrophil proliferation and differentiation.


description_brief: IL 2 signaling pathway
systematic_name: M7747
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_il2Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Interleukin 2 (IL-2) is a potent cytokine that can lead to cellular activation and proliferation. IL-2 Receptors are found on activated B-Cells, LPS treated Monocytes, and many T cells. The receptor is formed from three chains alpha (CD25), beta (CD122), and gamma (CD132). Primary signaling is through the JAK/Stat pathway and MAPKs.


description_brief: IL 3 signaling pathway
systematic_name: M17681
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_il3Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Interleukin-3 promotes the proliferation and differentiation of hematopoietic cells through binding to its receptor. The receptor for IL-3 is a heterodimer with a ligand-specific alpha chain (70 kD, CD123) and a common beta chain (shared with IL-5 and GM-CSF). Signaling is believed to be primarily through Stat5 and the MAPK pathways.


description_brief: IL 4 signaling pathway
systematic_name: M5415
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_il4Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Interleukin 4 (IL-4) is a cytokine that can lead to development of Th2 cells. The 140 kD IL-4 Receptor (CD124) is found on many cell types, even those of non-hematopoietic origen. The receptor is formed from two chains: IL-4R(alpha) and the IL-2R gamma chain (CD132). Primary signaling is through the JAK/Stat6 pathway and MAPKs.


description_brief: IL 5 Signaling Pathway
systematic_name: M18928
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_il5Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  IL-5 is an inflammatory signaling molecule that primarily stimulates eosinophil proliferation, maturation and activation. Eosinophils are leukocytes involved in inflammatory responses that defend against parasites and cause some aspects of asthma, allergic reactions, and perhaps autoimmune disorders. The action of IL-5 begins with an immune response in tissues, such as activation of macrophages and T cells that secrete IL-1, IL-4 and IL-6. The immune response can lead to IL-5 secretion by T cells, eosinophils and mast cells. Secreted IL-5 stimulates production and maturation of eosinophils in bone marrow that migrate to tissues in response to eotaxin and release factors that damage tissues, causing some of the undesirable consequences of inflammation. The receptor for IL-5 is a heterodimer of an alpha subunit that is required for IL-5 selective binding and a beta subunit that is also part of the IL-3 and GM-CSF receptors. Binding of IL-5 to the IL-5 receptor at the cell surface activates JAK/STAT signaling pathways that regulate transcription, proliferation, and differentiation.


description_brief: IL 6 signaling pathway
systematic_name: M5489
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_il6Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Interleukin-6 (IL-6) is a cytokine that provokes a broad range of cellular and physiological responses. In addition to playing a role in inflammation and hematopoiesis, IL-6 is involved in other processes such as neuronal differentiation and bone loss. To produce these effects IL-6 signals through a receptor composed of two different subunits, an alpha subunit that produces ligand specificity and gp130, a receptor subunit shared in common with other cytokines in the IL-6 family. Binding of IL-6 to its receptor initiates cellular events including activation of JAK kinases and activation of ras-mediated signaling. Activated JAK kinases phosphorylate and activate STAT transcription factors, particularly STAT3, that move into the nucleus to activate transcription of genes containing STAT3 response elements. The ras-mediated pathway, acting through Shc, Grb-2 and Sos-1 upstream and activating Map kinases downstream, activates transcription factors such as ELK-1 and NF-IL-6 (C/EBP-beta) that can act through their own cognate response elements in the genome. These factors and other transcription factors like AP-1 and SRF (serum response factor) that respond to many different signaling pathways come together to regulate a variety of complex promoters and enhancers that respond to IL-6 and other signaling factors.


description_brief: IL-10 Anti-inflammatory Signaling Pathway
systematic_name: M6778
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_il10Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  IL-10 is a cytokine with potent anti-inflammatory properties, repressing the expression of inflammatory cytokines such as TNF-alpha, IL-6 and IL-1 by activated macrophages. The IL-10 receptor is in the JAK/STAT class of receptors but activation of the JAK/STAT pathways by IL-10 does not appear on its own to be responsible for the anti-inflammatory properties of this cytokine. The anti-inflammatory actions of IL-10 appear to require induction of the enzyme heme oxygenase-1 (HO-1) through a map kinase pathway involving the p38 kinases. HO-1 is involved in the biosynthesis of heme, and catalyzes a reaction producing carbon monoxide, free iron, and the heme precursor biliverdin. HO-1 is induced by IL-10 and is also induced by oxidative stress. Blocking HO-1 with inhibitors or antisense blocks the anti-inflammatory actions of IL-10. The anti-inflammatory actions of HO-1 appear to be the result of signaling by carbon monoxide it produces since removal of CO blocks the anti-inflammatory action of IL-10 and HO-1. The anti-inflammatory actions of IL-10 may be therapeutically useful either directly or through modulation of HO-1 activity.


description_brief: IL12 and Stat4 Dependent Signaling Pathway in Th1 Development
systematic_name: M4319
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_il12Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Interleukin-12 (IL-12) promotes cell-mediated immunity by inducing Th1 cell differentiation and activation of both T cells and NK cells. Dendritic cells and macrophages in peripheral tissues act as antigen presenting cells and secrete IL-12 as one component of the antigen response, Th1 differentiation. The role of IL-12 in cellular immunity is largely mediated by the STAT-4 transcription factor. STAT-4 is essential for IL-12 activity and the phenotype of mice lacking STAT-4 is very similar to the phenotype of mice lacking the IL-12 receptor or IL-12. The role of IL-12 in Th1 differentiation may not be to induce the Th1 cell fate, but to stimulate growth of cells determined for the Th1 cell fate by the T-bet transcription factor. Several signaling pathways contribute to IL-12 activation of STAT-4 to regulate cell-mediated immune responses. The JAK kinases such as JAK2 and TYK2 interact with the activated IL-12 receptor and tyrosine phosphorylate the IL-12 receptor and STAT-4. IL-12 also activates a map kinase pathway activating the map kinase kinase MKK6 and p38. Phosphorylation of STAT-4 on serine 721 by p38 contributes to the full transcriptional activation of genes by STAT-4. Some of the events downstream of IL-12 appear to include genes activated indirectly by STAT-4, such as genes activated by the transcription factor ERM. ERM is in the Ets family of transcription factors, is activated by IL-12 and activates IL-12 inducible genes such as Interferon-gamma that are not activated by STAT-4 itself. Interferon-gamma transcription in T cells is also activated by other signals such as from the T cell receptor. Other proteins activated transcriptionally downstream of IL-12 and STAT-4 include the chemokine receptor CCR5 and IL-18 and its receptor. Some viruses, including HIV, repress cell-mediated immunity by blocking IL-12 signaling.


description_brief: IL-2 Receptor Beta Chain in T cell Activation
systematic_name: M8615
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_il2rbPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The IL-2 receptor is a key component of immune signaling and is required for the activation, proliferation, and survival of T cells. This receptor is composed of three polypeptide chains, the alpha, beta and gamma chains. The IL-2 receptor gamma chain is a common component for several other cytokine receptors, including IL-4, IL-7, IL-9 and IL-15. The IL-2 receptor beta chain is essential for IL-2 signaling and is also a component of the IL-15 receptor complex. The polypeptides of the IL-2 receptor do not themselves have intrinsic catalytic activity, but interact with cytoplasmic signaling proteins to transduce signals. br&gt;Different regions of the cytoplasmic domain of the IL-2 receptor beta chain interact and couple with distinct signaling pathways and cellular responses. JAK1 associates with the beta chain, and JAK3 with the gamma chain. Binding of IL-2 induces heterodimerization of receptor subunits, and activation of JAK kinase activity. Tyrosine residues in the beta chain cytoplasmic domain are phosphorylated during activation, recruiting other factors to the phosphorylated tyrosine residues through src homology 2 (SH2) domains. The adaptor protein Shc binds to phosphorylated tyrosine 338 of the beta chain. When bound, Shc is phosphorylated and couples through Grb2 and Sos-1 to activate Ras and stimulate T cell proliferation. Another key proliferative pathway activated by IL-2 is phosphorylation of STAT-5 by JAK kinases. STAT-5 is recruited to IL-2 beta phosphorylated tyrosines at multiple positions, including Y338, Y392 and Y510. Once phosphorylated, STAT-5 enters the nucleus to regulate the transcription of several genes, some proliferative such as cyclin genes and others that are involved in T cell immune function such as cytokine genes. The suppressors of cytokine activation, SOCS-3 and SOCS-1, oppose phosphorylation and activation of STAT-5 and JAK1 caused by IL-2. PI3 kinase is another protein recruited to IL-2 receptor beta chain tyrosines when phosphorylated. Activation of PI3 Kinase also contributes to the proliferative activity of IL-2 in T cells. The role of other tyrosines in the IL-2 receptor beta chain, Y355, Y358 and Y361, is not yet clear, but may be involved in signaling by the protein kinase p56lck. In addition to stimulating T cell activation and proliferation, IL-2 activation blocks T cell apoptosis through multiple pathways. Among the genes activated by STAT-5 are BCL-xL, an inhibitor of apoptosis, and fas-ligand, an activator of apoptosis in cells expressed the fas receptor. PI3 kinase also contributes to anti-apoptotic activity of IL-2 through AKT activation. T cell responses to IL-2 must be coordinated in part in the complex protein-protein interactions with the IL-2 receptor beta chain.


description_brief: IL22 Soluble Receptor Signaling Pathway
systematic_name: M8066
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_il22bpPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  IL-22 is an inflammatory cytokine related to IL-10 that is produced by T cells and that induces a response in cells through a heterodimeric cell surface receptor composed of IL-22R1 and IL-10R2C. One of the actions of IL-22 appears to be the induction of the acute phase inflammatory response in hetapocytes, acting through activation of STATs and transcriptional regulation. A gene with homology to the extracellular domain of the cell surface IL-22R1 receptor component was identified that lacked transmembrane and cytoplasmic domains. The protein derived from this gene was found to bind IL-22 and block its interaction with the cell surface receptor. The IL-22 soluble receptor (IL-22BP, IL-22 binding protein) also blocks some of the downstream effects of IL-22 such as STAT activation and the transcriptional induction of genes involved in the immune and inflammatory responses. The IL-22 soluble receptor may act as an anti-inflammatory agent.


description_brief: IL-7 Signal Transduction
systematic_name: M1296
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_il7Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  IL-7 is a key cytokine in the immune system, essential for normal development of B cells and T cells. Mice with the IL-7 receptor deleted lack B and T cells. Some humans with SCID (severe combined immunodeficiency disease) also have mutation of their IL-7 receptor gene leading to an absence of T cells and greatly impaired B cell production. The IL-7 receptor includes two polypeptides, a gamma chain and an alpha chain. The alpha-chain is unique to the IL-7 receptor while several other cytokines use the same gamma receptor chain as IL-7, including IL-2, IL-4, IL-9, IL-15 and IL-21. Binding of IL-7 to the alpha chain leads to dimerization of the alpha and gamma chains. JAK3 associated with the gamma chain tyrosine phosphorylates the alpha chain after dimerization. The importance of JAK3 in IL-7 signaling is supported by the similarity of the immune defects in JAK3 knockout mice and IL-7 knockout mice. The phosphorylated alpha chain serves as the site for recruiting other signaling molecules to the complex to be phosphorylated and activated, including STAT5, src kinases, PI3 kinase, Pyk2 and Bcl2 proteins. Some targets of IL-7 signaling contribute to cellular survival, including Bcl2 and Pyk2. Other targets contribute to cellular proliferation, including PI3 kinase, src family kinases (lck and fyn) and STAT5. The transcription factor STAT5 contributes to activation of multiple different downstream genes in B and T cells and may contribute to VDJ recombination through alteration of chromatin structure. The cell survival and cell proliferation signals induced by IL-7 combine to induce normal B and T cell development.


description_brief: Inactivation of Gsk3 by AKT causes accumulation of b-catenin in Alveolar Macrophages
systematic_name: M11106
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/H_gsk3Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Lipopolysaccharide. One of the key actions of AKT is to block apoptosis. AKT phosphorylation of NF-kB promotes the survival and activation of macrophages responding to LPS. Another substrate of AKT is the protein kinase Gsk3-beta. AKT phosphorylates and deactivates Gsk3-beta. Non-phosphorylated Gsk3-beta is active and phosphorylates beta-catenin, leading to its degradation in the ubiquitin dependent proteosome pathway. Stimulation by LPS causes the accumulation of beta-catenin in the nucleus and the activation of genes in concert with the transcription factor LEF1. This pathway is probably not restricted to alveolar pathway, but leads to the activation of beta-catenin dependent genes by LPS in other cells as well. Other pathways regulate this pathway also, such as the modulation of PI3 kinase activity by ceramide, and the inhibition of Gsk3-beta activity by the Wnt/frizzled/disheveled (DSH) pathway.


description_brief: Induction of apoptosis through DR3 and DR4/5 Death Receptors
systematic_name: M14971
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_deathPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Apoptosis is specifically induced via signaling through a family of receptors known collectively as 'death receptors' including Fas, TNFR, DR3, -4 and -5. Death receptor ligands characteristically initiate signaling via receptor oligomerization, recruitment of specialized adaptor proteins and activation of caspase cascades. Apo3L recruits initiator caspase 8 via the adapter protein FADD. Caspase 8 then oligomerizes and is activated via autocatalysis. Activated caspase 8 stimulates apoptosis via two parallel cascades: it directly cleaves and activates caspase-3, and it cleaves Bid (a Bcl-2 family protein). Truncated Bid (tBid) translocates to mitochondria, inducing cytochrome C release, which sequentially activates caspases 9 and 3. DR-3L can deliver pro- or anti-apoptotic signals. DR-3 promote apoptosis via the adaptor proteins TRADD/FADD and the activation of caspase 8. Alternatively, apoptosis inhibited via an adaptor protein complex including RIP which activates NF-kB and induces survival genes including IAP. Induction of apoptosis via Apo2L requires caspase activity, but the adaptor requirement is unclear.


description_brief: Influence of Ras and Rho proteins on G1 to S Transition
systematic_name: M14512
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_raccycdPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The cell cycle transition from G1 to S phase is a key regulatory point in the cell cycle. This transition is regulated by the checkpoint kinase cdk2 that activates the G1 to S transition when it is associated with cyclin E. Cdk2/Cyclin E causes the G1 to S transition through phosphorylation of the tumor suppressor Rb, releasing the transcription factor E2F-1. Other pathways acting through Rac, Ras and Rho also regulate the G1 to S transition. Ras regulates cyclin D1 expression to affect the G1 to S transition. Transforming forms of Ras or Raf induce cyclin D1 expression and cause early entry into S phase. Signaling from Ras to Raf to MEK to ERKs induces Cyclin D1 expression, allowing Cyclin D1 to complex with Cdk4 and Cdk6 and phosphorylate Rb. Rac-1 and PAK appear to induce Cyclin D1 expression and induce the G1 to S transition primarily through activation of NF-kB to activate the Cyclin D1 promoter. Rho activates cdk2 and also inhibits p21 and p27 to induce cyclin D1 and stimulate the G1 to S transition. Rho represses p21 expression to block p21 induction by Ras and to allow Ras induced progression from G1 to S. Cells that lack p21 do not require Rho for Ras to induce cell cycle progression from G1 to S phase. The cooperative action of Ras, Rac and Rho to induce Cyclin D1 expression is a key component of oncogenic transformation.


description_brief: Inhibition of Cellular Proliferation by Gleevec
systematic_name: M7897
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_gleevecPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The drug Gleevec (also known as imatinib mesylate or STI-571) was approved by the FDA in 2001 for the treatment of CML, chronic myeloid leukemia. While traditional cytotoxic cancer treatments such as chemotherapy or radiation therapy kill all dividing cells, Gleevec acts on a molecular target by a mechanism that is more specific to cancer cells. Traditional cytotoxic cancer agents have serious side effects such as nausea, weight loss, hair loss and severe fatigue that result from their lack of specificity in killing cells. Gleevec was designed as an inhibitor of a specific receptor associated with CML, and so produces less severe side effects than other cancer agents. CML is associated in most cases with a specific chromosomal defect, a translocation between chromosomes 9 and 22 that creates the Philadelphia chromosome. This translocation occurs at the site in the genome of a protein tyrosine kinase called abl, creating the abnormal bcr-abl protein, a fusion of the abl gene with another gene called bcr. The kinase activity of abl in the bcr-abl fusion is activated and unregulated, driving the uncontrolled cell growth observed in CML. White blood cells containing the bcr-abl mutation become able to proliferate in the absence of growth factors they normally require. Gleevec inhibits abl kinase activity, helping to reverse uncontrolled cell growth. Gleevec also inhibits the PDGF tyrosine kinase and the c-kit tyrosine kinase. There are a variety of cellular substrates of the bcr-abl kinase that may be involved in cellular transformation. Bcr-abl is associated with the cytoplasm as part of a large signaling complex. Some of the downstream factors in bcr-abl signaling include PI3 kinase/AKT and STAT transcription factors. The activation of bcr-abl also represses apoptosis through induction of anti-apoptosis factors such as Bad, allowing transformed cells to divide. JAK2 kinase activity appears to be one target of bcr-abl. Grb-2 phosphorylation by bcr-abl may play a role in down-regulation of tyrosine kinase signaling. STAT5 may be involved in the failure of apoptosis in bcr-abl cells. In addition to supporting the idea that cancer therapies targeting specific molecular targets should be efficacious with fewer side effects, Gleevec has also demonstrated that drugs inhibiting protein kinases can be developed successfully. Tyrosine kinases are important in a range of cellular processes, including other cancers, and will provide additional drug targets. Gleevec itself has already demonstrated potential in other cancers such as gastrointestinal stromal tumor that do not respond to existing treatments. Although Gleevec has produced very strong clinical responses in patients with early stage CML, patients with late stage disease have had an initial response followed by a relapse of drug resistant CML cells. Cancer cells in patients with Gleevec resistant cancer either had amplification of the bcr-abl gene, or mutation of a key amino acid involved in binding drug from threonine to isoleucine.


description_brief: Insulin Signaling Pathway
systematic_name: M765
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_insulinPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The appropriate signaling through the insulin pathway is critical for the regulation of glucose levels and the avoidance of diabetes. Insulin forms a complex with the Insulin Receptor (IR) and b chains to form the active signaling complex. Through recruitment of adaptor molecules and the activation of RAS, the activated IR can cause transcriptional activation.


description_brief: Integrin Signaling Pathway
systematic_name: M3342
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_integrinPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Integrins are cell surface receptors that interact with the extracellular matrix and mediate intracellular signals in response to the extracellular matrix including cellular shape, mobility, and progression through the cell cycle. Integrins do not themselves possess a kinase domain or enzymatic activity but rely on association with other signaling molecules to transmit signals. Interactions between the extracellular matrix and the actin cytoskeleton commonly take place at focal adhesions on the cell surface that contain localized concentrations of integrins, signaling molecules, and cytoskeletal elements. Talin forms a direct interaction with the integrin cytoplasmic domain, and interacts with cytoskeletal elements (actin) and signaling factors. Paxillin and CAS also localize in focal adhesions and may serve as a scaffold for other integrin signaling components like FAK and src. Interaction of FAK, CAS and src may be required for integrin regulation of cell cycle progression. The CrkL adaptor protein may regulate downstream integrin signaling. Growth factor signaling pathways and the caveolin receptor exhibit important cross talk with integrin receptors in cellular responses like activation of map kinase, proliferation and motility.


description_brief: Intrinsic Prothrombin Activation Pathway
systematic_name: M15997
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_intrinsicPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Blood coagulation or clotting takes place in 3 essential phases. The first phase is the activation of a prothrombin activator complex. The second phase is the activation of prothrombin. The third stage is clot formation as a result of fibrinogen cleavage by activated thrombin. The prothrombin activation complex is formed by two pathways each of which results in a different form of the prothrombin activator. The intrinsic mechanism of prothrombin activator formation begins with trauma to the blood or exposure of blood to collagen in a traumatized vessel wall. This usually also results in damage to fragile platelets. The formation of a clot by this mechanism usually takes 1 to 6 minutes. This cascade begins with the activation of factor XII and the release of platelet factor 3 (PF3) from damaged platelets. Activated factor XII cleaves and actives factor XI and prekallikrein (PK). Factor XII is also activated by activated prekallikrein (aPK) in an internal amplification loop. Calcium (Ca++) is required for the initial three steps. The prothrombin activator in the intrinsic pathway is very similar to the activator in the extrinsic pathway. Antithrombin III inhibits the activity of thrombin and also two of the steps in the formation of the activator. Protein C is activated by thrombin and with the Protein S cofactor provides a strong negative feedback in this phase of clot formation. When blood is collected, the intrinsic pathway is activated by contact with the collection devices causing damage to the platelets and activation of factor XII. Antithrombin III is a hundred to a thousand times more effective when bound by heparin. Use of nonwettable surface materials can increase the clot formation time to over an hour. Disease Significance: Most of the clotting factors are formed in the liver. Diseases of the liver or damage to the liver can depress the levels of these factors in the blood resulting in excessive bleeding. Vitamin K deficiency can also result in a similar condition since Vitamin K is essential for the formation of factor VII, IX, X and prothrombin. Vitamin K is synthesized in the intestinal tract by bacteria.


description_brief: Keratinocyte Differentiation
systematic_name: M19118
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_keratinocytePathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The epidermis, which provides a protective barrier that undergoes a constant renewal, is a multi-layered tissue with the proliferating cells located in the basal layer. As cells leave the basal layer the underog significant differentiation, biochemical and morphological remodeling. The final differentiation results in the formation of corneocytes. In vitro keratinocytes mimic this process. Several genes mark keratinocyte specific differentiation. Among the most frequently tracked markers are Transglutaminase, Cystatin and Involucrin. The keratinocyte differentiation studies have identified and provided significant detail regarding the involvement of three of the 4 major MAP kinase pathways from several diverse stimuli such as EGF, FAS, TNF and Calicium influx. The p38 cascade is represented twice since both p38alpha (p38) and p38delta (MAPK13) are involved. The keratinocyte differentiation cascased also provide for detailed study of the functions of individual PKC isoforms. It is interesting to note the contrasting functions of the PKC isoforms in this process. In recent studies it has been determined that the cPKC (conventional/classical Protein Kinase C) isoforms, which are calcium-, phospholipid-, and diacylglycerol-dependent are inhibitory where as the nPKC (novel Protein Kinase C) isoforms which are calcium independent are stimulatory for keratinocyte differentiation markers. On the right hand side is an earlier step showing the upregulation loop of TRAF2. This step occurs prior to the activation os ASK1 and the p38 cascade.


description_brief: Lck and Fyn tyrosine kinases in initiation of TCR Activation
systematic_name: M10765
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_tcraPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  T cell activation is initiated by recognition of antigen by the T cell receptor (TCR) in the context of Class II MHC on an antigen-presenting cell. The T cell receptor contains multiple subunits and interacts with several factors to transduce antigen-stimulated T cell activation. One of the key steps that initiates receptor activation is the tyrosine phosphorylation of TCR subunits by the src family protein kinases Lck and Fyn. T cell receptor phosphorylated by Lck and Fyn recruits the ZAP-70 protein kinase to the receptor complex, which becomes activated and stimulates downstream pathways like the Map kinase cascade. The CD45 protein tyrosine phosphatase activates Lck and Fyn by dephosphorylating these proteins and is required for TCR activation. Association of the CD4 coreceptor with Lck may also be involved in Lck activation.


description_brief: Lectin Induced Complement Pathway
systematic_name: M4732
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_lectinPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The complement cascade of proteolytic factors involved in cellular lysis can be initiated by several different factors, including antibody-dependent and antibody-independent recognition of infectious organisms. In the lectin-induced complement cascade, carbohydrates on the surface of microbial cells activate the complement cascade by binding to mannan-binding lectin (also called the mannan-binding protein, Mbl/Mbp). Mbp is an acute phase serum protein whose expression is induced by microbial infection. The binding of Mbl to microbial ligands activates the Mbl associated serine proteases Masp1 and Masp2, triggering the cleavage of C2 and C4 to create C4bC2a, a C3 convertase that cleaves large numbers of C3. Masp1 and Masp2 are similar to the C1 protease in the classical complement pathway. Once formed the C3 convertase cleaves and activates the remaining complement factors leading ultimately to formation of a pore in the bacterial membrane by the membrane attack complex (MAC) that lyses the bacterial cell. The lectin-induced pathway also appears to play an important role of the activation of phagocytotic cells by infection. Although the initiating event activating the complement cascade is distinct in the lectin-induced pathway, from the C3 convertase onward the lectin induced complement pathway is the same as the classical complement pathway. Since antibodies are not required in the lectin-induced pathway, this aspect of the immune response is part of the innate immune response. The importance of this pathway to the immune response has been demonstrated by the identification of children and adults with little or no Mbl who lacked normal phagocytotic responses and are highly susceptible to infection.


description_brief: Links between Pyk2 and Map Kinases
systematic_name: M7739
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_pyk2Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  This diagram is a compilation of Pyk2 effort cascades. In specific cell types the receptor and effoectors will vary. Binding of a transmembrane receptor triggers the activation of Ca2+ signaling and PKC. The signal is then transmitted to Pyk2 and further to the small G protein Rac1. In turn, Rac1 initiatates the JNK cascade, starting with PAK follwed by MEKK1, SEK1, and JNK. JNK activation causes induction of c-Jun gene binding. Pyk2 stimulation has also been shown to activate MKK3 leading to activation of p38. The other major mitogen activated kinase cascade for ERK1/2 is stimulated via RAS, RAF and MEKK1/2.


description_brief: MAPKinase Signaling Pathway
systematic_name: M13863
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_mapkPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The ever evolving mitogen-activated protein kinase (MAP kinase) pathways consist of four major groupings and numerous related proteins which constitute interrelated signal transduction cascades activated by stimuli such as growth factors, stress, cytokines and inflammation. The four major groupings are the Erk (red), JNK or SAPK (blue), p38 (green) and the Big MAPK or ERK5 (light blue) cascades. Signals from cell surface receptors such as GPCRs and growth factor receptors are transduced, directly or via small G proteins such as ras and rac, to multiple tiers of protein kinases that amplify these signals and/or regulate each other. The diagram is organized to illustrate the cascades by the background colors and also the tiers of kinases as indicated down the left hand side and separated by the horizontal dashed lines. In some cascades the first activation tier involves the MAPKKKKs, MAP kinase kinase kinase kinases or MAP4K proteins. The next tier are the serine/threonine MAPKKKs, MAP kinase kinase kinase or MAP3Ks such as RAF, TAK, ASK, and MEKK1. This level has the greatest amount of cross-communication curently known. The serine/threonine/tyrosine MAPKKs, MAP Kinase kinases or MAP2Ks, such as the MKK and MEK kinases, are one step up from the MAP kinase cascade, phosphorylating and activating these kinases. The focal tier, the MAPKs or MAP kinases includes JNK1, p38, and ERKs, and are the kinases that give each cascade its name BR&gt;The endpoints of these cascades, shown in the bottom tier, includes the MAPK activated protein kinases (MAPKAPK) and some of the numerous transcription factors that regulate genes involved in apoptosis, inflammation, cell growth and differentiation NOTES:- The shared color and the bold arrows show the major flow of each cascade. - The smaller arrows indicate cross communication between cascades. In many cases this is restricted to certain cell types or requires additional factors. - Kinases that have been identified as MAP kinases based on sequence or structural homolgies but have not yet been assigned to a cascade have been placed out side the grouping backrgounds. - The PAKs (p21 associated kinases) are not MAPKs but participate in the transduction to the JNK cascade are included for this reason.) - MEK4 appears to function in both the JNK and p38 cascades and so has a mixed color. MEK4 signal is much stronger in the JNK than the p38 cascade and so the bold arrow towards the JNK and the dashed arrow towards the p38 cascade indicate the relative strengths of signaling. - For space and readability concerns not all interactions and stimuli are indicated and the scaffold and phosphatase proteins are not shown.


description_brief: mCalpain and friends in Cell motility
systematic_name: M8719
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_mCalpainPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The mammalian calpain gene family currently contains 13 distinct large subunit products most of which complex with one of two smaller 30kDa subunits. ( An excellent introduction to the calpain family can be found on a web site created by Valery Thompson http://ag.arizona.edu/calpains/index.html ) One of the most carefully studied functions of the calpains is the regulation of integrin-mediated cell migration. Calpains digests the links between the actin cytoskeleton and several focal adhesion complex proteins; talin, paxillin and focal adhesion kinase. The release from the focal adhesion complex facilitates migration. Calpestatin is an inhibitor expressed in most cells. Calpestatin binds the four inhibitory domains of calpain. Release from calpestatin does not activate calpain. Activation requires additional signaling, coactivators and an appropriate calcium concentration. During cell migration calpain1 (mu-calpain) acts at the leading edge as a response to integrin signals or calcium fluxuations due to the stretch activated calcium channels. Calpain1 cleaves the target proteins, talin, exzrin, paxillin and the cytoplasmic tail of the integrins B1(a) and B3(b) to release the adhesion and form new adhesions. Calpain2 (M-calpain) is believed to be membrane bound and functions at the trailing edge of the migrating cell to cleave the integrins in response to growth factor receptor signals. PKA functions to down regulate or inhibit calpain2. Disease related notes: In Alzheimers disease, amyloid peptides interfere with calpain activity causing a mislocalization of cdk5. Deregulated cdk5 hyperphosphorylates tau promoting cell death in neurons. Mutations in the muscle specific calpain p94 lead to Limb Girdle muscular dystrophy 2A (LGMD2A). Over activity of calpains due to elevated calcium leads to tissue damage in the heart and brain


description_brief: Mechanism of Gene Regulation by Peroxisome Proliferators via PPARa(alpha)
systematic_name: M2404
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_PparaPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The most recognized mechanism by which peroxisome proliferators regulated gene expresssion is through a PPAR/RXR heterodimeric complex binding to a peroxisome proliferator-response element (PPRE) (classical mechanism). However, there are the possibility of several variations on this theme: 1). The peroxisome proliferator interacts with PPAR that preexists as a DNA complex with associated corepressors proteins. The interaction with ligand causes release of the corepressor and association with a coactivator, resulting in the classical mechanism. 2). The peroxisome proliferator interacts with PPAR as a soluble member of the nucleus. The binding of ligand results in RXR heterodimerization, DNA binding and coactivator recruitment. 3). In this scenario, PPAR exists in the cytosol, perhaps complexed to heat shock protein 90 and/or other chaperones. Binding of peroxisome proliferator causes a conformational change and translocation into the nucleus. Scenarios 4 and 5 require regulation of gene expression via non-classical mechanisms: 4). PPAR is capable of interacting with, and forming DNA binding heterodimers with, several nuclear receptors including the thyroid hormone receptor. The binding site for this non-RXR heterodimer need not be the classic DR-1 motif found in the PPRE. 5). PPAR may participate in the regulation of gene expression witout binding to DNA. By association with transcription factors such as c-jun or p65, PPAR diminishes the ability of AP1 or NFB to bind to their cognate DNA sequences, respectively. Also shown in this scheme are two means to modify the peroxisome proliferator response. Most importantly, growth factor signaling has a pronounced affect on PPAR via post-translational modification. PPAR is a phosphoprotein and its activity is affected by insulin. Several kinase pathways affects PPARa's activity, although the specific kinases and phosphorylation sites have not been conclusively determined.


description_brief: METS affect on Macrophage Differentiation
systematic_name: M14449
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_etsPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Terminal differentiation of cells is often accompanied by repression of cellular proliferation, suggesting that there is a mechanism by which these cellular functions are coordinated. Macrophage differentiation is one model system in which this occurs; as macrophages differentiate, they also stop proliferating. Transcriptional regulation plays a key role in cell cycle progression as well as many differentiation processes. Ras stimulates cell cycle progression in part through Ets transcription factors that bind to cell cycle regulatory genes to activate their expression. Ets transcription factors also help to induce early macrophage differentiation. The activation of Ras signaling by M-CSF activates transcription of genes involved in differentiation through the coordinate expression of both Ets factors and AP-1. Other genes involved in cell cycle regulation involved the coordinate action of E2F-1 and Ets transcription factors. Mets is a factor related in sequence to Ets2 that is upregulated during macrophage differentiation. Increased expression of the Mets protein during macrophage differentiation allows the creation of heterodimers with DP103 to act as transcriptional repressors of cell cycle progression genes, recruiting corepressor to promoters they interact with. DP103 is a gene previously identified as an RNA helicase involved in RNA processing that interacts with EBNA factors from Epstein Barr Virus. The transcriptional repression involving Mets with DP103 is selective, and does not involve all Ets regulated genes. While cell cycle genes are repressed by Mets, other gene activated by Ets factors such as those involved in differentiation are not repressed by Mets. The transcriptional repression by Mets also involved members of the Rb family of tumor suppressors, such as p107 and p130. This requirement for additional factors involved in regulating proliferation may allow for another level of control on cell proliferation and coordination with differentiation.


description_brief: mTOR Signaling Pathway
systematic_name: M16563
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_mtorPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  mTOR (mammalian target of rapamycin) appears to play a central role in signaling caused by nutrients and mitogens such as growth factors to regulate translation. The drug rapamycin acts on mammalian cells through the mTOR protein kinase, also known as FRAP. When bound to the immunophilin binding protein FKBP12, rapamycin inhibits mTOR kinase activity and has immunosuppressant activity. Rapamycin and the mTOR inhibitor CCI-779 are being tested as anti-cancer agents, acting to block mitogenic signaling. Recently, mTOR was also found to act as an ATP sensor to regulate cell growth. Upstream activation of PI 3 kinase activity that leads to oncogenic transformation can be blocked by inhibition of mTOR by rapamycin. Growth factor receptors first stimulate PI 3 kinase, and through inositol phosphates activate PDK-1 and AKT (protein kinase B). AKT phosphorylates mTOR. The phosphorylation of p70S6K and 4EBP by mTOR and the phosphorylation downstream of RPS6 and EIF-4B stimulate translational initiation and contribute to cell growth.


description_brief: Multiple antiapoptotic pathways from IGF-1R signaling lead to BAD phosphorylation
systematic_name: M19613
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_igf1rPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  IGF-1R, the type 1 receptor for insulin-like growth factor, mediates cell survival and growth in response to its ligands IGF-1 and IGF-2. This tyrosine kinase receptor is widely expressed in many cell types and is a key mediator of growth. Overexpression or activation of IGF-1R may be involved in the proliferation of transformed cells, making inhibition of IGF-1R signaling a strategy for the development of cancer drugs. IGF-1R activates three signaling pathways that converge to phosphorylate BAD protein and block apoptosis. The first pathway activated by IGF-1R stimulates PI3-kinase and the AKT pathway to phosphorylate BAD and block apoptosis. A second pathway activated by IGF-1R involves ras mediated activation of the map kinase pathway to block apoptosis. A third pathway involves interaction of raf with mitochondria in response to IGF-1R activation. The convergence of these pathways to block apoptosis may enhance the IGF-1R response.


description_brief: Multi-step Regulation of Transcription by Pitx2
systematic_name: M8516
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_pitx2Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Many transcription factors play essential roles in normal development by determining the proliferation and differentiation of cells. The coordinated transcriptional control of proliferation in specific developmental cell types is crucial in multiple developmental settings. One of a family of three bicoid-related transcription factors, Pitx2 acts downstream of the extracellular signaling protein Wnt to drive proliferation of cells with specific developmental fates, including cells in the pituitary, cardiac outflow region, and muscle. Wnt binds to Frizzled, a G-protein coupled receptor, activating homologs of the Drosophila Disheveled protein. Activation of Frizzled and Disheveled inhibits the kinase GSK-3 beta, part of a protein complex in the absence of Wnt signaling, causing beta-catenin protein to accumulate in the cytoplasm. Beta-catenin is known to alter the function of transcription factors like TCF/Lef. One result of Wnt signaling is activation of the transcription factor Lef by beta-catenin, inducing Pitx2 expression. Wnt activation also changes Pitx2 from a repressor to an activator by causing transcriptional corepressors like histone deacetylase 1 (HDAC1) bound to Pitx2 to be exchanged for coactivators. With coactivators bound, Pitx2 activates transcription of genes that regulate the cell cycle like Cyclin D2. Different coactivators are recruited by Pitx2 and other transcription factors like Myc to the Cyclin D2 promoter, with CBP/p300 recruited first, followed by NLI/Ldb/CLIM, Tip60/TRRAP, and PBP coactivators. Many of these coactivators help to alter histone acetylation and chromatin structure as part of transcriptional activation. The activation of cell cycle genes by Pitx2 ultimately stimulates the proliferation of specific cell types with the confluence of tissue-specific gene expression, growth factor signaling and coactivator recruitment.


description_brief: Nerve growth factor pathway (NGF)
systematic_name: M7860
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_ngfPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Nerve growth factor (NGF) is one of a family of neurotrophins that induce the survival and proliferation of neurons. In cell culture NGF induces the formation of neurite projections and in vivo may stimulate the innervation of tissues. NGF plays a role in the repair, regeneration, and protection of neurons, and as such could serve as a therapeutic agent in neurodegenerative conditions such as Alzheimer's disease. One potential method of NGF application would be through gene therapy or through implantation of cells that have been genetically modified ex vivo. NGF has also been suggested to play a role in other physiological systems and tissues such as the immune system. NGF has two receptors, TrkA and the p75(NTR). NGF may signal its neuroprotective actions through the tyrosine kinase TrkA receptor and trigger apoptosis in some cells through the p75 receptor. High-affinity binding of NGF requires both TrkA and p75(NTR). Binding of NGF to the TrkA receptor causes activation of the receptor tyrosine kinase and downstream signaling cascades. One of the downstream signaling pathways of NGF activates phospholipase C, releasing DAG and IP3 and activating associated downstream pathways such as protein kinase C. Another NGF-activated pathway is the ras-mediated activation of the map kinase pathway. This pathway is initiated through recruitment and activation of Shc, which leads to ras activation through Grb-2 and Sos-1. The Map kinase cascade includes raf, Mek and Erk. The downstream effectors of the ras pathway include activation of fos and jun to form AP-1, activating genes through this transcription factor. Other transcription factors involved in NGF responses include Egr and CREB. The Egr family of transcription factors as well as the Mek/Erk pathway contribute to NGF-induced neurite formation. The CREB family of transcription factors are involved in NGF-induced survival of sympathetic neurons. Further understanding of NGF signaling may be applied to the modulation of NGF responses in neurodegenerative conditions.


description_brief: Neuropeptides VIP and PACAP inhibit the apoptosis of activated T cells
systematic_name: M17941
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_vipPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Vasoactive intestinal peptide (VIP) and the structurally related pituitary adenylate cyclase-activating polypeptide (PACAP), two neuropeptides present in the lymphoid microenvironment, elicit a broad spectrum of biological functions, including the modulation of innate and adaptive immunity. Another important immunoregulatory function of VIP and PACAP is their inhibition effect on AICD in T cells. They inhibit the TCR-stimulated FasL expression and apoptosis of T cell through specific receptors and induction of intracellular cAMP. VIP down-regulate c-Myc synthesis, the NF-AT-dependent Egr2 and Egr3 expression, the NF-AT and NF-kB.


description_brief: NFAT and Hypertrophy of the heart (Transcription in the broken heart)
systematic_name: M2288
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_nfatPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Hypertrophy associated with both hypertension and obstruction to ventricular outflow leads to pathologic cardiac growth and it is associated with increase morbidity and mortality. Symptomatic ventricular disease takes a growing toll on the health of nations. As other cardiovascular diseases such as stroke and myocardial infraction are in decline as causes of mortality, the heart failure problem becomes increasingly urgent. Congenital heart defects occur in 1% of live births and fetal heart malformations are implicated in many pregnancies that end in still-birth or spontaneous abortion. The current paradigm suggests that the heart adapts to excess of hemodynamic loading by compensatory hypertrophy, which under condition of persistent stress, over time evolves into dysfunction and myocardial failure. There is considerable evidence that direct effects of increased mechanical stress are sensed within the ventricular wall and that signals critical for the generation of growth responses. Despite compelling statistics we still do not understand biochemically why heart defects are so prevalent. A single transcriptional regulator initially associated with the activation of the T-cells


description_brief: NFkB activation by Nontypeable Hemophilus influenzae
systematic_name: M2821
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_nthiPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The role of Hemophilus influenzae in ear infections and chronic obstructive pulmonary disease includes the induction of an inflammatory response through activation of the transcription factor NF-kB. In addition to activation of inflammatory cytokine genes like IL-1 and TNF, H. influenzae activates TLR2 expression and genes involved in mucus production. Hemophilus influenzae activates NF-kB by multiple mechanisms, starting with activation of the Toll-like receptor 2 (TLR2) by the p16 protein in the H. influenzae outer membrane. TLR2 plays a key role in innate immune responses and is expressed in high levels in lymphoid cells as well as low levels in epithelial cells. The role of TLR2 was supported by blocking NF-kB activation with a dominant negative TLR2 and increasing it with transfection of a normal TLR2 gene. TLR2 in turn activates TAK1, which activates two divergent signaling pathways. One of these pathways leads to IkB kinase activation, IkB phosphorylation and degradation, releasing the NF-kB heterodimer to translocate into the nucleus and activate transcription of target genes. In the alternate pathway, TAK1 also activates NF-kB through a Map kinase pathway, activating p38 and NF-kB in a nuclear translocation independent manner. Investigation of the mechanisms of H. influenzae signaling involved in NF-kB activation may provide the information needed to develop better treatments for inflammatory conditions caused by this pathogen. Other pathways modulate the role of NF-kB in H. influenzae pathogenesis. Glucocorticoids widely used as anti-inflammatory drugs increase TLR2 activation by H. influenzae through the NIK/I-kB kinase pathway, while they repress the p38 dependent activation of NF-kB. The repression of the p38 pathway by glucocorticoids occurs through activation of the MAP kinase phosphatase-1 (MKP-1) which dephosphorylates and deactivates p38. Another aspect of the inflammatory response to H. influenzae infection is the production of excessive mucus, contributing to the overall symptoms of infection. NF-kB activation of the Muc2 gene contributes to mucus overproduction, in addition to H. influenzae activation of the TGF-beta receptor, activating SMAD transcription factors SMAD3 and SMAD4. Understanding mechanisms that modify H. influenzae signaling will contribute to further understanding the pathogenesis and treatment of ear infections and chronic obstructive pulmonary disease.


description_brief: NF-kB Signaling Pathway
systematic_name: M15285
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_nfkbPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Nuclear factor kB (NF-kB) is a nuclear transcription factor that regulates expression of a large number of genes that are critical for the regulation of apoptosis, viral replication, tumorigenesis, inflammation, and various autoimmune diseases. The activation of NF-kB is thought to be part of a stress response as it is activated by a variety of stimuli that include growth factors, cytokines, lymphokines, UV, pharmacological agents, and stress. In its inactive form, NF-kB is sequestered in the cytoplasm, bound by members of the IkB family of inhibitor proteins, which include IkBa, IkBb, IkBg, and IkBe. The various stimuli that activate NF-kB cause phosphorylation of IkB, which is followed by its ubiquitination and subsequent degradation. This results in the exposure of the nuclear localization signals (NLS) on NF-kB subunits and the subsequent translocation of the molecule to the nucleus. In the nucleus, NF-kB binds with a consensus sequence (5'GGGACTTTCC-3') of various genes and thus activates their transcription. IkB proteins are phosphorylated by IkB kinase complex consisting of at least three proteins; IKK1/IKKa, IKK2/IKKb, and IKK3/IKKg. These enzymes phosphorylate IkB leading to its ubiquitination and degradation. Tumor necrosis factor (TNF) which is the best-studied activator binds to its receptor and recruits a protein called TNF receptor death domain (TRADD). TRADD binds to the TNF receptor-associated factor 2 (TRAF-2) that recruits NF-kB-inducible kinase (NIK). Both IKK1 and IKK2 have canonical sequences that can be phosphorylated by the MAP kinase NIK/MEKK1 and both kinases can independently phosphorylate IkBa or IkBb. TRAF-2 also interacts with A20, a zinc finger protein whose expression is induced by agents that activate NF-kB. A20 functions to block TRAF2-mediated NF-kB activation. A20 also inhibits TNF and IL-1 induced activation of NF-kB suggesting that it may act as a general inhibitor of NF-kB activation.


description_brief: Nitric Oxide Signaling Pathway
systematic_name: M11650
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_nos1Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Glutamatergic-mediated nitric oxide (NO) production occurs via the N-methyl-D-aspartic acid (NMDA) postsynaptic density protein 95 (PSD95)-neuronal nitric oxide synthase (NOS1) ternary complex. The increased intracellular Ca2+ stimulates the interaction of nNOS and calmodulin (CaM) and the translocaton of nNOS from the plasma membrane to the cytoplasm. The dephosphorylation of nNOS by Calcineurin catalyzes the conversion of arginine to citrulline and nitric oxide (NO), which turns on guanylate cyclase and the various cGMP regulated signaling pathways.


description_brief: NO2-dependent IL 12 Pathway in NK cells
systematic_name: M6231
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_no2il12Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Macrophages and NK cells help provide innate immunity against infection by intracellular parasites and communicate with each other to regulate this process. When stimulated, macrophages secrete the cytokine IL-12 that is essential for activation of the cytotoxic activity of natural killer (NK) cells. IL-12 stimulates this NK cell response through activation of a JAK/STAT signaling pathway. Binding of IL-12 to its receptor on NK cells causes tyrosine phosphorylation and activation of JAK2 and another JAK kinase, Tyk2. Tyk2 in turn phosphorylates the transcription factor STAT4, which can then translocate to the nucleus to activate genes, including the expression of interferon-gamma. IFN-gamma and IL-12 induce the differentiation of TH1 helper T cells that activate macrophages through interferon-gamma. A key modulator of NK cell activation by IL-12 is nitric oxide, NO, produced from arginine by the inducible nitric oxide synthase NOS2. Inactivation of the NOS2 gene in mice impairs the initial innate response to infection, including the activation of NK cells. This phenotype is similar to that of mice lacking interferon-gamma or IL-12 and a similar effect can be produced by inhibiting NOS2 with L-N6-iminoethyl-lysine (L-NIL) during infection, blocking the activation of NK cells by IL-12. NO production does not affect the activation of JAK2 by IL-12, but is required for Tyk2 activity, the downstream activation of STAT-4 and the production of interferon-gamma by NK cells. The role of NO in Tyk2 activation is not yet known, but does not seem to involve change the phosphorylation status of Tyk2. Curiously, activation of T cells by IL-12 does not appear to involved NO production, indicating a distinct mechanism is involved in NK cells. NO also plays a role as a feedback inhibitor of IL-12 production by macrophages, helping to prevent over-activation of the Th1 cells by IL-12. NO appears to make an important contribution to the early innate response to infections before specific immunity is active.


description_brief: Oxidative Stress Induced Gene Expression Via Nrf2
systematic_name: M14339
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_arenrf2Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Reactive oxygen species (ROS) can damage biological macromolecules and are detrimental to cellular health. Electrophilic compounds, xenobiotics and antioxidants are sources of reactive oxygen species, creating oxidative stress that can harm cells. Enzymes are involved in the Phase II detoxification of xenobiotics to reduce cellular stress include glutathione transferases, quinone reductase, epoxide hydrolase, heme oxygenase, UDP-glucuronosyl transferases, and gamma-glutamylcysteine synthetase. Expression of these genes protects cells from oxidative damage and can prevent mutagenesis and cancer. Transcription of these enzymes is coordinately regulated through antioxidant response elements (AREs). Nrf2 (NF-E2-related factor 2) and Nrf1 are transcription factors that bind to AREs and activate these genes. Inactive Nrf2 is retained in the cytosol by association a complex with the cytoskeletal protein Keap1. Cytosolic Nrf2 is phosphorylated and translocates into the nucleus in response to protein kinase C activation and Map kinase pathways. In the nucleus, Nrf2 activate genes through AREs by interacting with transcription factors in the bZIP family, including CREB, ATF4 and fos or jun. Nrf2 activation of genes is opposed by small maf proteins, including MafG and MafK, maintaining a counterbalance to Nrf2 and balancing the oxidation level of the intracellular environment.


description_brief: p38 MAPK Signaling Pathway
systematic_name: M862
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_p38mapkPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  p38 MAPKs are members of the MAPK family that are activated by a variety of environmental stresses and inflammatory cytokines. Stress signals are delivered to this cascade by members of small GTPases of the Rho family (Rac, Rho, Cdc42). As with other MAPK cascades, the membrane-proximal component is a MAPKKK, typically a MEKK or a mixed lineage kinase (MLK). The MAPKKK phosphorylates and activated MKK3/5, the p38 MAPK kinase. MKK3/6 can also be activated directly by ASK1, which is stimulated by apoptotic stimuli. P38 MAK is involved in regulation of Hsp27 and MAPKAP-2 and several transcription factors including ATF2, STAT1, THE Max/Myc complex, MEF-2, ELK-1 and indirectly CREB via activation of MSK1.


description_brief: p53 Signaling Pathway
systematic_name: M14863
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_p53Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  p53 is a transcription factor who's activity is regulated by phosphorylation. The function is p53 is to keep the cell from progressing through the cell cycle if there is damage to DNA present. It may do this in multiple ways from holding the cell at a checkpoint until repairs can be made to causing the cell to enter apoptosis if the damage cannot be repaired. The critical role of p53 is evidenced by the fact that it is mutated in a very large fraction of tumors from nearly all sources.


description_brief: PDGF Signaling Pathway
systematic_name: M2529
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_pdgfPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Platelet Derived Growth Factor (PDGF) plays a critical role in cellular proliferation and development. The biologically active form is a dimer formed from the A and B chains. PDGF is active to a differing degree depending on which dimer is formed (AA, AB, or BB). The PDGF Receptor (PDGFR) is also a dimer and can form from the combination of the alpha and beta chains in any order (alpha-alpha, alpha-beta, beta-beta). The PDGFR dimer is only formed after ligand binding so the alpha/beta composition of the receptor can be influenced by the form of PDGF that is present. Upon binding of ligand the PDGFR is tyrosine phosphorylated and leads to the phosphorylation of several other cellular proteins.


description_brief: Pertussis toxin-insensitive CCR5 Signaling in Macrophage
systematic_name: M2349
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_ccr5Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The chemokine receptors CCR5 and CXCR4 in macrophages are activated by their peptide ligands and also by the HIV envelope protein GP120 during HIV infection. One mechanism of signaling by these GPCRs is through activation of Gi signaling. These chemokine receptors can also signal through a Gi-independent pertussis toxin-insensitive pathway. This pathway elevates calcium influx into the cell through CRAC channels, ion channels that are activated by calcium release. Elevated calcium from CRAC is required for downstream activation of Pyk2, a focal adhesion-associated protein kinase. Non Gi signaling by these chemokine receptors also involves the Jnk and p38 Map kinase pathways leading to AP-1 activation and activation of genes such as MIP-1 and MCP-1. This pathway may be involved in the role of macrophages in the pathogenesis of AIDS.


description_brief: Phosphoinositides and their downstream targets.
systematic_name: M8809
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_ptdinsPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Nine currently identified phosphoinositide 3-kinases (PI 3-K) constitute a subfamily of lipid kinases that catalyze the addition of a phosphate molecule on the 3-position of the inositol ring of phosphoinositides. Phosphatidylinositol (PtdIns), the precursor of all phosphoinosi-tides (PI), constitutes less than 10% of the total lipid in eukaryotic cell membranes. Approximately 5% of cellular PI is phosphorylated at the 4-position (PtdIns-4-P), and another 5% is phosphorylated at both the 4- and 5-positions (PtdIns-4,5-P2 ). However, less than 0.25% of the total inositol-containing lipids are phosphorylated at the 3-position, consistent with the idea that these lipids exert specific regulatory functions inside the cell, as opposed to a structural function. Here we have chosen to highlight a group of the phosphoinositide targets of the PI3-Ks and their downstream targets. The downstream effects of these PI-3 targets are indicated in the lower band illustrating the important role the PI3Ks have in cell function and survival.


description_brief: Phospholipase C-epsilon pathway
systematic_name: M5576
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_plcePathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Proposed model for b2-AR- and prostanoid-receptor-mediated PLC and calcium signalling. Receptors coupling to Gs stimulate AC, resulting in elevated cAMP levels and activation of Epac1. Epac1 then catalyses GTP-loading on Rap2B, which leads to PLC-e activation. The proposed pathway may involve additional signalling components to attain PLC stimulation. The action of cAMP seems to be independent of PKA; Instead, the cAMP-activated Rap-GEF Epac seems to serve as a cAMP effector, inducing GTP loading and, hence, activation of Rap2B, which then leads to specific activation of PLC-e, which has been shown to interact with Rap GTPases. It is an attractive hypothesis, therefore, that the Rap-dependent PLC and calcium signalling pathway reported here is not restricted to Gs-and AC-coupled receptors, such as the b2-AR and the prostanoid receptor, but could be used by other receptors as well.


description_brief: Phospholipids as signalling intermediaries
systematic_name: M10579
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_edg1Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Sphingosine-1-phosphate (S1P) is an example of lipid messengers with both intracellular and extracellular functions. Intracellularly S1P regulates proliferation and survival; extracellularly S1P is a ligand for EDG1 (also known as S1P1). Activation of sphingosine kinase (SPHK), the enzyme that catalyzes the phosphorylation of sphingosine, increases cellular levels of S1P. Inhibitors of SPHK block formation of S1P and inhibit cellular proliferation induced by a variety of factors, including as an example platelet-derived growth factor (PDGF) and PMA. In a study using endothelial cells it was demonstrated that S1P induces activation of alpha-v and B3 integrins via RhoA. S1P also activates Akt via Gi and PI3K. The activated Akt phosphorlyates the Edg1 receptor on threonine 236 leading to the activation of Rac1 and subsequent signals leading to actin assembly, chemotaxis and lamellipodia formation. Edg1 stimulation also leads to the activation of the ERK signaling cascade resulting in anti-apoptotic reversal, proliferation and cell survival.


description_brief: Phosphorylation of MEK1 by cdk5/p35 down regulates the MAP kinase pathway
systematic_name: M89
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_cdk5Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Map kinases transduce responses to extracellular signals by a variety of routes, and communicate with other pathways through extensive crosstalk networks. A closely studied Map kinase cascade originates with tyrosine kinase activation, and activation of Ras. Ras activates Raf, Raf activates the Map kinase kinases Mek1 and Mek2 and these kinases activate downstream Map kinases like Erk1 and Erk2. Erk1 and Erk2 in turn activate transgenes like p35 through the Map kinase activated transcription factor EGR-1. Mek1 plays a central role in many different Map kinase pathways. Factors that activate Mek1 include growth factors like NGF, cytokines, chemokines, and phorbol ester, resulting in cellular proliferation and survival. Mek1 activation may also play a role in differentiation in neuronal tissues. In cultured neuronal PC-12 cells, NGF induces neurite outgrowth via Mek1 and the map kinase pathway. Constitutive activation of Mek1 can transform cells and may play a role in cancer. The crucial role of Mek1 in a variety of pathways including cellular transformation suggests that the cell must tightly regulate its activity. Cdk5 is a kinase that regulates the activity of Mek1. Although Cdk5 is a member of the cyclin-dependent kinase gene family, the activity of Cdk5 does not appear to be regulated by cyclins, but is activated by association with p35. Cdk5 does not act as a checkpoint kinase to regulate cell cycle progression, but acts as a regulatory kinase involved in other post-mitotic processes such as neuronal activity such as neuronal migration during development and neurite outgrowth. Mice lacking Cdk5 exhibit defects in neuronal development. One target of Cdk5 is Mek1. Phosphorylation of Mek1 by Cdk5 represses Mek1 activity and blocks downstream cellular responses. The activation of p35 by Map kinase pathways followed by deactivation of Map kinase signaling by the Cdk5/p35 complex completes the loop of a feedback circuit to terminate Map kinase signaling.


description_brief: PKC-catalyzed phosphorylation of inhibitory phosphoprotein of myosin phosphatase
systematic_name: M7014
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_myosinPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The phosphorylation of myosin affects its role in smooth muscle contraction, platelet formation and possibly other processes. Phosphorylation by myosin light chain kinase (MLCK) increases myosin activity and dephosphorylation by myosin phosphatase decreases myosin activity. CPI, a factor that binds to and inhibits myosin phosphatase, is a target of phosphorylation by PKC and PKN. The inhibitory activity of CPI is regulated by its own phosphorylation state; when CPI is phosphorylated, its inhibitory activity is increased. The activation of signal transduction cascades such as GPCR pathways can lead to activation of PKC, phosphorylation of CPI, inhibition of myosin phosphatase, increased myosin phosphorylation and increased smooth muscle contraction or platelet release. The action of histamine in vasoconstriction, for example, may be mediated by activation of PKC through the histamine receptor, resulting in phosphorylation of CPI-17, increased inhibition of myosin phosphatase, and increased smooth muscle contraction.


description_brief: Platelet Amyloid Precursor Protein Pathway
systematic_name: M6487
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_plateletAppPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The amyloid -beta peptide (Ab), a proteolytic fragment of amyloid precursor protein (APP), is the major componenet of senile plaques, the hallmark of alzhemiers disease. Platelets contain both APP and Ab and probably contribute greater than 90% of circulating APP. The soluble APP is the major inhibitor of coagulation factors IXa and XIa, and platelet aggregation. Agonists such as ADP, thrombin, epinephrine and collagen activate the release of APP and plasminogen activator inhibitor I (an important regulator of coagulation) from platelet storage granules. These important molecules released from platelets are key regulators of hemostasis, the physiologic arrest of hemorrhage at site of vascular leakage.


description_brief: Presenilin action in Notch and Wnt signaling
systematic_name: M16173
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_ps1Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Presenilin-1 (PS1) is associated with gamma secretase activity that cleaves amyloid precursor protein (APP) and is implicated in Alzheimer's disease. Presenilin-1 is also a component in gamma-secretase activity involved in signaling by the transmembrane protein Notch. Active gamma secretase requires PS-1 N-terminal fragment and a C-terminal fragment and is unique in catalyzing proteolysis within the transmembrane region of proteins. Other proteins such as nicastrin may also be components of the gamma-secretase. Binding of the ligand Delta by Notch appears to trigger two proteolytic cleavages of Notch. The first step cleaves an extracellular domain and is catalyzed by a metalloprotease termed alpha-secretase or TACE. The second cleavage step appears to occur within the transmembrane domain of Notch, and releases a Notch intracellular doman (NICD). Once released, NICD moves into the nucleus where it is involved in transcriptional regulation through CSL family transcription factors (CBF1, Su(H), Lag-1) or other transcriptional regulators such as LEF-1. Presenilin is also involved in the Wnt/frizzled signaling pathway through beta-catenin. Beta-catenin is a cytoskeletal component that enters the nucleus to act as a transcriptional cofactor. Binding of WNT to Frizzled causes disheveled (DSH) to inhibit Glycogen synthase kinase 3 beta (GSK-3b) activity. Phosphorylation of Beta-catenin induces the ubiquitination and proteolytic degradation of beta-catenin by the proteasome. Non-phosphorylated beta-catenin is stable and enters the nucleus to regulate transcription with TCF. The beta-catenin/TCF complex activates genes that promote cellular survival, proliferation and differentiation during development. Presenilin stimulates beta-catenin turnover, reducing its transcriptional activation.


description_brief: Protein Kinase A at the Centrosome
systematic_name: M15347
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_akapcentrosomePathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Protein kinase A regulatory subunit RIIalpha (PKA-RIIa) is tightly bound to centrosomal structures during interphase through interaction with the A-kinase anchoring protein AKAP350 (also known as AKAP450 and CGNAP), MAP2 and Pericentrin. This diagram illustrates these three PKA-RII binding complexes. The cyclin B-p34(cdc2) kinase (CDK1) has been shown to phosphorylate PKA-RIIa on T54 and this has been proposed to alter the subcellular localization of PKA-RIIa at the on set of mitosis. It has been demonstrated that PKA-RIIa dissociates and redistributes from centrosomes at mitosis. The focal point of this illustration is the AKAP350 complex. In addition to binding PKA-RIIa, AKAP350 binds PKN (Takahashi et al 1999) and the phosphatases PP1 and PPA2 (Takahashi et al 1999). PKN is a serine/threonine protein kinase, having a catalytic domain homologous to the PKC family in the C-terminal region and a unique regulatory region in the N-terminal region. PKN is activated by a small GTPase RhoA and unsaturated fatty acids such as arachidonic acid. The binding of both kinases and phophatases by the same scaffold protein provides a focal point where physiological events, such as cell cycle progression and intracellular membrane traffic, may be regulated by phosphorylation state of specific protein substrates. There are at least 4 isoforms of AKAP350 which lead to the possibility that they may behave differently at different subcellular locations. MAP2 is a member of a group of proteins that provide microtubule stabilization. MAP2 affinity appears to be dependent on PKA phosphorylation of MAP2. Pericentrin is also an AKAP (Diviani and Scott). Pericentrin binds Dynein which is also regulated by PKA leading to the possibility that pericentrin positions PKA to regulate dynein function (Diviani and Scott). Another example of AKAP/PKA interaction is illustrated in the AKAP95 role in mitosis and chromosome dynamics pathway.


description_brief: PTEN dependent cell cycle arrest and apoptosis
systematic_name: M10145
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_ptenPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  PTEN is a tumor suppressor gene. Recombinant PTEN is capable of dephosphorylating phosphatidylinositol 3,4,5-triphosphate, the product of phosphatidylinositol 3 -kinase. Many of the cancer-related mutations have been mapped to the phosphatase catalytic domain, it has been suggested that the phosphatase activity of PTEN is required for its tumor suppressor function. The activation of PKB/AKT is regulated in a complex manner via phosphorylation of AKT on Thr308 and Ser473 by PDK1 and ILK(integrin-linked kinase) respectively. Inactivation of PTEN will constitutively activate PKB/AKT pathway. In addition to its role in regulating the PI 3-K/AKT cell survival pathway, PTEN also inhibits growth factor-induced Shc phosphorylation and suppresses the mitogen-activated protein (MAP) kinase signaling pathway. PTEN also interact with FAK, a key molecule implicated in integrin signaling pathways, and it directly dephosphorylates tyrosine-phosphorylated FAK. PTEN down-regulation of p130CAS through FAK results in inhibition of cell migration and spreading.


description_brief: Rab GTPases Mark Targets In The Endocytotic Machinery
systematic_name: M8179
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_rabPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The eukaryotic cell contains compartments with distinct functions bounded by lipid bilayer membranes. The movement of membrane vesicles between these compartments allows proteins in the secretory pathway to move outward from the endoplasmic reticulum (ER) to the Golgi, trans Golgi network (TGN), secretory vesicles, and the plasma membrane and to be secreted into the extracellular environment. The trafficking of membrane vesicles is also essential for endocytosis and the movement of material from the extracellular environment into the early endosome (EE), late endosome (LE) and lysosome. The movement of vesicles and their contents between these compartments and their secretion are essential for a host of cellular functions, including the release of neurotransmitters and hormones. The movement of membrane vesicles between all of these compartments is regulated by members of the Rab family of GTPases, part of the ras superfamily of genes, regulated through binding of GTP and hydrolysis of bound GTP to GDP. At least eleven yeast genes in this family have been identified as Ypts, yeast transport proteins, and over sixty mammalian Rab genes have been identified in this highly conserved gene family. The products of the Rab genes regulate specific steps in vesicle transport. Rab1 is involved in the movement of membranes from the ER through the Golgi. Rab3 regulates secretory vesicle release and Rab27 is also involved in regulated release of secreted proteins. Rab5, 7 and 9 contribute to endocytosis while Rab4 and Rab11 mediate recycling from the endosome back to the plasma membrane. Rab11 is involved in both endocytosis and exocytosis. As with other Ras family GTPases, the activity of Rabs is regulated by guanine-nucleotide exchange factors (GEFs) and GAPs (GTPase activating proteins). Downstream effectors must also interact with Rabs to transmit their signals regulating each step of the membrane trafficking pathways including vesicle formation, movement of vesicles between compartments, vesicle docking, fusion and membrane remodeling. Downstream effectors of the Rabs include Rabphilin-3 (vesicle movement effector for Rab3), Rabphilin-11 (vesicle formation effector for Rab11), and EEA1 (vesicle fusion and membrane remodeling). If Rabs are involved in more than one role and other components of Rab signaling also interact with more than one Rab this will further increase the complexity of the system. Elucidating the interaction of Rabs and regulation of vesicle trafficking by other signaling pathways will be a key area of research in the future.


description_brief: Rac 1 cell motility signaling pathway
systematic_name: M8601
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_rac1Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Rac-1 is a small G-protein in the Rho family that regulates cell motility in response to extracellular signals. Several changes in cytoskeletal structure and other aspects of cell structure are involved in cell motility. Rac-1 is activated by GEF factors, and repressed by GAPs. GEFs are guanine nucleotide exchange factors, including Trio and Vav. Sos-1 is involved in Ras signaling and also acts as a GEF for Rac to transduce signals between Ras and Rac. SWAP-70 is a Rac GEF that binds IP3 and transduces signals from tyrosine kinases to Rac to modulate the cytoskeleton and cause membrane ruffling. GAPs are GTPase- activating proteins. Rac stimulates the formation of actin-based structures such as filopodia and lamellopodia, while GAPs such as chimerin oppose the formation of these Rac dependent structures. Several different factors downstream of Rac act on cytoskeletal structure and other aspects of cell motility. Pak1 provides a direct link from Rac to cell motility through phosphorylation of the myosin light chain. Pak1 also phosphorylates and activates LIM kinase, which phosphorylates cofilin as one target. Cofilin stimulates actin depolymerization and changes in cell structure, and phosphorylation of cofilin by LIM kinase represses its activity. In neurons, Rac acts through the protein kinase cdk5 and p35 to phosphorylate and downregulate Pak1, increasing neuronal migration. Rac-1 also interacts with several other factors to regulate a variety of processes. Interaction of Por1 with Rac-1 is involved in membrane ruffling. WAVE is a member of the WASP family of proteins that regulate actin organization and that is involved in Rac signaling to cause membrane ruffling. Interaction of Rac-1 with MEKK1 integrates Rac signaling with pathways signaling through map kinases.


description_brief: Ras Signaling Pathway
systematic_name: M17294
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_rasPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Ras activates many signaling cascades. Here we illustrate some of the well-characterized cascades in a generic compilation of effector molecules. The effectors mediate Ras stimulation to a diverse set of cellular signals. Many of these signals are interpreted differently depending on the cell type or microenvironment receiving the stimulus. Not all of these effectors are activated in any given cell type. The primary method of activation is to promote the translocation of the molecule to the plasma membrane where additional interactions lead to the activation of the molecule. RalGDS is a Guanine Exchange Factor (GEF) for Ral but also has other independent functions. RalGDS activates RalA/B-related small GTPases. RalBP1 is a GTPase activating protein that leads to the inhibition of the Rac and CDC42 GTPases. Ral can also interact with phospholipase D1 (PLD1) that can also be activated by RhoA. Ras stimulation of the lipid kinase activity of PI3K occurs through an interaction with the p110 catalytic subunit. PI3K phosphorylates the D3 position of phosphatidylinositides. In this example Pip2 is converted to PIP3. PIP3 stimulates the AKT/PKB kinase and several of the Rac-GEFs such as Sos1 AND Vav. AKT activation inhibits apoptosis by inhibiting the actions of Bad, Caspase9 and AFX. AKT further hinders apoptosis by phosphorylating the IkB repressor of NFkB. Stimulus of Rac causes among other things the activation of NFkB. Ras also stimulates the mitogen-activated kinases ERK1/2 via the Raf1 cascade. The Erk kinases translocate to the nucleus where they phosphorylate various transcription factors such as ELK1


description_brief: Ras-Independent pathway in NK cell-mediated cytotoxicity
systematic_name: M16355
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_nkcellsPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  NK (natural killer) cells are lymphocytes distinct from B and T cells that induce perforin-mediated lysis of tumor cells and virus-infected cells. NK cell-mediated cytotoxicity is activated by glycoproteins on the cell surface (activating receptors) and inhibited by MHC-1 with self-peptide bound. The MHC-1 inhibitory signal through Ig-family or lectin receptors prevents NK cells from killing normal cells. Abnormal MHC-1 expression in infected or tumor cells results in the release of perforin, the lysis of the abnormal cell and the release of cytokines that stimulate the immune response. MAP kinase inhibitors but not ras inhibitors are able to block NK cell cytotoxicity, indicating that the pathway can function by a ras-independent manner that involves the MAP kinase pathway. This pathway includes phosphoinositide-3-kinase (PI3K) as a key component, followed by Rac1 and the exchange factor Vav. The tyrosine kinase SYK and LAT may provide an additional pathway for activation of MAP kinases leading to NK cell activation, and also Pyk-2 activation by integrins. The protein tyrosine phosphatase SHP-1 appears to mediate the cytotoxicity inhibitory signal that blocks lysis of normal cells. The balance of these positive and negative signaling pathways regulates the role of NK cells in the immune response.


description_brief: RB Tumor Suppressor/Checkpoint Signaling in response to DNA damage
systematic_name: M18159
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_rbPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Cell cycle checkpoint controls at the G1 to S transition and the G2 to M transition prevent the cell cycle from progressing when DNA is damaged. The ATM protein kinase detects DNA damage and in response to this activates DNA repair factors and inhibits cell cycle progression. Two of the proteins that ATM phosphorylates in response to DNA damage are the tumor suppressor p53 and the checkpoint kinase chk1. In turn, the tumor suppressor p53 interacts with p21 to block the activity of cdk2 (cyclin dependent kinase 2) preventing passage from G1 to S phase and harmful replication of damaged DNA. One of the targets of cdk2 is the Rb gene product, another tumor suppressor. When dephosphorylated, Rb interacts with E2F transcription factors and prevents transcription of genes required for progression through the cell cycle. When phosphorylated by cell cycle dependent kinases like cdk2 and cdk4, Rb no longer interacts with E2F and the cell cycle proceeds through the G1-S checkpoint. DNA damage also regulates the G2-M phase transition by acting on the cell cycle regulator cdc2.


description_brief: Regulation of BAD phosphorylation
systematic_name: M85
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_badPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The function of the pro-apoptotic molecule BAD is regulated by phosphorylation of three sites (ser 112,136 and 155). Phosphorylation at these sites results in loss of the ability of BAD to heterodimerize with the survival proteins BCL-XL or BCL-2. Phosphorylated BAD binds to 14-3-3 and is sequestered in the cytoplasm. While ser-136 phosphorylation is concordant with the activation of Akt, Ser-112 phosphorylation requires activation of the Ras-MAPK pathway. BAD Ser 155 was found to be a major site of phosphorylation induced following stimulation by growth factors and prevented by protein kinase A inhibitors.


description_brief: Regulation of ck1/cdk5 by type 1 glutamate receptors
systematic_name: M16626
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_ck1Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Cdk5 is a cyclin dependent protein kinase involved in dopaminergic signaling in the neostriatal region of the brain. The role of cdk5 in dopamine responses occurs through phosphorylation of DARPP-32. Caseine kinase 1 (CK1) also regulates DARPP-32 phosphorylation and dopamine signaling. The phosphorylation of DARPP-32 by cdk5 reduced dopamine signaling. Depending on its phosphorylation state, DARPP-32 inhibits either protein phosphatase 1 (PP1) or PKA. The role of mGLUR1 in this process is supported by the induction of cdk5 and CK1 activity by the mGLUR1 agonist DHPG and the subsequent phosphorylation of DARPP-32 associated with DHPG treatment of nigrostriatal neurons. CK-1 and Ckd5 inhibitors block the DHPG induced DARPP-32 phosphorylation. Dopamine exerts a positive signal that increases dopamine response by reversing phosphorylation of DARPP-32 at threonine-75. Dopamine initiates this pathway through activation of the D1 dopamine receptor, a Gs coupled GPCR, elevating cAMP and activating PKA. PKA activates protein phosphatase 2A (PP2A) which dephosphorylates DARPP-32 and increases dopamine responsiveness. This also removes the inhibition of PKA by DARPP-32, forming a positive feedback loop for further DARPP-32 inactivation by PKA. Activation of the D2 dopamine receptor has the opposite effect, shifting the DARPP-32 population toward the threonine-75 phosphorylated form.


description_brief: Regulation of eIF2
systematic_name: M6924
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_eif2Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Protein phosphorylation plays an important role in the control of translation by eukaryotic initiation factor-2 (eIF-2). eIF-2 binds GTP and Met-tRNAi and transfers the Met-tRNA to the 40S subunit, to form the 43S preinitiation complex. Later in the cycle, prior to elongation, the bound GTP is hydrolyzed , releasing eIF-2-GDP. For eIF-2 to promote another round of initiation, GDP must be exchanged for GTP, a reaction catalyzed by eIF-2B. Kinases activated by viral infection (PKR), endoplasmic reticulum stress (PERK/PEK), amino acid deprivation (GCN2), and hemin deficiency (HRI) can phosphorylate the a subunit of eIF-2. This phosphorylation stabilizes the eIF-2-GDP-eIF-2B complex, inhibiting the turnover of eIF-2B. eIF-2B is also inhibited by GSK-3b phosphorylation. These events result in a shut-down of cellular protein synthesis and can lead to apoptosis.


description_brief: Regulation of eIF4e and p70 S6 Kinase
systematic_name: M4791
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_eif4Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  eIF-4F and p70 S6 kinase play critical roles in translational regulation. eIF-4F is a complex whose functions include the recognition of the mRNA 5' cap structure (eIF-4E), delivery of an RNA helicase to the 5' region (eIF-4A), bridging of the mRNA and the ribosome (eIF-4G), and circularization of the mRNA via interaction between eIF-4G and the poly(A) binding protein (PABP). Several stimuli, including growth factors and cytokines, regulate the eIF-4 complex and p70 S6 kinase by initiating a phosphorylation cascade involving the sequential activation of PI3-K, PDK1/2, Akt/PKB, and FRAP/mTOR kinase. FRAP/mTOR, together with an unidentified kinase, phosphorylates 4E-BP, leading to its dissociation from and activation of eIF-4E. MNK1/2, activated by ERK and p38 MAPK, phosphorylates and activates eIF-4E. Both processes contribute to the association of eIF-4E and eIF-4G to form the active eIF-4F complex, a necessary component of the 48S initiation complex. Phosphorylation of ribosomal protein S6 by p70 S6 kinase stimulates the translation of mRNAs with a 5' oligopyrimidine tract which typically encode components of the protein synthesis.


description_brief: Regulation of hematopoiesis by cytokines
systematic_name: M5298
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_stemPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The process of hematopoesis is regulated by various cytokines. The combination of cytokines stimulates the proliferation and/or differentiation of the various hematopoietic cell types. Bone marrow stromal cells are the major source of hematopoietic cytokines in the non-infecteous state. In the presence of infection, cytokines produced by activated macrophages and TH cells induce hematopoietic activity. The induction by cytokines results in rapid expansion of the population of white blood cells to fight infection. The specific cytokines that affect a step of cell differentiation are placed adjacent to the arrow representing that step. Lines with '?' indicate likely, but still hypothetical pathways.


description_brief: Regulation of p27 Phosphorylation during Cell Cycle Progression
systematic_name: M17977
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_p27Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  p27/Kip1 regulates the cell cycle by inhibiting the checkpoint kinase cdk2/cyclin E and blocking cell cycle progression through the G1-S transition. Cancer cells in some cases have reduced levels of p27, supporting the importance of p27 in cell cycle regulation. The activity of p27 is regulated by phosphorylation, synthesis and degradation. Phosphorylation of p27 at threonine-187 by cdk2 causes p27 to associate with an SCF complex that targets p27 for proteolytic degradation. The F box protein Skp2 binds specifically to threonine-187 phosphorylated p27, recruiting it to the SCF complex for degradation. Other components of the p27 ubiquitin ligase complex include Skp1, Cul1, and Roc1/Rbx-1. Cks-1 has also been identified in a reconstituted system as an essential component for recruitment of p27 for degradation by the SCF complex. Signaling by cytokines may modulate cell survival, proliferation, or apoptosis through modulation of p27 expression. Cytokine and AKT signaling pathways activate forkhead transcription factors that induce p27 expression at the transcriptional level.


description_brief: Regulation of PGC-1a
systematic_name: M15181
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_pgc1aPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a) is a tissue-specific coactivator that enhances the activity of many nuclear receptors and coordinates transcriptional programs important for energy metabolism and energy homeostasis. Inappropriate increases in PGC-1a activity have been linked to a number of pathological conditions including heart failure and diabetes. PGC-1a is highly expressed in metabolically active tissues including brown fat, skeletal muscle and heart. PGC-1a has been implicated in mitochondrial biogenesis in the heart and increased mitochondrial respiration in brown fat. PGC-1a is a coactivator for many factors including, CBP, Scr-1, PPARa, GR (glucocorticoid receptor), THR (thyroid hormone receptor), several orphan receptors and MEF2. This pathway illustrates two of the cofactor regulatory factors MEF2 and PPARa) and an example orphan receptor feedback inhibition loop. Glut4 is used as an example of the downstream elements leading to changes in metabolism. Ichida et al discovered the ERRa repression of PGC-1a. Their results suggest a novel mechanism of transcriptional control wherein ERR-a can function as a specific molecular repressor of PGC-1a. This suggests that other co-activators might also have specific repressors, adding another layer of combinatorial complexity in transcriptional regulation. Czubryt et al identified PGC-1 a as a key target of the MEF2/HDAC regulatory pathway and demonstrated this pathway's importance in maintenance of cardiac mitochondrial function. The linking of MEF2/HDAC provides an potential explanation for the increase in mitochondrial number observed in response to CaMK signaling.


description_brief: Regulation of transcriptional activity by PML
systematic_name: M4891
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_pmlPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The PML nuclear bodies are ring-shaped nuclear substructures associated with the regulation of transcription, transformation, cell growth, and apoptosis and are characterized by the presence of the protein PML. The activities of PML as a tumor suppressor and apoptosis inducing factor are exerted through the numerous proteins it interacts with in the PML-nuclear bodies including the tumor suppressor p53. DNA damage induced activation of p53-dependent apoptosis requires PML. PML acts as a coactivator for p53 and increases acetylation of p53 by the transcriptional coactivator CBP. This acetylation of p53 is reversed by the deacetylase SirT1, the human homolog of the yeast gene Sir2, and this deacetylation opposes the transcriptional activation of p53. The tumor suppressor Rb also interacts with the PML nuclear body, increasing transcriptional repression of genes involved in cell cycle progression, suggesting that PML may affect cellular transformation through more than one mechanism. PML interacts directly with Ubc9, which modifies PML through the attachment of the ubiquitin-like peptide Sumo-1. Sumo-1 modification of PML is not necessary for the nuclear bodies to form, but may affect the recruitment of proteins that interact with PML. PML is involved in non-p53 mediated apoptotic pathways, such as DAXX-mediated apoptosis induced by Fas and TNF and regulates the transcriptional repressor activity of Daxx. The sequestration of Daxx by the PML nuclear bodies relieves the repression of other transcription factors like Pax3 by Daxx. Tumor suppression by PML may in general involve the formation of specific regulatory transcription complexes, including those with DAXX, p53 and CBP. Factors that affect the assembly of PML into the PML nuclear bodies affect the proliferation and transformation of cells. Viral early proteins can interact with PML to disrupt the nuclear bodies, allowing increased proliferation of cells and reduced apoptosis, good conditions for DNA virus infection. Another factor that disrupts the formation of PML nuclear bodies is a translocation between the PML and RAR-alpha genes found in acute promyelocytic leukemia (APL) patients. Binding of retinoic acid to the RAR-alpha steroid hormone receptor activates transcription of retinoic-acid responsive genes. The translocation found in APL patients creates two chimeric proteins, RARalpha-PML and PML-RARalpha. Retinoic acid given to APL patients causes the reappearance of nuclear bodies, and the reversal of cellular transformation, effecting a cure for these patients.


description_brief: Repression of Pain Sensation by the Transcriptional Regulator DREAM
systematic_name: M18899
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_dreamPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The molecular events that lead to the perception of pain are a key research field in medicine and drug discovery. The opioid receptors modulate pain signaling in response to endogenous peptide ligands and opiate drugs such as morphine. The kappa opioid receptor plays a key role in the profound analgesia of opiates and is activated by the endogenous peptide ligand dynorphin, encoded by the prodynorphin gene. Production of prodynorphin is transcriptionally regulated by a downstream regulatory element (DRE) in the prodynorphin gene. A transcription factor called DREAM (DRE antagonistic modulator) binds to the DRE and represses prodynorphin transcription when bound. DREAM binds calcium with 4 EF-hand motifs and the binding of DREAM to DNA is repressed in the presence of calcium. Many transcription factors are regulated by calcium indirectly through calcium sensitive kinases and phosphatases, but DREAM is unique to date in being a transcription factor that directly binds calcium and is regulated by calcium binding. DREAM may also regulate other genes such as c-fos. DREAM is expressed in spinal cord neurons in regions involved in pain signaling. The regulation of prodynorphin expression by DREAM also leads to the hypothesis that DREAM is involved in pain signaling. Transgenic mice lacking the DREAM gene were unusually pain insensitive and had elevated spinal levels of dynorphin and tonic activation of the kappa opioid receptor, supporting this hypothesis. Other functions of DREAM may exist such as regulation of presenilins and potassium channel activity in the heart. DREAM is also known as calsenilin and KChIP3 through its association with these other proteins. These processes were not affected in mice lacking the DREAM gene however.


description_brief: Reversal of Insulin Resistance by Leptin
systematic_name: M18053
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_leptinPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The insulin resistance of type II diabetes appears to be caused in part by the presence of high levels of lipids in cells such as skeletal muscle where this would not normally be found. The presence of excess lipid stores in skeletal muscle cells interferes with energy metabolism, impairing glucose oxidation and insulin response. Skeletal muscle is one of the primary glucose-consuming tissues, giving it a central role in insulin resistance. The increased risk of diabetes associated with obesity may be caused by increased lipid deposits in skeletal muscle and liver, creating insulin resistance. Leptin is a peptide hormone secreted by adipose tissue that has been associated with many processes. One of the target tissues of leptin is the hypothalamus where it can act to regulate feeding behavior and metabolism. Another leptin target is skeletal muscle. Activation of leptin signaling in skeletal muscle activates the AMP-activated protein kinase (AMP-kinase), known to play a key role in signaling in response to nutrients throughout evolution. AMPK phosphorylates and inactivates the enzyme ACC, acetyl-CoA carboxylase. ACC catalyzes the production of malonyl-CoA from acetyl-CoA. Malonyl-CoA in turn is an inhibitor of the import of fatty acids into mitochondria by carnitine palmitoyl-transferase I for oxidation and energy production. In the presence of leptin, AMPK is activated, ACC is inhibited, and malonyl-CoA levels fall, increasing the oxidation of fatty acids and reducing the lipid content of cells. The reduced lipid content in skeletal muscle allows insulin signaling and glucose consumption to return to their normal levels, reducing insulin resistance.


description_brief: Rho cell motility signaling pathway
systematic_name: M1001
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_rhoPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  RhoA is a small G-protein in the Rho family that regulates cell morphology via actin cytoskeleton reorganization in response to extracellular signals. The majority of RhoA activations is due to disruption of intramolecular autoinhibitory interactions. Changes in cytoskeletal structure and other aspects of cell structure are involved in cell morphology. RhoA is activated by GEF factors, and repressed by GAPs. GEFs are guanine nucleotide exchange factors. GAPs are GTPase-activating proteins. The RhoGAP ARHGAP1 also acts as a GAP for Rac and CDC42. Active RhoA increases the stability of actin-based structures such as stress fibers and focal adhesions. Several different factors downstream of RhoA act on cytoskeletal structures to affect stability of these structures. Rock1 provides a direct link from RhoA to cell morphology through phosphorylation of the myosin light chain. Rock1 also phosphorylates and activates LIM kinase, which phosphorylates cofilin. Cofilin stimulates actin depolymerization and changes in cell structure, and phosphorylation of cofilin by LIM kinase represses this activity. According to Nimnual et al. Rho activity is reduced as a result of Rac-induced redox-dependent inhibition. Related Disease: Non-syndromic deafness appears to be the result of amino acid substitutions in the 52-amino acid C-terminal end of Dia 1. This modification creates a constituatively active Dia 1 protein. A mutation in the RhoGAP Oligophrenin-1 is thought to contribute to a form of mental retardation due to loss of Rho inhibition in neuronal development.


description_brief: Rho-Selective Guanine Exchange Factor AKAP13 Mediates Stress Fiber Formation
systematic_name: M17668
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_akap13Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The A-kinase anchor protein 13 (AKAP13, also known as AKAP-LBC) is one of a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. AKAP13 is a splice variant of the oncogene Lbc. Alternative splicing of the AKAP13 gene results in at least 3 transcript variants encoding different isoforms containing a Dbl oncogene homology (DH) domain and a pleckstrin homology (PH) domain. The DH domain is associated with guanine nucleotide exchange activation for the Rho/Rac family of small GTP binding proteins, resulting in the conversion of the inactive GTPase to the active form capable of transducing signals. The PH domain has multiple functions. These splice variants contain a fragment that was originally identified as Ht31 which acts as a scaffolding protein to regulate the Rho signaling pathway and as protein kinase A-anchoring protein creating a coordination of these two signalling pathways. Diviani et al. found that in HEK293 cells LPA induced stimulation preferentially activates AKAP13 via G-alpha12. As yet targets for the anchored PKA have not been identified. AKAP13 and Rho do not appear to be phosphorylated by PKA. Diviani et al also found that the Lbc oncogene and protooncogene splice variant show higher activation and stress fiber localization. This appears to be a result of the presence of N terminal inhibitory sequences. A similar model of regulation has been proposed for Dbl and Vav.


description_brief: Role of BRCA1, BRCA2 and ATR in Cancer Susceptibility
systematic_name: M9703
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_atrbrcaPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  BRCA1 and BRCA2 were identified genetically as breast cancer susceptibility genes when a single copy of the gene is mutated and are involved in the cellular response to DNA damage, including blocking cell cycle progression and inducing DNA repair to preserve the integrity of the genome during cell division. BRCA1 and BRCA2 induce double-stranded repair of breaks using homologous recombination, in part through activation of RAD51. BRCA1 acts as a ubiquitin ligase targeting the protein FancD2 that activates checkpoint control, integrating the ATM response to ionizing radiation and the FA response to cross-linking agents like mitomycin C. Mutation of one of the several components of the FA complex involved in maintaining integrity of the genome leads to the condition Fanconi anemia. One member of the FA complex was recently identified as BRCA2, which leads to Fanconi anemia when both copies of the gene are mutated. Another related factor involved in the response of cells to DNA damage is the kinase ATM. ATM is mutated in patients with AT, a condition with many similar traits to Fanconi anemia. Like ATM, ATR serves as a checkpoint kinase that halts cell cycle progression and induces DNA repair when DNA is damaged. Loss of ATR results in a loss of checkpoint control in response to DNA damage, leading to cell death, and deletion of the ATR gene in mice is embryonic lethal. ATRIP is a protein that interacts with ATR and is a substrate for its kinase activity. ATRIP is required for ATR function, and removal of ATRIP also leads to a loss of checkpoint control of the cell cycle. ATR and ATM kinase targets include repair enzymes like Rad51, and the checkpoint kinases Chk1 and Chk2, as well as BRCA1 and BRCA2. The close relationship of the genes involved in breast cancer and Fanconi anemia has helped illuminate this signaling system, and may help lead to improved understanding and treatment of these conditions.


description_brief: Role of EGF Receptor Transactivation by GPCRs in Cardiac Hypertrophy
systematic_name: M7552
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_cardiacEGFPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  One of responses to increased blood pressure is cardiac hypertrophy through increased size of ventricular myocardial cells leading to increased thickness of the ventricular walls. Cardiac hypertrophy allows the heart to handle the increased stress caused by elevated blood pressure but is also a risk factor associated with heart disease. Cardiac hypertrophy results from cross-talk between G-protein coupled receptor signaling and the EGF receptor pathway. Several GPCR ligands are known to stimulate cardiac hypertrophy, including factors that regulate blood pressure such as angiotensin II and endothelin- 1. These factors stimulate phospholipase C through Gq activation, and the production of 1P3 and diacylglycerol second messengers. PKC-delta is activated by DAG and interacts with the metalloproteinase ADAM12. ADAM12 cleaves the membrane-bound HB-EGF to release soluble EGF ligand that activates EGF receptor in myocardial cells. EGF receptor activation downstream through small G proteins and the MAP kinase pathway ultimately leads to cardiac hypertrophy. Signals by GPCR ligands such as angiotensin II result in transcriptional translation of immediate early genes like fos and other genes involved in long-term remodeling of heart tissue and the physiological response to stress in the heart such as the atrial natriuretic factor. Factors such as the AKT kinase, reactive oxygen species (ROS) and NE-kB also are involved in signaling that leads to hypertrophy, although their role is not yet clear. Blocking this pathway at various steps may prevent heart disease through the prevention of cardiac hypertrophy, but may also have other consequences.


description_brief: Role of ERBB2 in Signal Transduction and Oncology
systematic_name: M18719
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_her2Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Her2 or ERBB2 belongs to a class of proteins having high homology with epidermal growth factor receptor (EGFR or ERBB1). It encodes a protein with the molecular weight of 185 KDa. Unlike other members of EGFR family, no ligand for Her2 has been found and it usually associates with members of ERBB1 family to form functional heterodimers. It has been shown that it can form dimers with ERBB (EGFR), ERBB3 and ERBB4 as well as gp130 subunits of IL-6 receptor. In at least some cell types, the association between gp130 and HRBB2 is essential for HRBB2-ERBB3 phosphorylation and subsequent MAP kinase signaling. Although ERBB1 can form homodimers, the signaling for ERBB1 is usually transient and the receptor undergoes internalization after ligand binding and activation. EGFR-HER2 complex increases the signaling capacity of EGFR by increasing the ligand affinity as well as the recycling of the heterodimer. Of all the ERBB heterodimers, ERBB2-ERBB3 heterodimers perhaps elicit the strongest signal. Removing ERBB3 from the cell has a drastic effect on ERBB2 mediated signaling and downstream effectors. The clinical importance of HER2 cannot be overstated. In addition, monoclonal antibody (Herceptin) against this receptor has been shown to be an effective treatment of breast cancer patients who have a high level of HER2 over expression.


description_brief: Role of Erk5 in Neuronal Survival
systematic_name: M16811
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_erk5Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Axons extend significant distances to innervate target tissues. At the site of innervation, target tissues release neurotrophins including NGF, BDNF and neurotrophin-3 that stimulate the survival of the associated neuron. Local signaling by activated Trk receptors at the synaptic terminus mediates some presynaptic neuronal responses to neurotrophins. Map kinase pathways activated by Trk receptor activate Erk1 and Erk2 at the terminus stimulating axonal growth, and PI3K activates AKT in the terminus as well. Activation of these kinases does not propagate a signal to the cell body though and does not induce a transcriptional response. This local signaling at the terminus or local signaling at the cell body appears distinct from the signaling pathway that transduces the survival signal from the target tissue. Retrograde axonal transport plays an essential role in neuronal survival induced by neurotrophins released at the target tissue. Failure of retrograde neurotrophin signaling may play a role in neurodegenerative conditions. The neuronal survival signal is initiated by binding of neurotrophins to Trk receptors in the presynaptic membrane, then travels back along the axon to the neuronal cell body. To transmit the signal back along the axon, activated Trk receptors are internalized through receptor-mediated endocytosis and receptor containing vesicles then rapidly travel back to the cell body along axonal microtubules. Several reports indicate that neurotrophins remain receptor-bound during the retrograde axonal transport to the cell body, but recently it was reported that retrograde transport of NGF was not required to induce neuronal survival. Once in the cell body, Trk receptors activate multiple pathways. A key pathway activated by Trk after retrograde transport involves Erk5, also called BMK1. Trk activates Mek5, which activates Erk5, inducing phosphorylation of the CREB and Mef2 transcription factors. Erk5 does not directly phosphorylate CREB, but translocates into the nucleus and phosphorylates the kinase Rsk, which phosphorylates CREB in turn. Both CREB and Mef2 induce a transcriptional program that contributes to neuronal survival. Local activation of Erk5 on the cell body does not appear to induce the same signaling system or neuronal survival, indicating that the retrograde transport is an essential part of the survival signaling system. Also, activation of Erk1 and Erk2 in the cell body can induce CREB activation and neuronal survival, but these kinases are not activated by neurotrophins applied to the axonal terminus. Another pathway activated by retrograde neurotrophin signaling though Erk5 is PI3 Kinase.


description_brief: Role of MAL in Rho-Mediated Activation of SRF
systematic_name: M10547
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_malPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Serum response factor (SRF) is a transcription factor, which binds to a serum response element (SRE) associated with a variety of genes including (i)immediate early genes such as c-fos, fosB, junB, egr-1 and -2, (ii)neuronal genes such as nurr1 and nur77, and (iii)muscle genes such as actins and myosins. By regulating expression of these genes, SRF controls cell growth and differentiation, neuronal transmission as well as muscle development and function. SRF can be activated by serum, lysophosphatidic acid (LPA), lipopolysaccharide (LPS), 12-O-tetradecanoylphorbol-13-acetate (TPA), cytokines, tumor necrosis factor-alpha (TNFalpha), agents that increase intracellular Ca2+, T-cell virus1 activator protein, hepatitis B virus activator proteins pX, activated oncogenes and protooncogenes and extracellular stimuli such as antioxidant and UV light. In serum-starved cells, MAL is predominantly cytoplasmic where it is sequestered by actin monomers. Upon serum stimulation, Rho becomes active and, through its interaction with ROCK and mDia1, causes an accumulation of F-actin and a commensurate decrease in the level of G-actin. As a consequence, MAL is no longer sequestered and is free to translocate to the nucleus where it associates with SRF and activates SRE-mediated gene expression.


description_brief: Role of Mitochondria in Apoptotic Signaling
systematic_name: M16257
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_mitochondriaPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Mitochondria participate in apoptotic signaling pathways through the release of mitochondrial proteins into the cytoplasm. Cytochrome c, a key protein in electron transport, is released from mitochondria in response to apoptotic signals, and activates Apaf-1, a protease released from mitochondria. Activated Apaf-1 activates caspase-9 and the rest of the caspase pathway. Smac/DIABLO is released from mitochondria and inhibits IAP proteins that normally interact with caspase-9 to inhibit apoptosis. Apoptosis regulation by Bcl-2 family proteins occurs as family members form complexes that enter the mitochondrial membrane, regulating the release of cytochrome c and other proteins. TNF family receptor that cause apoptosis directly activate the caspase cascade, but can also activate Bid, a Bcl-2 family member, which activates mitochondria-mediated apoptosis. Bax, another Bcl-2 family member, is activated by this pathway to localize to the mitochondrial membrane and increase its permeability, releasing cytochre c and other mitochondrial proteins. Bcl-2 and Bcl-xL prevent pore formation, blocking apoptosis. AIF (Apoptosis inducing factor) is another mitochondrial factor that is released into the cytoplasm to induce apoptosis. AIF-induced apoptosis is important during development but is not caspase dependent.


description_brief: Role of nicotinic acetylcholine receptors in the regulation of apoptosis
systematic_name: M16884
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_achPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Nicotinic acetylcholine receptors are essential for neuromuscular signaling and are also expressed in non-neuronal tissues, where their function is less clear. Although nicotinic acetylcholine receptors are primarily known for their action as ligand-gated ion channels transducing action potentials across synapses, they may have other actions. Nicotinic acetylcholine receptors in neurons alter apoptotic signaling, protecting against cell death in some settings, and this action may in some cases be directed through alternative signaling pathways. In neurons the alpha-7 nicotinic receptor activates PI3 kinase through a src-family kinase, activating the anti-apoptotic kinase AKT. One pathway involved in AKT signaling involves phosphorylation of the forkhead transcription factor FKHRL1, causing its retention in the cytoplasm associated with 14-3-3, and blocking expression of the apoptotic fas protein. The PI3 kinase/AKT pathway protects a broad range of neurons against apoptotic cell death and may block apoptosis triggered by beta-amyloid fragments that contributes to the progression of Alzheimers disease. If so, nicotinic agents may prove useful in the treatment of this and other neurodegenerative conditions. There are several proteins that modulate the response of nicotinic acetylcholine receptors, include synapse formation. Prior to synapse formation, nicotinic receptors are randomly dispersed in the post-synaptic membrane. A neuronal protein, agrin, binds to the Musk receptor in the muscle membrane, stimulating clustering of nicotinic receptors and synapse formation. Rapsyn is present at high levels at synapses with nicotinic receptors, bringing them together at high densities and anchoring clustered receptors to the cytoskeleton. Members of the Src family of tyrosine kinases also play a role in clustering caused by Rapsyn, phosphorylating the nicotinic receptors, rapsyn, and other targets. Nicotinic receptors expressed in non-neuronal tissues may also be involved in the response to smoking. In lung epithelial cells, nicotine from cigarette smoke blocks apoptosis by activating the anti-apoptotic kinase AKT, contributing perhaps to carcinogenesis and resistance to chemotherapy. Activation of nicotinic acetylcholine receptors in dermal fibroblasts may contribute to the altered wound healing and skin elasticity related to smoking. Activation of keratinocyte nicotinic receptors may also alter the properties of skin.


description_brief: Role of Parkin in the Ubiquitin-Proteasomal Pathway
systematic_name: M13917
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_parkinPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The motor defects of Parkinson's disease are related to the loss of dopaminergic neurons in specific brain regions. Examination of these neurons in diseased tissue has revealed the presence of Lewy bodies, dense aggregates that include the protein alpha-synuclein. A genetic basis for most cases of Parkinson's disease has not yet been identified, but mutations in alpha-synuclein have been associated with at least one rare form of the disease, and mutations in another protein, the parkin gene, are associated with another inherited form of Parkinson's disease. Parkin is found in Lewy bodies along with alpha-synuclein and the parkin protein is an E3 ubiquitin ligase. Parkin appears to work in conjuction with ubiquitin activating (Uba)1, an E1 protein and the ubiquitin-conjugating (Ubc) enzymes UbcH7 and 8. The E1 delivers ubiquitin to the E2 in a cycle that creates an increasing chain of ubiquitin. The Parkin E3 ligates this onto substrates and so tags these proteins in normal cells, targeting them for destruction in the proteosome. One of the proteins that parkin normally targets for destruction is a specific O-glycosylated form of alpha-synuclein. Failure of parkin-mediated degradation of alpha-synuclein may be a key factor leading to the death of dopaminergic neurons. Another substrate of parkin is a GPCR-like protein called Pael-R that accumulates in the ER of affected cells and may cause neuronal cell death. The involvement of Parkin and alpha-synuclein mutations in genetic forms of Parkinson's suggest that failure of ubiquitination and protein degradation may be causative in other forms of Parkinson's. Questions remaining include the cause of the lack of effective ubiquitination in individuals lacking obvious genetic defects in this pathway and how to use this knowledge of ubiquitination and protein degradation in Parkinson's disease to identify therapeutic strategies.


description_brief: Role of PI3K subunit p85 in regulation of Actin Organization and Cell Migration
systematic_name: M5291
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_cdc42racPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Migration of cells is involved in essential functions such as development, invasiveness of cancer cells, leukocyte movement toward chemotactic signals, and fibroblast response to injury. Cells can migrate in a specific direction in response to extracellular signals through pathways that trigger changes in the cytoskeleton, particularly actin filaments, increasing lamellipodia and filopodia formation and decreasing focal adhesions. Factors like PDGF activate PI3 kinase and multiple pathways downstream to stimulate cell migration. One pathway regulating migration through the p85 regulatory subunit of PI3 kinase does not require PI3-kinase activity. In this pathway, p85 of PI3-kinase activates cdc42, which activates N-Wasp (Wiskott-Aldrich Syndrome Protein) to regulate ARP-2/3. ARP-2/3 is a complex of proteins localized at the leading edge of moving cells that nucleates the formation of new actin fibers and interacts with Wasp to stimulate migration. The cdc42 pathway also regulates p21-activate kinase 1 (PAK1). Another pathway by which PI3 kinase regulates migration is through the small GTPase Rac. PAK1 is a downstream target of Rac as well as cdc42. Downstream of Rac and PAK1, Myosin light chain kinase (MLCK) phosphorylates myosin light chain to increase cell migration. The regulation of the localization and activity of signaling factors creates coordinated pathways linking extracellular signals and cellular migration.


description_brief: Role of b-arrestins in the activation and targeting of MAP kinases
systematic_name: M668
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_bArr-mapkPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The binding of -arrestins to agonist-occupied GPCRs triggers the assembly of a MAP kinase activation complex using -arrestin as a scaffold, with subsequent activation of a -arrestin-bound pool of ERK1/2. The receptor-arrestinERK complexes are localized to endosomal vesicles, and their formation does not result in nuclear translocation of activated ERK1/2 or stimulation of cell proliferation. The function of -arrestin-bound ERK1/2 is presently unknown. Activation of ERK1/2 by -arrestin scaffolds may favor the phosphorylation of plasma membrane, cytosolic, or cytoskeletal ERK1/2 substrates, or it may lead to transcriptional activation through the ERK-dependent activation of other kinases. The model depicts -arrestin scaffolding of the ERK1/2 MAP kinase cascade, based upon data obtained with the protease-activated PAR2 and angiotensin AT1a receptors. A similar mechanism has been proposed for regulation of the JNK3 MAP kinase cascade by AT1a receptors.


description_brief: Role of Tob in T-cell activation
systematic_name: M18215
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_tob1Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Regulation of T cell activation is a crucial component of balanced functioning of the immune system. If the T cell response is too great and activation of self-responsive cells or unstimulated cells is not suppressed, then autoimmune disorders or tissue injury can result. Unstimulated T cells are maintained in a quiescent state and the activity of self-reactive T cells is maintained in an anergic state in which IL-2 expression is repressed. IL-2 is a cytokine with a key role in the activation and proliferation of T cells. The maintenance of T cells in the anergic or unstimulated state may not involve just an absence of activation, but an active repression of IL-2 expression, T cell proliferation and activation. TGF beta may play a role in suppressing T cell activation. Tob is a factor identified recently that represses T cell activation that is a member of a family of genes with anti-proliferative properties. Tob expression is highest in unstimulated and anergic T cells, and is reduced in activated T cells. Tob interacts with the TGF activated transcription factors SMAD2 and SMAD4, increasing their binding to the IL-2 promoter, and helping to repress IL-2 expression. This role of Tob suggests that interference in Tobs function may lead to autoimmune disease.


description_brief: Roles of b-arrestin-dependent Recruitment of Src Kinases in GPCR Signaling
systematic_name: M111
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_bArrestin-srcPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The binding of -arrestins to agonist-occupied GPCRs coincides with the recruitment of Src family tyrosine kinases, including c-Src, Hck and c-Fgr (Src-TK), to the receptor-arrestin complex. Several signaling events have been reported to involve -arrestin-dependent Src recruitment. These include the regulation of clathrin-dependent 2-adrenergic receptor endocytosis by tyrosine phosphorylation of dynamin, Ras-dependent activation of the ERK1/2 MAP kinase cascade and stimulation of cell proliferation by 2-adrenergic and neurokinin NK1 receptors, and stimulation of chemokine CXCR1 receptor-mediated neutrophil degranulation


description_brief: Selective expression of chemokine receptors during T-cell polarization
systematic_name: M4047
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_nktPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Chemokine receptors expressed by T helper cells help recruit cells to specific locations based on their chemoattractant ligands. The polarization of T cells into Th1 and Th2 cells is associated with their expression of different subsets of chemokine receptors. Naive CD4 positive cells that have not been exposed to antigen express CXCR4 and CCR7. The most abundant chemokine receptors on Th1 cells involved in the cellular immune response to microbial agents include CXCR3, CCR1, CCR2 and CCR5, while Th2 cells express CCR2, CCR3 and CCR5. An additional class of T cells termed semi-nave cells may be induced by TGF-beta to express yet another class of chemokine receptors, CCR4 and CCR7. Although the expression of chemokine receptors in different cells is preferred in these cases, it is not absolute or exclusive, and there is overlap in expression between Th1 and Th2 cells. Although CCR7 positive cells have been reported to lack effector action, not be polarized, and to home only to lymphoid tissues, other studies have found CCR7 positive Th1 and Th2 cells and have identified CCR7 positive cells in non-lymphoid tissues. CCR4 appears associated with homing of lymphocytes to the skin, and CCR9 is associated with homing to the small intestine, while other chemokines like CXCR3 and CCR5 are associated with homing toward inflamed tissues more broadly. The expression of different chemokine receptors by subsets of T helper cells plays an important role in the migration and homing of these cells in tissues, and targeting of the immune response to specific cells.


description_brief: Signal transduction through IL1R
systematic_name: M12095
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_il1rPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Interleukin-1 (IL-1) is a pro-inflammatory cytokine that signals primarily through the type 1 IL-1 receptor (IL-1R1). The activities of IL-1 include induction of fever, expression of vascular adhesion molecules, and roles in arthritis and septic shock. The inflammatory activities of IL-1 are partially derived by transcriptionally inducing expression of cytokines such as TNF-alpha and interferons, as well as inducing the expression of other inflammation-related genes. There are two forms of IL-1 encoded by distinct genes, IL-1 alpha and IL-1 beta. IL-1 beta is produced as a 269 amino acid precursor that is cleaved by IL-1beta converting enzyme (ICE) to the active IL-1 beta form that is secreted. IL-1 signaling is opposed by the naturally occurring peptide IL-1 receptor antagonist which is a therapeutic agent for the treatment of arthritis. The type 1 IL-1 receptor protein binds IL-1 beta but requires the IL-1 receptor accessory protein (IL-1RAcP) to transduce a signal. IL-1 binding causes activation of two kinases, IRAK-1 and IRAK-2, associated with the IL-1 receptor complex. IRAK-1 (IL-1 Receptor Associated Kinase) activates and recruits TRAF6 to the IL-1 receptor complex. TRAF6 activates two pathways, one leading to NF-kB activation and another leading to c-jun activation. The TRAF associated protein ECSIT leads to c-Jun activation through the Map kinase/JNK signaling system. TRAF6 also signals through the TAB1/TAK1 kinases to trigger the degradation of I-kB, and activation of NF-kB. The IL-1 signaling cascade represents a highly conserved response to pathogens through evolution, with homologs in insects and even in plants. The signal transduction cascade utilized by IL-1 receptor is similar to that of TNF, resulting in NF-kB activation, and is most similar to that of the Toll-like receptors that also participate in inflammatory signaling responses to pathogen components like endotoxin.


description_brief: Signaling of Hepatocyte Growth Factor Receptor
systematic_name: M19358
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_metPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The hepatocyte growth factor receptor, also called c-Met, is activated by HGF and stimulates proliferation of hepatocytes and other cell types. Mutated forms of the HGF receptor are associated with oncogenesis and metastasis, making the HGF receptor a potential therapeutic target for cancer drugs. Changes in cell motility, cell shape, adhesion, resistance to apoptosis, and anchorage independent growth all contribute to the role of c-Met in cancer. The HGF receptor is a heterodimer with tyrosine kinase activity and associates with a multiprotein complex involved in downstream signal transduction. The HGF receptor can associate with several different signaling systems, including src, Grb2/SOS, PI3 kinase and Gab1. One of the major substrates of the activated HGF receptor tyrosine kinase is the adaptor protein Gab1. Gab1 interacts with Crk and CrkL, two proteins with SH2 and SH3 protein interaction domains that couple to signaling further downstream. The actions of HGF on paxillin, DOCK180 and Rap1 mediated through GAB1 and other members of this complex alter cell motility. Regulation of Rho, Rac1 and CDC42 pathways in response to HGF all contribute to changes in cellular motility. Another target of the HGF receptor kinase is the focal adhesion kinase, FAK. The activation of FAK induces the formation of focal adhesions, a preliminary step to increased cell motility and tissue invasion by transformed cells, and paxillin phosphorylation may also alter cell adhesion of Met transformed cells. Src and p130cas are required for the role of FAK in HGF induced cellular transformation. HGF also blocks anoikis, the induction of apoptosis through suspension of cells, by acting on Erk and AKT kinases. This activity may contribute to anchorage independent growth of Met transformed cells. Signaling by integrins also plays a key role in the activation of tissue invasive growth by HGF. The alpha6beta4 integrin acts as a cofactor along with Meta to participate in cell growth and proliferation. In addition to altering cell adhesion, proliferation and cell motility, HGF alters cellular transcription through activation of STAT3. STAT3 activation by HGF is independent of PI3 kinase or map kinases and alters gene expression leading to changes in cellular shape. Although HGF is associated with cellular proliferation and survival, in rat liver epithelial cells HGF induces apoptosis and inhibits cell growth.


description_brief: Signaling Pathway from G-Protein Families
systematic_name: M9664
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_gpcrPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  G-aS-coupled receptors stimulate adenylyl cyclase (AC), which synthesizes cAMP from ATP. In contrast Gai-coupled receptors inhibit AC and so reduce cAMP formation. The bg subunits from Gai and other G proteins are able to activate the MAP kinase pathways and PLCb. GPCRs coupled to the Gaq family of G proteins stimulate PLCb, which cleaves membrane phospholipids to produce IP3, which mobilizes intracellular calcium, and DAG, which activates PKC. Second messenger pathways then activate a range of effector systems to change cell behaviour; in many cases this includes the regulation of gene transcription. Dotted line shows a more indirect pathway.


description_brief: Skeletal muscle hypertrophy is regulated via AKT/mTOR pathway
systematic_name: M16991
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_igf1mtorPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Skeletal muscle atrophies with disuse while with increased use and increased load skeletal muscle exhibits hypertrophy, with an increase in the size of existing muscle fibers. One signaling pathway involved in regulating skeletal muscle atrophy and hypertrophy is the AKT/mTOR pathway. The mTOR pathway activity increases in response to muscle activity during hypertrophy and decreases in activity during atrophy. Blocking this pathway genetically or with the mTOR inhibitor rapamycin blocks hypertrophy and genetic activation of the pathway induces hypertrophy. One agent that promotes muscle hypertrophy is the growth factor IGF-1. IGF-1 activates AKT, GSK-3beta and mTOR to promote hypertrophy. In contrast, the calcineurin pathway is not involved in hypertrophy and is down-regulated by agents such as IGF-1 that promote hypertrophy. Calcineurin may modulate other aspects of muscle function such as the development of slow muscle fibers through transcriptional regulation. These pathways lead to regulation of protein translation, with increased translation apparently acting as a key regulatory point in skeletal muscle hypertrophy. Agents such as IGF-1 that stimulate skeletal muscle hypertrophy may provide treatments for muscle atrophy and wasting.


description_brief: SODD/TNFR1 Signaling Pathway
systematic_name: M2699
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_soddPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The tumor necrosis factor (TNF) receptor superfamily contains several members with homologous cytoplasmic domains known as death domains (DD). The intracellular DD are important in initiating apoptosis and other signaling pathways following ligand binding by the receptors.1 In the absence of ligand, DD-containing receptors are maintained in an inactive state. TNF RI contains a cytoplasmic DD required for signaling pathways associated with apoptosis and NF-kB activation.2,3 Jiang et al.4 identified a widely expressed 60 kDa protein, named SODD (silencer of death domains), associated with the DD of TNF RI and DR3. Overexpression of SODD suppresses TNF-induced cell death and NF-kB activation demonstrating its role as a negative regulatory protein for these signaling pathways. TNF-induced receptor trimerization aggregates the DD of TNF RI and recruits the adapter protein TRADD.3,5 This in turn promotes the recruitment of the DD-containing cytoplasmic proteins FADD, TRAF2 and RIP to form an active TNF RI signaling complex (Figure 1A).6-9 In contrast, SODD acts as a silencer of TNF RI signaling and does not interact with TRADD, FADD, or RIP (Figure 1B).4 It is associated with the DD of TNF RI and maintains TNF RI in an inactive, monomeric state. TNF-induced aggregation of TNF RI promotes the disruption of the SODD-TNF RI complex. SODD does not interact with the DD of other TNF receptor superfamily members such as Fas, DR4, DR5, or TNF RII. SODD association with TNF RI may represent a general model for the prevention of spontaneous TNF signaling by other DD-containing receptors.


description_brief: Sonic Hedgehog (Shh) Pathway
systematic_name: M11792
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_shhPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Sonic Hedgehog (Shh) is one of a family of three secreted proteins, including Indian Hedgehog (Ihh) and Desert Hedgehog (Dhh), that play distinct and crucial roles in development. The morphogenic signal Shh provides in the developing CNS induces proliferation of neuronal precursor cells in the developing cerebellum and other tissues. Proliferative signaling by Shh is involved in the development of cancer, including specific brain and skin cancers such as basal cell carcinomas, while activation of Shh signaling in neurons may also provide a means to induce neuronal regeneration. Mitogenic Shh signaling does not appear to involve Map kinase pathways, but may involve induction of Cyclin D1 expression to maintain Rb in the hyperphosphorylated state and allow progression through the G1 phase of the cell cycle. Activation of myc may be one mechanism by which Shh induces cell cycle progression. Activation of Shh proliferative signaling occurs through binding to a receptor complex including Patched (Ptc-1) and Smoothened, a G-protein coupled receptor. Patched is an integral membrane protein with twelve transmembrane domains that acts as an inhibitor of Smoothened activation. Patched has been classified as a tumor suppressor due to its inhibition of Smoothened and the presence of inactivated Ptc-1 mutations in some cancers. One possibility is that Ptc-1, which resembles transmembrane channels, may not directly associate with Smoothened but may repress Smoothened signaling by transporting an endogenous Smoothened inhibitor across the plasma membrane into the cytoplasm. Small non-peptidic agonists and antagonists of the Shh pathway have been identified and appear to act at the level of the Smoothened receptor, providing pharmacological tools to study Shh signaling. The pathway downstream of the Smoothened receptor has remained somewhat unclear, but involves the Gli family of transcriptional activators, including Gli-1, Gli-2, and Gli-3, homologs of the drosophila gene cubitis interruptis. Kinases including GSK-3 and PKA oppose activation of the Shh pathway, perhaps by regulating the stability of Shh pathway intermediate signaling factors transcription factors. Supressor of Fused (SUFU) interacts directly with Gli proteins, repressing Shh signaling while Dyrk1 is a kinase that acts by a distinct pathway to stimulate Gli1 activation of transcription. The multiplicity of factors involved in Shh signaling creates many opportunities for therapeutic intervention in the treatment of cancer and possibly neurodegenerative diseases.


description_brief: Sonic Hedgehog (SHH) Receptor Ptc1 Regulates cell cycle
systematic_name: M13022
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_ptc1Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Sonic Hedgehog (Shh) is a secreted protein identified genetically as an important developmental factor. Shh provides a morphogenic signal in the developing CNS, organizing the spatial patterning of cells in the midbrain and inducing proliferation of neuronal precursor cells in the developing cerebellum, neural tube and retina. Proliferative signaling by Shh is involved in the development of cancer, including specific brain and skin cancers such as basal cell carcinomas. Sonic hedgehog signaling may proceed by more than one mechanism. One signaling pathway is activated by Shh binding to Patched (Ptc-1) which releases inhibition of the GPCR Smoothened, activating the Shh signaling pathway and allowing progression through the G1 phase of the cell cycle. Shh can also affect progression through the G2/M transition. Patched binds to phosphorylated Cyclin B1, one component of the M-phase promoting factor (MPF), along with the kinase Cdc2. The interaction of Cyclin B1 with Patched blocks MPF activity, blocking progression through the G2/M transition. Shh binding leads to degradation of Ptc-1, release of Cyclin B1, and entry of the cyclin B1 into the nucleus. Patched acts as a tumor suppressor by blocking MPF activity. Blockade of the Hedgehog pathway by cyclopamine demonstrated the therapeutic potential of Hedgehog inhibition in the treatment of some cancers.


description_brief: Sprouty regulation of tyrosine kinase signals
systematic_name: M1389
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_spryPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Four different members of the Sprouty protein family block the cellular proliferation and differentiation induced by several different growth factors, including EGF and FGF. One mechanism by which Sprouty proteins inhibit signaling is through binding to Grb-2, a signaling intermediary between the tyrosine kinase growth factors and the Ras/map kinase pathway. Binding of Sprouty to Grb-2 prevents Grb-2 and Sos-1 from interacting with downstream signaling factors that activate Ras and map kinases, including Ras, Raf-1, Mek1, Erk1/2 and downstream transcription factors. The action of Sprouty as an inhibitor of this pathway requires Sprouty phosphorylation and membrane localization, at the site of the factors it interacts with. The inhibition of growth factor signaling by Sprouty is specific to the Ras pathway since the PI3 Kinase pathway responsible for cell survival signals from growth factor receptors is not inhibited by Sprouty. Tyrosine kinase activity of growth factor receptors is also not affected. The mechanism by which Sprouty inhibits Ras activation may be by blocking the nucleotide exchange activity of Sos. Sprouty expression is induced by growth factor receptor activation of Ras signaling, provided a self-regulatory feedback inhibition mechanism that regulates growth factor signaling through Ras. In addition to blocking the Ras pathway, Sprouty also induces protein tyrosine phosphatase 1B activity. Activation of PTP1B by Sprouty is responsible for the inhibition of cellular migration that Sprouty causes, but is not involved in regulation of cellular proliferation. While blocking receptor tyrosine kinase signaling, at least one member of the Sprouty family, Sprouty-2, also acts by one mechanism to stimulate EGF receptor signaling. Cbl targets the EGF receptor for tagging with ubiquitin and proteolytic destruction. Sprouty-2 binds to Cbl and blocks the ubiquitination and destruction of the EGF receptor, increasing EGF signaling.


description_brief: b-arrestins in GPCR Desensitization
systematic_name: M7772
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_bArrestinPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Role of -arrestins in the desensitization, sequestration and intracellular trafficking of GPCRs. Homologous desensitization of GPCRs (1) results from the binding of -arrestins (-arr) to agonist -occupied receptors following phosphorylation of the receptor by GRKs. -arrestin binding sterically precludes coupling between the receptor and heterotrimeric G proteins, leading to termination of signaling by G proteins effectors. Receptor-bound -arrestins also act as adapter proteins, binding to components of the clathrin endocytic machinery including clathrin, 2-adaptin (AP-2). Receptor sequestration (2) reflects the dynamin (Dyn)-dependent endocytosis of GPCRs via clathrin-coated pits. Once internalized, GPCRs exhibit two distinct patterns of -arrestin interaction. `Class A' GPCRs, for example the 2 adrenergic receptor, rapidly dissociate from -arrestin upon internalization. These receptors are trafficked to an acidified endosomal compartment, wherein the ligand is dissociated and the receptor dephosphorylated by a GPCR-specific protein phosphatase PP2A isoform, and are subsequently recycled to the plasma membrane (3). `Class B' receptors, for example the angiotensin II AT1a receptor, form stable receptor--arrestin complexes. These receptors accumulate in endocytic vesicles and are either targeted for degradation or slowly recycled to the membrane via as yet poorly defined routes.


description_brief: Stathmin and breast cancer resistance to antimicrotubule agents
systematic_name: M16966
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_stathminPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Stathmin is a ubiquitous, cytosolic 19-kDa protein, which is phosphorylated on up to four sites in response to many regulatory signals within cells. Its molecular characterization indicates a functional organization including an N-terminal regulatory domain that bears the phosphorylation sites, linked to a putative alpha-helical binding domain predicted to participate in coiled-coil, protein-protein interactions. In addtion to the protein kinases that phospjhorylate Stathmin such as CaMK, MAPK, p34cdc2, PKA, a few other proteins have been suggested to interact with stathmin in vivo. One of them was identified as BiP, a member of the hsp70 heat-shock protein family. Another is a previously unidentified, putative serine/threonine kinase, KIS, which might be regulated by stathmin or, more likely, be part of the kinases controlling its phosphorylation state. Finally, two proteins, CC1 and CC2, predicted to form alpha-helices participating in coiled-coil interacting structures. It has been also suggest that the action of antimicrotubule drugs can be affected by stathmin in at least two ways: (a) altered drug binding; and (b) growth arrest at the G2 to M boundary. Mutant p53 breast cancers exhibiting high levels of stathmin may be resistant to antimicrotubule agents.


description_brief: Stress Induction of HSP Regulation
systematic_name: M2587
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_hsp27Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Mammalian cells can respond to a variety of stresses such as heat, cold, oxidative stress, metabolic disturbance, and environmental toxins through necrotic or apoptotic cell death, while increased expression and phosphorylation of heat shock proteins such as Hsp27 can protect cells against cellular stress. Heat shock proteins commonly exhibit molecular chaperone activity and also interact with a wide variety of proteins to exert specific effects. The small heat shock protein Hsp27 exists as monomers, dimers, and oligomers in the cell, and each form has distinct activities. Oligomers are the main form of Hsp27 with molecular chaperone activity and are disrupted by phosphorylation of Hsp27 to form dimers and monomers. S-thiolation of Hsp27 on cysteine also dissociates oligomers and may provide another route of regulating the action of Hsp27 in stress. Map kinase cascades mediate Hsp27 phosphorylation. Heat stress activates the p38 kinase cascade and induces phosphorylation of Hsp27 by the downstream Map kinases Mapkapk2 and Mapkap3. Cytokines such as TNF and IL-1 can also induce Hsp27 phoshorylation through this Map kinase cascade, protecting cells in some settings against cytotoxic responses. In stressful conditions, dissociation of oligomeric Hsp27 by phosphorylation may allow lower molecular weight forms to perform other non-chaperone functions. One action of Hsp27 induced by stress is to protect cells against apoptosis and a common component of apoptotic pathways is the mitochondrial release of cytochrome c. One way that Hsp27 reduces apoptosis is by preventing the release of cytochrome c and by binding to cytochrome c in the cytosol. Downstream, Hsp27 also blocks caspase 9 activation and the subsequent activation of caspase 3, inhibiting the rest of the proteolytic caspase cascade. Yet a further role of Hsp27 in blocking apoptosis is through blocking Fas-induced apoptosis. Fas is a receptor in the TNF receptor gene family that induces apoptosis when stimulated by its cell-bound ligand, Fas-ligand. Fas induces apoptosis through two pathways, one mediated by the protein Daxx. Phosphorylated Hsp27 dimers block apoptosis by binding with Daxx and preventing downstream activation of the kinase Ask1. The interaction of Hsp27 with actin filaments may also prevent apoptosis triggered by some agents like staurosporine that damage actin. Unphosphorylated Hsp27 monomers regulate actin filament growth by binding to the end of fibers and capping them. Finally, Hsp27 appears to prevent damage to cells by reactive oxygen species (ROS), by altering the oxidative environment of the cell through induction of glutathione expression, as well as blocking apoptosis induced by ROS. Modulation of Hsp27 expression and phosphorylation may provide a useful means to alter cellular sensitivity to stress.


description_brief: T Cell Receptor Signaling Pathway
systematic_name: M19784
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_tcrPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The T Cell Receptor plays a key role in the immune system. The specificity of the receptor is governed by the binding site formed from the mature alpha and beta chains (shown here) or gamma and delta chains in gamma/delta T Cells. It is the ability of this receptor to bind a complex of foreign peptide in the groove of an MHC molecule that leads to T cell activation. Upon activation the T cell can assist in activating other cells or carry out cytolytic attacks depending on the particular T cell type. The CD3 complex and CD4 (Th cells) or CD8 (Tc cells) work to transmit the activation signal to the T cell's transcriptional machinary upon engagement of the receptor.


description_brief: T Cytotoxic Cell Surface Molecules
systematic_name: M13247
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_tcytotoxicPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Cytotoxic T cells are a key part of the cellular immune response, killing cells that display foreign antigen on their surface, primarily virus-infected cells. Transformed cells can also be detected and eliminated by cytotoxic T cells. There are two mechanisms by which activated cytotoxic T cells kill cells presenting specific antigen. One method involves the release of secretory granules containing perforin and granzyme to induce lysis of the targeted cell. Cytotoxic T cells also express Fas ligand to bind to Fas on target cells and induce apoptosis. Communication with and interaction with other cell types is essential for cytotoxic T cell function. Distinct types of T cells are characterized and their activities determined by the proteins they express on their cell surface. Cytotoxic T cells will only respond to antigen presented on the surface of cells bound to MHC I proteins, not antigens present in solution. The T cell receptor, with the multiprotein CD3 complex, is responsible for the recognition of specific antigens, triggering the activation and proliferation of cells. Cytotoxic T cell activation also requires additional signals provided by helper T cells in addition to signals provided by antigen-presenting cells. Thy1 provides a general marker of T cells, and the presence of CD8 protein that binds to MHC distinguishes cytotoxic T cells from CD4 positive helper T cells. CD28 expressed by T cells acts as a costimulatory signal with the T cell receptor when it binds its ligand, a B-7 coreceptor, on antigen-presenting cells. Inappropriate regulation of the costimulatory signal can lead to too great or too small of an immune response. Interaction of activated cytotoxic T cells is aided by increased expression of LFA-1, a cell-adhesion molecule that binds to ICAM on target cells. CD2 is a T cell adhesion molecule. Mice with a disrupted CD2 gene are largely normal and appear to have a normal immune system, but CD2 on cytotoxic T cells may assist in interaction with target cells.


description_brief: T Helper Cell Surface Molecules
systematic_name: M6427
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_thelperPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  T helper cells play an essential role coordinating the activities of other parts of the immune system, including B cells, cytotoxic T cells, macrophages and other cells. The crucial nature of helper T cells in the normal immune response is demonstrated by the severe immune deficiency associated with the HIV-induced helper T cell depletion. To communicate with other cells, helper T cells express a range of cell surface molecules, a few of which are illustrated in this figure. Like all T cells, helper T cells express T cell receptors complexed with the CD3 proteins that are responsible for the recognition and response of the cell to specific antigens. CD4 is commonly used as a marker for helper T cells, in contrast to cytotoxic T cells, which express CD8. CD4 is used by HIV to gain cell entry, as well as the CCR5 chemokine receptor. Thy1 provides a more general cell surface antigen used to identify both T helper and cytotoxic T cells. CD28 provides a costimulatory signal in association with the activation of the T cell receptor complex by an antigen presenting cell that is required for the T cell to become activated. Adhesion molecules on the surface of T cells assist in their interaction with other cells. LFA-1 binds to its ligand ICAM-1 in a variety of cells and T cells themselves also express ICAM-1. The CD45 protein tyrosine phosphatase dephosphorylates factors in the pathways involved in B cells and T cells activation. Although CD45 is required for T cell receptor activation, exclusion of CD45 from the local membrane region near the T cell receptor appears important for efficient T cell activation. Helper T cells can be subdivided further into Th1 and Th2 cells, distinguished by their response to different antigens, differing cytokine expression and expression of different chemokine receptors CD2 is required for efficient helper T cell maturation and stimulates their differentiation, but does not select for a specific increase in Th1 or Th2 populations of cells.


description_brief: TACI and BCMA stimulation of B cell immune responses.
systematic_name: M12985
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_tall1Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  TACI and BCMA signal transduction pathway that enhances cell survival APRIL and BAFF (also called TALL-I and BLyS) are TNF family members that act as ligands for the BCMA and TACI receptors. Both APRIL and BAFF bind to both the BCMA and TACI receptors to activate the humoral immune response, stimulating B cell immunoglobulin production and proliferation. BAFF is found as a membrane bound form in T cells and a soluble form that is released from the cell to stimulate B cell proliferation and differentiation. As members of the TNF receptor gene family, BCMA and TACI interact with TRAF family members to transduce signals downstream to NF-kappaB activation and MAP kinase pathways. Abnormally active BAFF or APRIL signaling may play a role in autoimmune disorders such as lupus.


description_brief: TGF beta signaling pathway
systematic_name: M18933
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_tgfbPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  TGF-beta regulates growth and proliferation of cells, blocking growth of many cell types. The TGF-beta receptor includes type 1 and type 2 subunits that are serine-threonine kinases and that signal through the SMAD family of transcriptional regulators. Defects in TGF-beta signaling, includes mutation in SMADs, have been associated with cancer in humans. Prior to activation, receptor regulated SMADs are anchored to the cell membrane by factors like SARA (SMAD Anchor for Receptor Activation) that brings the SMADs into proximity of the TGF receptor kinases. Binding of TGF induces phosphorylation and activation of the TGF-beta R1 receptor by the TGF-beta R2 receptor. The activated TGF-beta R1 phosphorylates SMAD2 and SMAD3, which bind to the SMAD4 mediator to move into the nucleus and form complexes that regulate transcription. SMADs regulate transcription in several ways, including binding to DNA, interacting with other transcription factors, and interacting with transcription corepressors and coactivators like p300 and CBP. SMAD-7 represses signaling by other SMADs to down-regulate the system. Other signaling pathways like the MAP kinase-ERK cascade are activated by TGF-beta signaling, modulate SMAD activation. SnoN also regulates TGF-beta signaling, by binding to SMADs to block transcriptional activation. TGF-beta signaling causes degradation of SnoN, releasing SMADs to regulate transcription, and also activates expression of SnoN, to down-regulate SMAD signaling at later times.


description_brief: Th1/Th2 Differentiation
systematic_name: M6705
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_th1th2Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Helper T cells are found in two distinct cell types, Th1 and Th2, distinguished by the cytokines they produce and respond to and the immune responses they are involved in. Th1 cells produce pro-inflammatory cytokines like IFN-g, TNF-b and IL-2, while Th2 cells produce the cytokines IL-4, IL-5, IL-6 and IL-13. The cytokines produced by Th1 cells stimulate the phagocytosis and destruction of microbial pathogens while Th2 cytokines like IL-4 generally stimulate the production of antibodies directed toward large extracellular parasites. IL-5 stimulates eosinophil responses, also part of the immune response toward large extracellular parasites Th1 and Th2 are produced by differentiation from a non-antigen exposed precursor cell type, Thp. Exposure of Thp cells to antigen by antigen-presenting cells may result in their differentiation to Th0 cells, not yet committed to become either Th1 or Th2 cells, although the existence of Th0 cells is controversial. Cells committed as either Th1 and Th2 cells are called polarized, whether they are effector cells actively secreting cytokines or are memory cells. The stimulation of Thp cells by exposure to antigen-presenting cells induces the proliferation of undifferentiated cells, and their expression of IL-2 and IL-2 receptor. The differentiation of Th1 cells and Th2 cells depends on the cytokines they are exposed to. IL-12 causes Th1 differentiation and blocks Th2 cell production , while IL-4 causes Th2 differentiation and antagonizes Th1 development. IL-18 also induces Th1 differentiation. Polarized Th1 and Th2 cells also express distinct sets of chemokine receptors that further modify their homing and other cellular responses. Improved understanding of Th1 and Th2 differentiation will improve our overall understanding of the immune system, its response to infection and aberrant responses that lead to disease.


description_brief: The 4-1BB-dependent immune response
systematic_name: M2064
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_41BBPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The activation of T cells requires a co-stimulatory signal with T cell receptor activation, provided in many cases by activation of CD28 in resting T cells. 4-1BB (CD137) is a member of the TNF receptor gene family that provides another T cell co-stimulatory signal. 4-1BB is expressed by activated cytotoxic and helper T cells and its expression is induced by a variety of T cell stimuli, including activation of the T cell receptor or stimulation with mitogens. The ligand for 4-1BB (4-1BBL) is induced on activated antigen-presenting cells including macrophages, activating T cells expressing 4-1BB. Mice lacking 4-1BB survive and have an altered though functional immune response. T cells of mice lacking 4-1BB proliferate more rapidly than normal T cells, but have reduced cytokine secretion. The costimulatory signal provided by 4-1BB may act in combination with CD28 activation to prolong the T cell response, and may also act independently of CD28. Stimulation of T cells with the 4-1BB ligand may provide a therapeutic immune response in the treatment of cancer or viral infection. 4-1BB in T cells activates several signaling pathways. Like other members of the TNF receptor family, the 4-1BB receptor does not have an intrinsic kinase activity. TRAF2 is a signaling adapter that mediates signaling by other members of the TNF receptor family and that also binds to the cytoplasmic domain of ligand activated 4-1BB to activate intracellular kinase cascades. TRAF1 also binds to the cytoplasmic domain of 4-1BB although with lower affinity than TRAF2. One downstream effector activated by 4-1BB through TRAF2 is the transcription factor NF-kB. 4-1BB also activates map kinase pathways, including p38 and JNK activation. ASK1 dependent pathways can activate both p38 and JNK, and dominant negative ASK1 blocks their activation. Other kinase pathways may also be involved in 4-1BB activation of p38 and JNK, such as activation of germinal center kinase (GCK) or related kinases involved in activation of JNK and p38 by TNF. Map kinase activation along with NF-kB activation results in transcriptional activation of cytokine genes involved in T cell activation and signaling. The co-stimulatory signaling provided by 4-1BB shares some features with CD28 signaling, providing an explanation for the ability of 4-1BB to replace the CD28 costimulatory signal in some settings.


description_brief: The Co-Stimulatory Signal During T-cell Activation
systematic_name: M1467
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_ctla4Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  For a T cell to be activated by a specific antigen, the T cell receptor must recognize complexes of MHCI with the antigen on the surface of an antigen-presenting cell. T cells and the T cell receptor complex do not respond to antigen in solution, but even for the specific antigen they only respond to antigen-MHC-1 complexes on the cell surface. This interaction is necessary for T cell activation, but it is not sufficient. T cell activation also requires a co-stimulatory signal involving interaction of CD28 on the T cell with CD80 or CD86 (B7 family genes) on the antigen-presenting cell. CD28 activates a signal transduction pathway acting through PI-3K, Lck and Grb-2/ITK to provide its co-stimulatory signal for T cell activation. Another means to control T cell activation is by expressing factors that down-regulate T cell activation. Signaling by activated T cell receptors induces expression of CTLA-4, a receptor that opposes T cell activation. CTLA-4 has a higher affinity than CD28 for B7 proteins, terminating T cell activation. ICOS is a protein related to CD28 that is only expressed on activated T cells, and that provides another important co-stimulatory signal. The requirement for co-stimulatory signals provides additional control mechanisms that prevent inappropriate and hazardous T cell activation.


description_brief: The IGF-1 Receptor and Longevity
systematic_name: M13158
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_longevityPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  A demonstrated means to increase lifespan in a wide range of organisms is through the restriction of caloric intake. Reducing the consumption of calories increases the lifespan of many different organisms, including mice. Although caloric restriction has not been demonstrated experimentally to increase human lifespan, short-term changes in physiological measures like insulin responsiveness have been observed. Caloric restriction not only increases lifespan, but decreases age-related deterioration of systems and physiological responses, reducing age related diseases like cancer and neurodegenerative disease. Caloric restriction in animals reduces the levels of plasma glucose and insulin and reduces inflammatory responses and may reduce oxidative stress through reduced oxidative metabolism, further contributing to the health benefits of reduced calorie intake. The reduction in inflammation may be related to reduces plasma glucose and in humans could reduce an inflammation connection to cancer, heart disease, and Alzheimers disease. Genetic analysis has indicated several genes that influence lifespan, particularly those that alter pituitary development, reduce growth hormone secretion, reduce food intake, and reduce apoptosis (p66 Shc). All of these appear to converge on an IGF-1 receptor pathway and to reproduce many of the effects of caloric restriction. Although dwarf mice with defective growth hormone or IGF-1 signaling also have significantly increased lifespan, humans with defects in growth hormone signaling tend to develop diseases that shorten their lifespan. One of the downstream targets of IGF-1 signaling is to repress stress resistance proteins including antioxidant enzymes like superoxide dismutase, and heat shock proteins, so a reduction in IGF signaling may extend lifespan by increasing the expression of stress resistance genes. The link between caloric restriction and IGF signaling may be that a reduction in food intake reduces the expression of IGF-1, increasing the expression of stress resistance proteins. In addition to the IGF-1R mutation, p66 Shc mutation also increases lifespan without significant aberration of other systems. Shc is a target of IGF-1R phosphorylation, and a major inducer of cellular responses to oxidative stress. Shc increases levels of intracellular reactive oxygen species, repressing the forkhead factor FKHRL1. Alhtough FKHRL1 is also involved in apoptosis, in the absence of Shc, FKHRL1 mediates increased resistance to oxidative stress. Exploration of the genes that induce longevity in animals models may enlighten the role of these genes in human disease and lifespan.


description_brief: Thrombin signaling and protease-activated receptors
systematic_name: M3494
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_par1pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Thrombin is an extracellular protease that is involved in the clotting of blood and inflammation through its action on platelets and endothelial cells in the vasculature and that plays a role in thrombosis and myocardial infarction. The protease activated receptors PAR1 and PAR4 are cellular targets of thrombin signaling and members of the G-protein coupled receptor gene family. Both of these receptors are cleaved in their N-terminus by thrombin, unmasking a portion of the receptor sequence that acts itself as a tethered peptide ligand that activates the receptor. The tethered ligand that activates PAR1 is SFLLRN and the tethered ligand that activates PAR4 is GYPGQV. Other members of the family include PAR2 which is activated by trypsin rather than thrombin and PAR3 which seems to play a role in the activation of other PARs but does not itself transduce a signal directly. Addition of peptide agonist exogenously in solution can also activate PAR1, PAR2 and PAR4. PAR1 activation may be involved in the dilation of arteries during inflammation through the action of thrombin on endothelial cells and in platelet activation by thrombin during clotting. PAR1 and PAR2 activation cause bronchodilation in airway and may protect against asthma. PAR 4 activation by thrombin activates platelets during clotting and mice lacking PAR4 have impaired clotting and platelets that do not respond to thrombin signaling. The action of thrombin on PAR1 and PAR4 on platelets and endothelial cells may also contribute to vascular permeability and inflammation. Activated PARs appear to couple primarily through Gq-mediated stimulation of inositol phosphate metabolism and intracellular calcium levels to activate platelets. PAR1 and PAR4 also appear to couple to multiple G-proteins and transduce signals through more than one G-protein mediated pathway in some circumstances. Signaling by PAR1 and PAR4 through Galpha12 pathways couples to Rho signaling and changes in cytoskeletal structure and cell shape. Gi activation does not appear necessary for platelet activation by PAR1 or PAR4, and platelet activation by these receptors requires an ADP signal perhaps acting through the platelet-associated purinergic receptor P2Y12. Gi-coupled signaling may play a role in mitogenic PAR signaling in some settings through Map kinase activation. Activation of Rho by PAR1 can induce cellular transformation through a Galpha12 mediated mechanism and sustained rho-dependent phosphorylation of the myosin light chain by PAR1 contributes to cytoskeletal changes and activation of platelets. Since the activation of PARs by protease cleavage is irreversible the primary mechanism for down-regulation of the PAR signaling cascade appears to be internalization and degradation of PAR receptors.


description_brief: TNF/Stress Related Signaling
systematic_name: M9670
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_stressPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  TNF acts on several different signaling pathways through two cell surface receptors, TNFR1 and TNFR2 to regulate apoptotic pathways, NF-kB activation of inflammation, and activate stress-activated protein kinases (SAPKs). Interaction of TNFR1 with TRADD leads to activation of NF-kB and apoptosis pathways, while interaction with TRAF2 has generally been thought to be involved in stress kinase and NF-kB activation but is not required for TNF to induce apoptosis. Activation of NF-kB is mediated by TRAF2 through the NIK kinase and also by RIP but the observation that TNF activates NF-kB in mice lacking TRAF2 indicates that TRAF-2 does not play an essential role in this process. Stress-activated protein kinases, also called JNKs, are a family of map kinases activated by cellular stress and inflammatory signals. Binding of TNF to the TNFR1 receptor activates the germinal center kinase (GCK) through the TNF adaptor Traf2, activating the map kinase MEKK1. Both GCK and MEKK1 interact with Traf2, and GCK is required for MEKK1 activation by TNF, but GCK kinase activity does not appear to be required for MEKK1 activation. Instead, GCK activates MEKK1 by causing MEKK1 oligomerization and autophosphorylation. Tank increases the affinity of Traf2 for GCK to increase Map kinase activation by TNF. Once activated, MEKK1 stands at the top of a map kinase pathways leading to transcriptional regulation, including JNK phosphorylation of c-Jun to stimulate transcriptional activation by AP-1, a heterodimer of c-jun and fos or ATF proteins. The activation of the p38 Map kinase also contributes to AP-1 activation leading to the transcriptional activation of many stress and growth related genes. RIP has been suggested as a component of the p38 pathway in addition to playing a role in NF-kB activation. MEKK1 knockout mice support the role of MEKK1 in JNK activation in some cells but did not support MEKK1 dependent activation of NF-kB. Alternative redundant mechanisms may obscure the role of MEKK1 in NF-kB mechanisms. TNF activation of stress kinase pathways and downstream transcription factors may help to modulate the apoptotic pathways also activated by TNF.


description_brief: TNFR1 Signaling Pathway
systematic_name: M3618
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_tnfr1Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  TNFR1 (a.k.a. p55, CD120a) is the receptor for TNF(alpha) and also will bind TNF(beta). Upon binding TNF(alpha) a TNFR1+ cell is triggered to undergo apoptosis. This critical regulatory process is accomplished by activating the proteolytic caspase cascade that results in the degradation of many critical cellular proteins.


description_brief: TNFR2 Signaling Pathway
systematic_name: M10082
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_tnfr2Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  TNFR2 is the receptor for the 171 amino acid 19 kD TNF(beta) (a.k.a. lymphotoxin). TNF(beta) is produced by activated lymphocytes and can be cytotoxic to many tumor and other cells. In neutrophils, endothelial cells and osteoclasts TNF(beta) can lead to activation while in many other cell types it can lead to increased expression of MHC and adhesion molecules.


description_brief: Toll-Like Receptor Pathway
systematic_name: M984
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_tollPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The innate immune response responds in a general manner to factors present in invading pathogens. Bacterial factors such as lipopolysaccharides (LPS, endotoxin), bacterial lipoproteins, peptidoglycans and also CpG nucleic acids activate innate immunity as well as stimulating the antigen-specific immune response and triggering the inflammatory response. Members of the toll-like receptor (TLR) gene family convey signals stimulated by these factors, activating signal transduction pathways that result in transcriptional regulation and stimulate immune function. TLR2 is activated by bacterial lipoproteins, TLR4 is activated by LPS, and TLR9 is activated by CpG DNA; peptidoglycan recognition protein (PGRP) is activated by peptidoglycan (PGN). The downstream signaling pathways used by these receptors are similar to that used by the IL-1 receptor, activating the IL-1 receptor associated kinase (IRAK) through the MyD88 adaptor protein, and signaling through TRAF-6 and protein kinase cascades to activate NF-kB and Jun. NF-kB and c-Jun activate transcription of genes such as the proinflammatory cytokines IL-1 and IL-12. Several recent reports have suggested that the functional outcomes of signaling via TLR2, TLR4 and PGRP are not equivalent. For example, while the LPS-induced, p38-dependent response was dependent upon PU.1 binding, the PGN-induced, p38 response was not. The intracelular receptor for PGN, PGRP is conserved from insects to mammals. In insects, PGRP activates prophenoloxidase cascade, a part of the insect antimicrobial defense system. Because mammals do not have the prophenoloxidase cascade, its function in mammals is unknown. However, it was suggested that an identical protein Tag7 was a tumor necrosis factor-like (TNF-like) cytokine. PGRP/Tag7 possesses cytotoxicity and triggers intranucleosomal DNA fragmentation in target cells in the same way as many known members of the TNF family. Fragmentation of DNA is one of the characteristics of apoptosis. The possibility that in another system, PGRP/Tag7 would induce NF-kB activation, as observed for TRAIL (TNF-related apoptosis-inducing ligand) receptors canot be ruled out.


description_brief: TPO Signaling Pathway
systematic_name: M11520
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_tpoPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Thrombopoietin (TPO) binds to its receptor inducing aggregation and activation. TPO signals its growth regulating effects to the cell through several major pathways including MAPK (ERK and JNK), Protein Kinase C, and JAK/Stat.


description_brief: Transcription factor CREB and its extracellular signals
systematic_name: M9070
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_crebPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The transcription factor CREB binds the cyclic AMP response element (CRE) and activates transcription in response to a variety of extracellular signals including neurotransmitters, hormones, membrane depolarization, and growth and neurotrophic factors. Protein kinase A and the calmodulin-dependent protein kinases CaMKII stimulate CREB phosphorylation at Ser133, a key regulatory site controlling transcriptional activity. Growth and neurotrophic factors also stimulate CREB phosphorylation at Ser133. Phosphorylation occurs at Ser133 via p44/42 MAP Kinase and p90RSK and also via p38 MAP Kinase and MSK1. CREB exhibit deficiencies in spatial learning tasks, while flies overexpressing or lacking CREB show enhanced or diminished learning, respectively.


description_brief: Transcription Regulation by Methyltransferase of CARM1
systematic_name: M7968
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_carm1Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Several forms of post-translational modification regulate protein activities. Recently, protein methylation by CARM1 (coactivator-associated arginine methyltransferase 1) has been observed to play a key role in transcriptional regulation. CARM1 associates with the p160 class of transcriptional coactivators involved in gene activation by steroid hormone family receptors. CARM1 also interacts with CBP/p300 transcriptional coactivators involved in gene activation by a large variety of transcription factors, including steroid hormone receptors and CEBP. One target of CARM1 is the core histones H3 and H4, which are also targets of the histone acetylase activity of CBP/p300 coactivators. Recruitment of CARM1 to the promoter region by binding to coactivators increases histone methylation and makes promoter regions more accessible for transcription. Another target of CARM1 methylation is a coactivator it interacts with, CBP. Methylation of CBP by CARM1 blocks CBP from acting as a coactivator for CREB and redirects the limited CBP pool in the cell to be available for steroid hormone receptors. Other forms of post-translational protein modification such as phosphorylation are reversible in nature, but as of yet a protein demethylase is not known.


description_brief: Trefoil Factors Initiate Mucosal Healing
systematic_name: M15926
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_tffPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Maintaining the integrity of the gastrointestinal tract despite the continual presence of microbial flora and injurious agents is essential. Epithelial repair requires restitution and regeneration. During restitution, epithelial cells spread and migrate across the basement membrane to re-establish surface-cell continuity, a process that is independent of cell proliferation. Epithelial continuity depends on a family of small abundant secreted proteins, the trefoil factors (TFFs). The trefoil factor (TFF) family comprises the gastric peptides pS2/TFF1 and spasmolytic peptide (SP)/TFF2, and the intestinal trefoil factor (ITF)/TFF3. Their fundamental action is to promote epithelial-cell restitution within the gastrointestinal tract. TFFs are abundantly secreted onto the mucosal surface by mucus-secreting cells. Their expression is rapidly and coordinately upregulated at the margins of mucosal injury. Secreted TFF acts on adjacent mucosal cell populations either extracellularly (augmenting barrier function) or intracellularly (transcriptional and signalling events). TFF response elements in TFF gene promoters allow increases in TFF expression through auto-induction and cross-induction of other TFFs, in addition to mucin expression and possibly tumor suppression. Cell migration is the result of integrated disruption of cellcell and cellsubstratum adhesion and prevention of apoptosis through cell detachment. Epithelial movement therefore requires integration of motogenic and cell-survival signals. This is achieved by activation of several intracellular signalling pathways that converge on ERK/MAPK and possibly NF-B activation. Serine phosphorylation of the extracellular signal-regulated kinases (ERKs)/mitogen-activated protein kinases (MAPKs) 1 and 2 is central to trefoil factor -mediated signalling, lying downstream of EGFR activation and possibly FAK activation (through recruitment of GRB2 and SOS). Cell migration might result from cooperation between ERK/MAPKs and Rho proteins, FAK activation, beta-integrin clustering and beta-catenin activation. Abrogation of cell death has been shown to require both PI3K activation and ERK/MAPK activation; the former operates through serine/threonine phosphorylation of AKT/protein kinase B, serine phosphorylation of BAD (BCL-2 agonist of cell death) and inhibition of mitochondrial cytochrome c release and formation of the apoptosome (APAF1, caspase-9 (CASP9) and cytochrome c (CYT-c). Translocation of phosphorylated ERK/MAPK to the nucleus leads to amplification and de-restriction of TFF expression to ensure sustained action.


description_brief: Trka Receptor Signaling Pathway
systematic_name: M9134
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_trkaPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Nerve growth factor (NGF) is a neurotrophic factor that stimulates neuronal survival and growth through TrkA, a member of the trk family of tyrosine kinase receptors that also includes TrkB and TrkC. Some NGF responses are also mediated or modified by p75LNTR, a low affinity neurotrophin receptor. Binding of NGF to TrkA stimulates neuronal survival, and also proliferation. Pathways coupled to these responses are linked to TrkA through association of signaling factors with specific amino acids in the TrkA cytoplasmic domain. Cell survival through inhibition of apoptosis is signaled through activation of PI3-kinase and AKT. Ras-mediated signaling and phospholipase C both activate the MAP kinase pathway to stimulate proliferation.


description_brief: Tumor Suppressor Arf Inhibits Ribosomal Biogenesis
systematic_name: M11358
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_arfPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Cyclin-dependent kinase inhibitor-2A (CDKN2A) goes by the colloquial designation p16, which is sometimes referred to as p16(INK4). The alpha transcript of CDKN2A has been shown to encode p16(INK4a), a recognized tumor suppressor that induces a G1 cell cycle arrest by inhibiting the phosphorylation of the RB protein by the cyclin-dependent kinases CDK4 and CDK6. The beta transcript of CDKN2A encodes p14(ARF). The predicted 132-amino acid p14(ARF) is shorter than the corresponding mouse protein, p19(ARF), and the 2 proteins share only 50% identity. However, both proteins have the ability to elicit a p53 response, manifest in the increased expression of both CDKN1A and MDM2, and resulting in a distinctive cell cycle arrest in both the G1 and G2/M phases. Two unrelated proteins encoded by the INK4A-ARF locus function in tumor suppression. ARF binds to MDM2 and promotes the rapid degradation of MDM2. This interaction is mediated by the E1-beta-encoded N-terminal domain of ARF and a C-terminal region of MDM2. ARF-promoted MDM2 degradation is associated with MDM2 modification and concurrent p53 stabilization and accumulation. The p19(Arf) tumor suppressor inhibits production of ribosomal RNA, retarding processing of 47/45S and 32S precursors. These effects correlate with but do not strictly depend upon inhibition of rRNA biosynthesis or cell cycle arrest, are not mimicked by p53, and require neither p53 nor Mdm2. Arf mutants lacking conserved amino acid residues 2-14 do not block rRNA synthesis and processing or inhibit cell proliferation. Evolution may have linked a primordial nucleolar Arf function to Mdm2 and p53, creating a more efficient checkpoint-signaling pathway for coordinating ribosomal biogenesis and cell cycle progression.


description_brief: uCalpain and friends in Cell spread
systematic_name: M13143
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_uCalpainPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The mammalian calpain gene family curently contains 13 distinct large subunit products most of which complex with one of two smaller 30kDa subunits. ( An excellent introduction to the Calpain family can be found on a web site created by Valery Thompson http://ag.arizona.edu/calpains/index.html ) Spreading cells display newly transiently formed integrin adhesion clusters containing Calpain1 (mu-Calpain), cleaved Talin, B3-Integrin and SPTAN1(Spectrin). Recruitment of Rac to these clusters leads to the activation of Rac and the formation of Rac-induced Focal clusters. The Calpain1 in the integrin clusters initially inactivates RhoA allowing for the formation of lamellipodia. The subsequent activation of newly synthesized RhoA transforms these clusters into Focal Adhesion Complexes and the formation of contractile actin-myosin stress fibers. These mature adhesions do not contain calpain.


description_brief: VEGF, Hypoxia, and Angiogenesis
systematic_name: M12975
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_vegfPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Vascular endothelial growth factor (VEGF) plays a key role in physiological blood vessel formation and pathological angiogenesis such as tumor growth and ischemic diseases. Hypoxia is a potent inducer of VEGF in vitro. The increase in secreted biologically active VEGF protein from cells exposed to hypoxia is partly because of an increased transcription rate, mediated by binding of hypoxia-inducible factor-1 (HIF1) to a hypoxia responsive element in the 5'-flanking region of the VEGF gene. bHLH-PAS transcription factor that interacts with the Ah receptor nuclear translocator (Arnt), and its predicted amino acid sequence exhibits significant similarity to the hypoxia-inducible factor 1alpha (HIF1a) product. HLF mRNA expression is closely correlated with that of VEGF mRNA.. The high expression level of HLF mRNA in the O2 delivery system of developing embryos and adult organs suggests that in a normoxic state, HLF regulates gene expression of VEGF, various glycolytic enzymes, and others driven by the HRE sequence, and may be involved in development of blood vessels and the tubular system of lung. VEGF expression is dramatically induced by hypoxia due in large part to an increase in the stability of its mRNA. HuR binds with high affinity and specificity to the VRS element that regulates VEGF mRNA stability by hypoxia. In addition, an internal ribosome entry site (IRES) ensures efficient translation of VEGF mRNA even under hypoxia. The VHL tumor suppressor (von Hippel-Lindau) regulates also VEGF expression at a post-transcriptional level. The secreted VEGF is a major angiogenic factor that regulates multiple endothelial cell functions, including mitogenesis. Cellular and circulating levels of VEGF are elevated in hematologic malignancies and are adversely associated with prognosis. Angiogenesis is a very complex, tightly regulated, multistep process, the targeting of which may well prove useful in the creation of novel therapeutic agents. Current approaches being investigated include the inhibition of angiogenesis stimulants (e.g., VEGF), or their receptors, blockade of endothelial cell activation, inhibition of matrix metalloproteinases, and inhibition of tumor vasculature. Preclinical, phase I, and phase II studies of both monoclonal antibodies to VEGF and blockers of the VEGF receptor tyrosine kinase pathway indicate that these agents are safe and offer potential clinical utility in patients with hematologic malignancies.


description_brief: Vitamin C in the Brain
systematic_name: M15422
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_vitCBPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Vitamin C (ascorbic acid) was first identified by virtue of the essential role it plays in collagen modification, preventing the nutritional deficiency scurvy. Vitamin C acts as a cofactor for hydroxylase enzymes that post-translationally modify collagen to increase the strength and elasticity of tissues. Vitamin C reduces the metal ion prosthetic groups of many enzymes, maintaining activity of enzymes, also acts as an anti-oxidant. Although the prevention of scurvy through modification of collagen may be the most obvious role for vitamin C, it is not necessarily the only role of vitamin C. Svct1 and Svct2 are ascorbate transporters for vitamin C import into tissues and into cells. Both of these transporters specifically transport reduced L-ascorbic acid against a concentration gradient using the intracellular sodium gradient to drive ascorbate transport. Svct1 is expressed in epithelial cells in the intestine, upregulated in cellular models for intestinal epithelium and appears to be responsible for the import of dietary vitamin C from the intestinal lumen. The vitamin C imported from the intestine is present in plasma at approximately 50 uM, almost exclusively in the reduced form, and is transported to tissues to play a variety of roles. Svct2 imports reduced ascorbate from the plasma into very active tissues like the brain. Deletion in mice of the gene for Svct2 revealed that ascorbate is required for normal development of the lungs and brain during pregnancy. A high concentration of vitamin C in neurons of the developing brain may help protect the developing brain from free radical damage. The oxidized form of ascorbate, dehydroascorbic acid, is transported into a variety of cells by the glucose transporter Glut-1. Glut-1, Glut-3 and Glut-4 can transport dehydroascorbate, but may not transport significant quantities of ascorbic acid in vivo.


description_brief: WNT Signaling Pathway
systematic_name: M16517
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_wntPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Wnt family members are secreted glycoproteins who bind to cell surface receptors such as Frizzled. Wnt members can play a role in the expression of many genes by interacting with multiple disparate signaling pathways. Shown is the Wnt/beta-catenin pathway.


description_brief: Y branching of actin filaments
systematic_name: M7825
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_actinYPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Mammalian cell motility requires actin polymerization in the direction of movement to change membrane shape and extend cytoplasm into lamellipodia. The polymerization of actin to drive cell movement also involves branching of actin filaments into a network oriented with the growing ends of the fibers near the cell membrane. Manipulation of this process helps bacteria like Salmonella gain entry into cells they infect. Two of the proteins involved in the formation of Y branches and in cell motility are Arp2 and Arp3, both members of a large multiprotein complex containing several other polypeptides as well. The Arp2/3 complex is localized at the Y branch junction and induces actin polymerization. Activity of this complex is regulated by multiple different cell surface receptor signaling systems, activating WASP, and Arp2/3 in turn to cause changes in cell shape and cell motility. Wasp and its cousin Wave-1 interact with the Arp2/3 complex through the p21 component of the complex. The crystal structure of the Arp2/3 complex has revealed further insights into the nature of how the complex works. Activation by Wave-1, another member of the WASP family, also induces actin alterations in response to Rac1 signals upstream. Wave-1 is held in an inactive complex in the cytosol that is activated to allow Wave-1 to associate with Arp2/3. While WASP is activated by interaction with Cdc42, Wave-1, is activated by interaction with Rac1 and Nck. Wave-1 activation by Rac1 and Nck releases Wave-1 with Hspc300 to activate actin Y branching and polymerization by Arp2/3. Different members of this gene family may produce different actin cytoskeletal architectures. The immunological defects associated with mutation of the WASP gene, the Wiskott-Aldrich syndrome for which WASP was named, indicates the importance of this system for normal cellular function.


description_brief: Glycolysis / Gluconeogenesis
systematic_name: M11521
exact_source: hsa00010
external_details_URL: http://www.genome.jp/pathway/hsa00010
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Glycolysis is the process of converting glucose into pyruvate and generating small amounts of ATP (energy) and NADH (reducing power). It is a central pathway that produces important precursor metabolites: six-carbon compounds of glucose-6P and fructose-6P and three-carbon compounds of glycerone-P, glyceraldehyde-3P, glycerate-3P, phosphoenolpyruvate, and pyruvate. Acetyl-CoA, another important precursor metabolite, is produced by oxidative decarboxylation of pyruvate. When the enzyme genes of this pathway are examined in completely sequenced genomes, the reaction steps of three-carbon compounds from glycerone-P to pyruvate form a conserved core module , which is found in almost all organisms and which often corresponds to operon structures in bacterial genomes. Gluconeogenesis is a synthesis pathway of glucose from noncarbohydrate precursors. It is essentially a reversal of glycolysis with minor variations of alternative paths.


description_brief: Citrate cycle (TCA cycle)
systematic_name: M3985
exact_source: hsa00020
external_details_URL: http://www.genome.jp/pathway/hsa00020
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  The citrate cycle (TCA cycle, Krebs cycle) is an important aerobic pathway for the final steps of the oxidation of carbohydrates and fatty acids. The cycle starts with acetyl-CoA, the activated form of acetate, derived from glycolysis and pyruvate oxidation for carbohydrates and from beta oxidation of fatty acids. The two-carbon acetyl group in acetyl-CoA is transferred to the four-carbon compound of oxaloacetate to form the six-carbon compound of citrate. In a series of reactions two carbons in citrate are oxidized to CO2 and the reaction pathway supplies NADH for use in the oxidative phosphorylation and other metabolic processes. The pathway also supplies important precursor metabolites including 2-oxoglutarate. At the end of the cycle the remaining four-carbon part is transformed back to oxaloacetate. According to the genome sequence data, many organisms seem to lack genes for the full cycle , but contain genes for specific segments.


description_brief: Pentose phosphate pathway
systematic_name: M1386
exact_source: hsa00030
external_details_URL: http://www.genome.jp/pathway/hsa00030
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  The pentose phosphate pathway is a process of glucose turnover that produces NADPH as reducing equivalents and pentoses as essential parts of nucleotides. There are two different phases in the pathway. One is irreversible oxidative phase in which glucose-6P is converted to ribulose-5P by oxidative decarboxylation, and NADPH is generated. The other is reversible non-oxidative phase in which phosphorylated sugars are interconverted to generate xylulose-5P, ribulose-5P, and ribose-5P. Phosphoribosyl pyrophosphate (PRPP) formed from ribose-5P is an activated compound used in the biosynthesis of histidine and purine/pyrimidine nucleotides. This pathway map also shows the Entner-Doudoroff pathway where 6-P-gluconate is dehydrated and then cleaved into pyruvate and glyceraldehyde-3P.


description_brief: Primary bile acid biosynthesis
systematic_name: M3214
exact_source: hsa00120
external_details_URL: http://www.genome.jp/pathway/hsa00120
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Bile acids are steroid carboxylic acids derived from cholesterol in vertebrates. The primary bile acids, cholic acid and chenodeoxycholic acid, are synthesized in the liver and conjugated with taurine or glycine before secretion via bile into the intestine. The conversion from cholesterol to cholic and chenodeoxycholic acids involves four steps: 1) the initiation of synthesis by 7alpha-hydroxylation of sterol precursors, 2) further modifications to the ring structures, 3) side-chain oxidation and shortening (cleavage) by three carbons, and 4) conjugation of the bile acid with taurine or glycine.


description_brief: Steroid hormone biosynthesis
systematic_name: M14933
exact_source: hsa00140
external_details_URL: http://www.genome.jp/pathway/hsa00140
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Steroid hormones derived from cholesterol are a class of biologically active compounds in vertebrates. The cholesterol side-chain cleavage enzyme CYP11A1 catalyzes conversion of cholesterol, a C27 compound, to the first C21 steroid, pregnenolone, which is converted by a bifunctional enzyme complex to the gestagen hormone, progesterone. Pregnenolone and progesterone are the starting materials for the three groups of steroids: C21 steroids of glucocorticoids and mineralocorticoids, C19 steroids of androgens, and C18 steroids of estrogens. (i) Progesterone is converted by hydroxylations at carbons 21 and 11 to corticosterone, which is further modified by hydroxylation and oxydoreduction at carbon 18 to yield aldosterone, a mineralcorticoid. Cortisol, the main glucocorticoid, is formed from 17alpha-hydroxyprogesterone with 11-deoxycortisol as an intermediate. (ii) Male hormone testosterone is formed from pregnenolone by two pathways, delta5 pathway via dehydroepiandrosterone and delta4 pathway via androstenedione. The enzyme CYP17A1 is responsible for the 17,20 lyase and 17alpha-hydroxylase activities in respective pathways. (iii) Female hormones estrone and estradiol are formed from testosterone and 4-androstene-3,17-dione by oxidative removal of the C19 methyl group and subsequent aromatization of ring A. In addition to these three groups, recent studies show that there is another group, termed neurosteroids, synthesized in the brain rather than the peripheral endocrine gland.


description_brief: Glycine, serine and threonine metabolism
systematic_name: M766
exact_source: hsa00260
external_details_URL: http://www.genome.jp/pathway/hsa00260
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Serine is derived from 3-phospho-D-glycerate, an intermediate of glycolysis , and glycine is derived from serine. Threonine is an essential amino acid, which animals cannot synthesize. In bacteria and plants, threonine is derived from aspartate.


description_brief: Cysteine and methionine metabolism
systematic_name: M10911
exact_source: hsa00270
external_details_URL: http://www.genome.jp/pathway/hsa00270
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Cysteine and methionine are sulfur-containing amino acids. Cysteine is synthesized from serine through different pathways in different organism groups. In bacteria and plants, cysteine is converted from serine (via acetylserine) by transfer of hydrogen sulfide. In animals, methionine-derived homocysteine is used as sulfur source and its condensation product with serine (cystathionine) is converted to cysteine. Cysteine is metabolized to pyruvate in multiple routes. Methionine is an essential amino acid, which animals cannot synthesize. In bacteria and plants, methionine is synthesized from aspartate. S-Adenosylmethionine (SAM), synthesized from methionine and ATP, is a methyl group donor in many important transfer reactions including DNA methylation for regulation of gene expression. SAM may also be used to regenerate methionine in the methionine salvage pathway.


description_brief: Glycosaminoglycan biosynthesis - chondroitin sulfate
systematic_name: M19166
exact_source: hsa00532
external_details_URL: http://www.genome.jp/pathway/hsa00532
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Glycosaminoglycans (GAGs) are linear polysaccharide chains consisting of repeating disaccharide units and form proteglycans by covalently attaching to their core proteins. Chondroitin sulfate (CS) is a glycosaminoglycan with the disaccharide unit GalNAc(b1-4)GlcA(b1-3), modified with ester-linked sulfate at certain positions. Dermatan sulfate (DS) is a modified form of CS, in which a portion of D-glucuronate residues is epimerized to L-iduronates. CS and DS are linked to serine residues in core proteins via a linkage tetrasaccharide formed by the transfer of xylose and three more residues. The assembly process of CS is initiated by the transfer of N-acetylgalactosamine to the linkage tetrasaccharide. The polymerization step is catalyzed by bifunctional enzymes (chondroitin synthases) that have both b13 glucuronosyltransferase and b14 N-acetylgalactosaminyltransferase activities. Chondroitin polymerization also requires the action of the chondroitin polymerizing factor. Sulfation of chondroitin in vertebrates is a complex process, with multiple sulfotransferases involved in 4-O sulfation and 6-O sulfation of N-acetylgalactosamine residues. Additional enzymes exist for epimerization of glucuronic acid to iduronic acid in DS, sulfation at the C-2 position of the uronic acids, and other patterns of sulfation found in unusual species of chondroitin.


description_brief: ABC transporters
systematic_name: M11911
exact_source: hsa02010
external_details_URL: http://www.genome.jp/pathway/hsa02010
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  The ATP-binding cassette (ABC) transporters form one of the largest known protein families, and are widespread in bacteria, archaea, and eukaryotes. They couple ATP hydrolysis to active transport of a wide variety of substrates such as ions, sugars, lipids, sterols, peptides, proteins, and drugs. The structure of a prokaryotic ABC transporter usually consists of three components; typically two integral membrane proteins each having six transmembrane segments, two peripheral proteins that bind and hydrolyze ATP, and a periplasmic (or lipoprotein) substrate-binding protein. Many of the genes for the three components form operons as in fact observed in many bacterial and archaeal genomes. On the other hand, in a typical eukaryotic ABC transporter, the membrane spanning protein and the ATP-binding protein are fused, forming a multi-domain protein with the membrane-spanning domain (MSD) and the nucleotide-binding domain (NBD).


description_brief: RNA degradation
systematic_name: M963
exact_source: hsa03018
external_details_URL: http://www.genome.jp/pathway/hsa03018
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  The correct processing, quality control and turnover of cellular RNA molecules are critical to many aspects in the expression of genetic information. In eukaryotes, two major pathways of mRNA decay exist and both pathways are initiated by poly(A) shortening of the mRNA. In the 5' to 3' pathway, this is followed by decapping which then permits the 5' to 3' exonucleolytic degradation of transcripts. In the 3' to 5' pathway, the exosome, a large multisubunit complex, plays a key role. The exosome exists in archaeal cells, too. In bacteria, endoribonuclease E, a key enzyme involved in RNA decay and processing, organizes a protein complex called degradosome. RNase E or R interacts with the phosphate-dependent exoribonuclease polynucleotide phosphorylase, DEAD-box helicases, and additional factors in the RNA-degrading complex.


description_brief: DNA replication
systematic_name: M16853
exact_source: hsa03030
external_details_URL: http://www.genome.jp/pathway/hsa03030
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  A complex network of interacting proteins and enzymes is required for DNA replication. Generally, DNA replication follows a multistep enzymatic pathway. At the DNA replication fork, a DNA helicase (DnaB or MCM complex) precedes the DNA synthetic machinery and unwinds the duplex parental DNA in cooperation with the SSB or RPA. On the leading strand, replication occurs continuously in a 5 to 3 direction, whereas on the lagging strand, DNA replication occurs discontinuously by synthesis and joining of short Okazaki fragments. In prokaryotes, the leading strand replication apparatus consists of a DNA polymerase (pol III core), a sliding clamp (beta), and a clamp loader (gamma delta complex). The DNA primase (DnaG) is needed to form RNA primers. Normally, during replication of the lagging-strand DNA template, an RNA primer is removed either by an RNase H or by the 5 to 3 exonuclease activity of DNA pol I, and the DNA ligase joins the Okazaki fragments. In eukaryotes, three DNA polymerases (alpha, delta, and epsilon) have been identified. DNA primase forms a permanent complex with DNA polymerase alpha. PCNA and RFC function as a clamp and a clamp loader. FEN 1 and RNase H1 remove the RNA from the Okazaki fragments and DNA ligase I joins the DNA.


description_brief: Spliceosome
systematic_name: M2044
exact_source: hsa03040
external_details_URL: http://www.genome.jp/pathway/hsa03040
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  After transcription, eukaryotic mRNA precursors contain protein-coding exons and noncoding introns. In the following splicing, introns are excised and exons are joined by a macromolecular complex, the spliceosome. The standard spliceosome is made up of five small nuclear ribonucleoproteins (snRNPs), U1, U2, U4, U5, and U6 snRNPs, and several spliceosome-associated proteins (SAPs). Spliceosomes are not a simple stable complex, but a dynamic family of particles that assemble on the mRNA precursor and help fold it into a conformation that allows transesterification to proceed. Various spliceosome forms (e.g. A-, B- and C-complexes) have been identified.


description_brief: Proteasome
systematic_name: M10680
exact_source: hsa03050
external_details_URL: http://www.genome.jp/pathway/hsa03050
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  The proteasome is a protein-destroying apparatus involved in many essential cellular functions, such as regulation of cell cycle, cell differentiation, signal transduction pathways, antigen processing for appropriate immune responses, stress signaling, inflammatory responses, and apoptosis. It is capable of degrading a variety of cellular proteins in a rapid and timely fashion and most substrate proteins are modified by ubiquitin before their degradation by the proteasome. The proteasome is a large protein complex consisting of a proteolytic core called the 20S particle and ancillary factors that regulate its activity in various ways. The most common form is the 26S proteasome containing one 20S core particle and two 19S regulatory particles that enable the proteasome to degrade ubiquitinated proteins by an ATP-dependent mechanism. Another form is the immunoproteasome containing two 11S regulatory particles, PA28 alpha and PA28 beta, which are induced by interferon gamma under the conditions of intensified immune response. Other regulatory particles include PA28 gamma and PA200. Although PA28 gamma also belongs to a family of activators of the 20S proteasome, it is localized within the nucleus and forms a homoheptamer. PA28 gamma has been implicated in the regulation of cell cycle progression and apoptosis. PA200 has been identified as a large nuclear protein that stimulates proteasomal hydrolysis of peptides.


description_brief: Protein export
systematic_name: M6981
exact_source: hsa03060
external_details_URL: http://www.genome.jp/pathway/hsa03060
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  The protein export is the active transport of proteins from the cytoplasm to the exterior of the cell, or to the periplasmic compartment in Gram-negative bacteria. The sec dependent pathway is the general protein export system that transports newly synthesized proteins into or across the cell membrane. The translocation channel is formed from a conserved trimeric membrane protein complex, called the Sec61/SecY complex. The twin-arginine translocation (Tat) pathway is another protein transport system that transports folded proteins in bacteria, archaea, and chloroplasts. Many Tat systems comprise three functionally different membrane proteins, TatA, TatB, and TatC, but TatA and TatE seem to have overlapping functions, with TatA having by far the more important role.


description_brief: PPAR signaling pathway
systematic_name: M13088
exact_source: hsa03320
external_details_URL: http://www.genome.jp/pathway/hsa03320
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that are activated by fatty acids and their derivatives. PPAR has three subtypes (PPARalpha, beta/delta, and gamma) showing different expression patterns in vertebrates. Each of them is encoded in a separate gene and binds fatty acids and eicosanoids. PPARalpha plays a role in the clearance of circulating or cellular lipids via the regulation of gene expression involved in lipid metabolism in liver and skeletal muscle. PPARbeta/delta is involved in lipid oxidation and cell proliferation. PPARgamma promotes adipocyte differentiation to enhance blood glucose uptake.


description_brief: Base excision repair
systematic_name: M5500
exact_source: hsa03410
external_details_URL: http://www.genome.jp/pathway/hsa03410
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Base excision repair (BER) is the predominant DNA damage repair pathway for the processing of small base lesions, derived from oxidation and alkylation damages. BER is normally defined as DNA repair initiated by lesion-specific DNA glycosylases and completed by either of the two sub-pathways: short-patch BER where only one nucleotide is replaced and long-patch BER where 2-13 nucleotides are replaced. Each sub-pathway of BER relies on the formation of protein complexes that assemble at the site of the DNA lesion and facilitate repair in a coordinated fashion. This process of complex formation appears to provide an increase in specificity and efficiency to the BER pathway, thereby facilitating the maintenance of genome integrity by preventing the accumulation of highly toxic repair intermediates.


description_brief: Nucleotide excision repair
systematic_name: M18937
exact_source: hsa03420
external_details_URL: http://www.genome.jp/pathway/hsa03420
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Nucleotide excision repair (NER) is a mechanism to recognize and repair bulky DNA damage caused by compounds, environmental carcinogens, and exposure to UV-light. In humans hereditary defects in the NER pathway are linked to at least three diseases: xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). The repair of damaged DNA involves at least 30 polypeptides within two different sub-pathways of NER known as transcription-coupled repair (TCR-NER) and global genome repair (GGR-NER). TCR refers to the expedited repair of lesions located in the actively transcribed strand of genes by RNA polymerase II (RNAP II). In GGR-NER the first step of damage recognition involves XPC-hHR23B complex together with XPE complex (in prokaryotes, uvrAB complex). The following steps of GGR-NER and TCR-NER are similar.


description_brief: Mismatch repair
systematic_name: M13515
exact_source: hsa03430
external_details_URL: http://www.genome.jp/pathway/hsa03430
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  DNA mismatch repair (MMR) is a highly conserved biological pathway that plays a key role in maintaining genomic stability. MMR corrects DNA mismatches generated during DNA replication, thereby preventing mutations from becoming permanent in dividing cells. MMR also suppresses homologous recombination and was recently shown to play a role in DNA damage signaling. Defects in MMR are associated with genome-wide instability, predisposition to certain types of cancer including HNPCC, resistance to certain chemotherapeutic agents, and abnormalities in meiosis and sterility in mammalian systems. The Escherichia coli MMR pathway has been extensively studied and is well characterized. In E. coli, the mismatch-activated MutS-MutL-ATP complex licenses MutH to incise the nearest unmethylated GATC sequence. UvrD and an exonuclease generate a gap. This gap is filled by pol III and DNA ligase. The GATC sites are then methylated by Dam. Several human MMR proteins have been identified based on their homology to E. coli MMR proteins. These include human homologs of MutS and MutL. Although E. coli MutS and MutL proteins are homodimers, human MutS and MutL homologs are heterodimers. The role of hemimethylated dGATC sites as a signal for strand discrimination is not conserved from E. coli to human. Human MMR is presumed to be nick-directed in vivo, and is thought to discriminate daughter and template strands using a strand-specific nick.


description_brief: Homologous recombination
systematic_name: M11675
exact_source: hsa03440
external_details_URL: http://www.genome.jp/pathway/hsa03440
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Homologous recombination (HR) is essential for the accurate repair of DNA double-strand breaks (DSBs), potentially lethal lesions. HR takes place in the late S-G2 phase of the cell cycle and involves the generation of a single-stranded region of DNA, followed by strand invasion, formation of a Holliday junction, DNA synthesis using the intact strand as a template, branch migration and resolution. It is investigated that RecA/Rad51 family proteins play a central role. The breast cancer susceptibility protein Brca2 and the RecQ helicase BLM (Bloom syndrome mutated) are tumor suppressors that maintain genome integrity, at least in part, through HR.


description_brief: MAPK signaling pathway
systematic_name: M10792
exact_source: hsa04010
external_details_URL: http://www.genome.jp/pathway/hsa04010
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  The mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals express at least four distinctly regulated groups of MAPKs, extracellular signal-related kinases (ERK)-1/2, Jun amino-terminal kinases (JNK1/2/3), p38 proteins (p38alpha/beta/gamma/delta) and ERK5, that are activated by specific MAPKKs: MEK1/2 for ERK1/2, MKK3/6 for the p38, MKK4/7 (JNKK1/2) for the JNKs, and MEK5 for ERK5. Each MAPKK, however, can be activated by more than one MAPKKK, increasing the complexity and diversity of MAPK signalling. Presumably each MAPKKK confers responsiveness to distinct stimuli. For example, activation of ERK1/2 by growth factors depends on the MAPKKK c-Raf, but other MAPKKKs may activate ERK1/2 in response to pro-inflammatory stimuli.


description_brief: ErbB signaling pathway
systematic_name: M12467
exact_source: hsa04012
external_details_URL: http://www.genome.jp/pathway/hsa04012
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  The ErbB family of receptor tyrosine kinases (RTKs) couples binding of extracellular growth factor ligands to intracellular signaling pathways regulating diverse biologic responses, including proliferation, differentiation, cell motility, and survival. Ligand binding to the four closely related members of this RTK family -epidermal growth factor receptor (EGFR, also known as ErbB-1 or HER1), ErbB-2 (HER2), ErbB-3 (HER3), and ErbB-4 (HER4)-induces the formation of receptor homo- and heterodimers and the activation of the intrinsic kinase domain, resulting in phosphorylation on specific tyrosine residues (pY) within the cytoplasmic tail. Signaling effectors containing binding pockets for pY-containing peptides are recruited to activated receptors and induce the various signaling pathways. The Shc- and/or Grb2-activated mitogen-activated protein kinase (MAPK) pathway is a common target downstream of all ErbB receptors. Similarly, the phosphatidylinositol-3-kinase (PI-3K) pathway is directly or indirectly activated by most ErbBs. Several cytoplasmic docking proteins appear to be recruited by specific ErbB receptors and less exploited by others. These include the adaptors Crk, Nck, the phospholipase C gamma (PLCgamma), the intracellular tyrosine kinase Src, or the Cbl E3 ubiquitin protein ligase.


description_brief: Calcium signaling pathway
systematic_name: M2890
exact_source: hsa04020
external_details_URL: http://www.genome.jp/pathway/hsa04020
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Ca2+ that enters the cell from the outside is a principal source of signal Ca2+. Entry of Ca2+ is driven by the presence of a large electrochemical gradient across the plasma membrane. Cells use this external source of signal Ca2+ by activating various entry channels with widely different properties. The voltage-operated channels (VOCs) are found in excitable cells and generate the rapid Ca2+ fluxes that control fast cellular processes. There are many other Ca2+-entry channels, such as the receptor-operated channels (ROCs), for example the NMDA (N-methyl-D-aspartate) receptors (NMDARs) that respond to glutamate. There also are second-messenger-operated channels (SMOCs) and store-operated channels (SOCs). The other principal source of Ca2+ for signalling is the internal stores that are located primarily in the endoplasmic/sarcoplasmic reticulum (ER/SR), in which inositol-1,4,5-trisphosphate receptors (IP3Rs) or ryanodine receptors (RYRs) regulate the release of Ca2+. The principal activator of these channels is Ca2+ itself and this process of Ca2+-induced Ca2+ release is central to the mechanism of Ca2+ signalling. Various second messengers or modulators also control the release of Ca2+. IP3, which is generated by pathways using different isoforms of phospholipase C (PLCbeta, delta, epsilon, gamma and zeta), regulates the IP3Rs. Cyclic ADP-ribose (cADPR) releases Ca2+ via RYRs. Nicotinic acid adenine dinucleotide phosphate (NAADP) may activate a distinct Ca2+ release mechanism on separate acidic Ca2+ stores. Ca2+ release via the NAADP-sensitive mechanism may also feedback onto either RYRs or IP3Rs. cADPR and NAADP are generated by CD38. This enzyme might be sensitive to the cellular metabolism, as ATP and NADH inhibit it. The influx of Ca2+ from the environment or release from internal stores causes a very rapid and dramatic increase in cytoplasmic calcium concentration, which has been widely exploited for signal transduction. Some proteins, such as troponin C (TnC) involved in muscle contraction, directly bind to and sense Ca2+. However, in other cases Ca2+ is sensed through intermediate calcium sensors such as calmodulin (CALM).


description_brief: Cytokine-cytokine receptor interaction
systematic_name: M9809
exact_source: hsa04060
external_details_URL: http://www.genome.jp/pathway/hsa04060
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Cytokines are soluble extracellular proteins or glycoproteins that are crucial intercellular regulators and mobilizers of cells engaged in innate as well as adaptive inflammatory host defenses, cell growth, differentiation, cell death, angiogenesis, and development and repair processes aimed at the restoration of homeostasis. Cytokines are released by various cells in the body, usually in response to an activating stimulus, and they induce responses through binding to specific receptors on the cell surface of target cells. Cytokines can be grouped by structure into different families and their receptors can likewise be grouped.


description_brief: Chemokine signaling pathway
systematic_name: M4844
exact_source: hsa04062
external_details_URL: http://www.genome.jp/pathway/hsa04062
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Inflammatory immune response requires the recruitment of leukocytes to the site of inflammation upon foreign insult. Chemokines are small chemoattractant peptides that provide directional cues for the cell trafficking and thus are vital for protective host response. In addition, chemokines regulate plethora of biological processes of hematopoietic cells to lead cellular activation, differentiation and survival. The chemokine signal is transduced by chemokine receptors (G-protein coupled receptors) expressed on the immune cells. After receptor activation, the alpha- and beta-gamma-subunits of G protein dissociate to activate diverse downstream pathways resulting in cellular polarization and actin reorganization. Various members of small GTPases are involved in this process. Induction of nitric oxide and production of reactive oxygen species are as well regulated by chemokine signal via calcium mobilization and diacylglycerol production.


description_brief: Cell cycle
systematic_name: M7963
exact_source: hsa04110
external_details_URL: http://www.genome.jp/pathway/hsa04110
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Mitotic cell cycle progression is accomplished through a reproducible sequence of events, DNA replication (S phase) and mitosis (M phase) separated temporally by gaps known as G1 and G2 phases. Cyclin-dependent kinases (CDKs) are key regulatory enzymes, each consisting of a catalytic CDK subunit and an activating cyclin subunit. CDKs regulate the cell's progression through the phases of the cell cycle by modulating the activity of key substrates. Downstream targets of CDKs include transcription factor E2F and its regulator Rb. Precise activation and inactivation of CDKs at specific points in the cell cycle are required for orderly cell division. Cyclin-CDK inhibitors (CKIs), such as p16Ink4a, p15Ink4b, p27Kip1, and p21Cip1, are involved in the negative regulation of CDK activities, thus providing a pathway through which the cell cycle is negatively regulated. Eukaryotic cells respond to DNA damage by activating signaling pathways that promote cell cycle arrest and DNA repair. In response to DNA damage, the checkpoint kinase ATM phosphorylates and activates Chk2, which in turn directly phosphorylates and activates p53 tumor suppressor protein. p53 and its transcriptional targets play an important role in both G1 and G2 checkpoints. ATR-Chk1-mediated protein degradation of Cdc25A protein phosphatase is also a mechanism conferring intra-S-phase checkpoint activation.


description_brief: Oocyte meiosis
systematic_name: M16817
exact_source: hsa04114
external_details_URL: http://www.genome.jp/pathway/hsa04114
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  During meiosis, a single round of DNA replication is followed by two rounds of chromosome segregation, called meiosis I and meiosis II. At meiosis I, homologous chromosomes recombine and then segregate to opposite poles, while the sister chromatids segregate from each other at meoisis II. In vertebrates, immature oocytes are arrested at the PI (prophase of meiosis I). The resumption of meiosis is stimulated by progesterone, which carries the oocyte through two consecutive M-phases (MI and MII) to a second arrest at MII. The key activity driving meiotic progression is the MPF (maturation-promoting factor), a heterodimer of CDC2 (cell division cycle 2 kinase) and cyclin B. In PI-arrested oocytes, MPF is initially inactive and is activated by the dual-specificity CDC25C phosphatase as the result of new synthesis of Mos induced by progesterone. MPF activation mediates the transition from the PI arrest to MI. The subsequent decrease in MPF levels, required to exit from MI into interkinesis, is induced by a negative feedback loop, where CDC2 brings about the activation of the APC (anaphase-promoting complex), which mediates destruction of cyclin B. Re-activation of MPF for MII requires re-accumulation of high levels of cyclin B as well as the inactivation of the APC by newly synthesized Emi2 and other components of the CSF (cytostatic factor), such as cyclin E or high levels of Mos. CSF antagonizes the ubiquitin ligase activity of the APC, preventing cyclin B destruction and meiotic exit until fertilization occurs. Fertilization triggers a transient increase in cytosolic free Ca2+, which leads to CSF inactivation and cyclin B destruction through the APC. Then eggs are released from MII into the first embryonic cell cycle.


description_brief: p53 signaling pathway
systematic_name: M6370
exact_source: hsa04115
external_details_URL: http://www.genome.jp/pathway/hsa04115
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  p53 activation is induced by a number of stress signals, including DNA damage, oxidative stress and activated oncogenes. The p53 protein is employed as a transcriptional activator of p53-regulated genes. This results in three major outputs; cell cycle arrest, cellular senescence or apoptosis. Other p53-regulated gene functions communicate with adjacent cells, repair the damaged DNA or set up positive and negative feedback loops that enhance or attenuate the functions of the p53 protein and integrate these stress responses with other signal transduction pathways.


description_brief: Ubiquitin mediated proteolysis
systematic_name: M15247
exact_source: hsa04120
external_details_URL: http://www.genome.jp/pathway/hsa04120
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Protein ubiquitination plays an important role in eukaryotic cellular processes. It mainly functions as a signal for 26S proteasome dependent protein degradation. The addition of ubiquitin to proteins being degraded is performed by a reaction cascade consisting of three enzymes, named E1 (ubiquitin activating enzyme), E2 (ubiquitin conjugating enzyme), and E3 (ubiquitin ligase). Each E3 has specificity to its substrate, or proteins to be targeted by ubiquitination. Many E3s are discovered in eukaryotes and they are classified into four types: HECT type, U-box type, single RING-finger type, and multi-subunit RING-finger type. Multi-subunit RING-finger E3s are exemplified by cullin-Rbx E3s and APC/C. They consist of a RING-finger-containing subunit (RBX1 or RBX2) that functions to bind E2s, a scaffold-like cullin molecule, adaptor proteins, and a target recognizing subunit that binds substrates.


description_brief: Endocytosis
systematic_name: M1519
exact_source: hsa04144
external_details_URL: http://www.genome.jp/pathway/hsa04144
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Endocytosis is a mechanism for cells to remove ligands, nutrients, and plasma membrane (PM) proteins, and lipids from the cell surface, bringing them into the cell interior. Transmembrane proteins entering through clathrin-dependent endocytosis (CDE) have sequences in their cytoplasmic domains that bind to the APs (adaptor-related protein complexes) and enable their rapid removal from the PM. In addition to APs and clathrin, there are numerous accessory proteins including dynamin. Depending on the various proteins that enter the endosome membrane, these cargoes are sorted to distinct destinations. Some cargoes, such as nutrient receptors, are recycled back to the PM. Ubiquitylated membrane proteins, such as activated growth-factor receptors, are sorted into intraluminal vesicles and eventually end up in the lysosome lumen via multivesicular endosomes (MVEs). There are distinct mechanisms of clathrin-independent endocytosis (CIE) depending upon the cargo and the cell type.


description_brief: Peroxisome
systematic_name: M6391
exact_source: hsa04146
external_details_URL: http://www.genome.jp/pathway/hsa04146
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Peroxisomes are essential organelles that play a key role in redox signalling and lipid homeostasis. They contribute to many crucial metabolic processes such as fatty acid oxidation, biosynthesis of ether lipids and free radical detoxification. The biogenesis of peroxisomes starts with the early peroxins PEX3, PEX16 and PEX19 and proceeds via several steps. The import of membrane proteins into peroxisomes needs PEX19 for recognition, targeting and insertion via docking at PEX3. Matrix proteins in the cytosol are recognized by peroxisomal targeting signals (PTS) and transported to the docking complex at the peroxisomal membrane. Peroxisomes' deficiencies lead to severe and often fatal inherited peroxisomal disorders (PD). PDs are usually classified in two groups. The first group is disorders of peroxisome biogenesis which include Zellweger syndrome, and the second group is single peroxisomal enzyme deficiencies.


description_brief: Apoptosis
systematic_name: M8492
exact_source: hsa04210
external_details_URL: http://www.genome.jp/pathway/hsa04210
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Apoptosis is a genetically controlled mechanisms of cell death involved in the regulation of tissue homeostasis. The 2 major pathways of apoptosis are the extrinsic (Fas and other TNFR superfamily members and ligands) and the intrinsic (mitochondria-associated) pathways, both of which are found in the cytoplasm. The extrinsic pathway is triggered by death receptor engagement, which initiates a signaling cascade mediated by caspase-8 activation. Caspase-8 both feeds directly into caspase-3 activation and stimulates the release of cytochrome c by the mitochondria. Caspase-3 activation leads to the degradation of cellular proteins necessary to maintain cell survival and integrity. The intrinsic pathway occurs when various apoptotic stimuli trigger the release of cytochrome c from the mitochondria (independently of caspase-8 activation). Cytochrome c interacts with Apaf-1 and caspase-9 to promote the activation of caspase-3. Recent studies point to the ER as a third subcellular compartment implicated in apoptotic execution. Alterations in Ca2+ homeostasis and accumulation of misfolded proteins in the ER cause ER stress. Prolonged ER stress can result in the activation of BAD and/or caspase-12, and execute apoptosis.


description_brief: Vascular smooth muscle contraction
systematic_name: M9387
exact_source: hsa04270
external_details_URL: http://www.genome.jp/pathway/hsa04270
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  The vascular smooth muscle cell (VSMC) is a highly specialized cell whose principal function is contraction. On contraction, VSMCs shorten, thereby decreasing the diameter of a blood vessel to regulate the blood flow and pressure. The principal mechanisms that regulate the contractile state of VSMCs are changes in cytosolic Ca2+ concentration (c). In response to vasoconstrictor stimuli, Ca2+ is mobilized from intracellular stores and/or the extracellular space to increase c in VSMCs. The increase in c, in turn, activates the Ca2+-CaM-MLCK pathway and stimulates MLC20 phosphorylation, leading to myosin-actin interactions and, hence, the development of contractile force. The sensitivity of contractile myofilaments or MLC20 phosphorylation to Ca2+ can be secondarily modulated by other signaling pathways. During receptor stimulation, the contractile force is greatly enhanced by the inhibition of myosin phosphatase. Rho/Rho kinase, PKC, and arachidonic acid have been proposed to play a pivotal role in this enhancement. The signaling events that mediate relaxation include the removal of a contractile agonist (passive relaxation) and activation of cyclic nucleotide-dependent signaling pathways in the continued presence of a contractile agonist (active relaxation). Active relaxation occurs through the inhibition of both Ca2+ mobilization and myofilament Ca2+ sensitivity in VSMCs.


description_brief: Wnt signaling pathway
systematic_name: M19428
exact_source: hsa04310
external_details_URL: http://www.genome.jp/pathway/hsa04310
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Wnt proteins are secreted morphogens that are required for basic developmental processes, such as cell-fate specification, progenitor-cell proliferation and the control of asymmetric cell division, in many different species and organs. There are at least three different Wnt pathways: the canonical pathway, the planar cell polarity (PCP) pathway and the Wnt/Ca2+ pathway. In the canonical Wnt pathway, the major effect of Wnt ligand binding to its receptor is the stabilization of cytoplasmic beta-catenin through inhibition of the bea-catenin degradation complex. Beta-catenin is then free to enter the nucleus and activate Wnt-regulated genes through its interaction with TCF (T-cell factor) family transcription factors and concomitant recruitment of coactivators. Planar cell polarity (PCP) signaling leads to the activation of the small GTPases RHOA (RAS homologue gene-family member A) and RAC1, which activate the stress kinase JNK (Jun N-terminal kinase) and ROCK (RHO-associated coiled-coil-containing protein kinase 1) and leads to remodelling of the cytoskeleton and changes in cell adhesion and motility. WNT-Ca2+ signalling is mediated through G proteins and phospholipases and leads to transient increases in cytoplasmic free calcium that subsequently activate the kinase PKC (protein kinase C) and CAMKII (calcium calmodulin mediated kinase II) and the phosphatase calcineurin.


description_brief: Notch signaling pathway
systematic_name: M7946
exact_source: hsa04330
external_details_URL: http://www.genome.jp/pathway/hsa04330
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  The Notch signaling pathway is an evolutionarily conserved, intercellular signaling mechanism essential for proper embryonic development in all metazoan organisms in the Animal kingdom. The Notch proteins (Notch1-Notch4 in vertebrates) are single-pass receptors that are activated by the Delta (or Delta-like) and Jagged/Serrate families of membrane-bound ligands. They are transported to the plasma membrane as cleaved, but otherwise intact polypeptides. Interaction with ligand leads to two additional proteolytic cleavages that liberate the Notch intracellular domain (NICD) from the plasma membrane. The NICD translocates to the nucleus, where it forms a complex with the DNA binding protein CSL, displacing a histone deacetylase (HDAc)-co-repressor (CoR) complex from CSL. Components of an activation complex, such as MAML1 and histone acetyltransferases (HATs), are recruited to the NICD-CSL complex, leading to the transcriptional activation of Notch target genes.


description_brief: Hedgehog signaling pathway
systematic_name: M1053
exact_source: hsa04340
external_details_URL: http://www.genome.jp/pathway/hsa04340
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  The Hedgehog (Hh) family of secreted signaling proteins plays a crucial role in development of diverse animal phyla, from Drosophila to humans, regulating morphogenesis of a variety of tissues and organs. Hh signaling is also involved in control of stem cell proliferation in adult tissues and aberrant activation of the Hh pathway has been linked to multiple types of human cancer. Members of the Hh family bind to patched (ptc), thus releasing smoothened (smo) to transduce a signal. Transcriptional activation occurs through the GLI family of proteins resulting in activation of target genes.


description_brief: TGF-beta signaling pathway
systematic_name: M2642
exact_source: hsa04350
external_details_URL: http://www.genome.jp/pathway/hsa04350
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  The transforming growth factor-beta (TGF-beta) family members, which include TGF-betas, activins and bone morphogenetic proteins (BMPs), are structurally related secreted cytokines found in species ranging from worms and insects to mammals. A wide spectrum of cellular functions such as proliferation, apoptosis, differentiation and migration are regulated by TGF-beta family members. TGF-beta family member binds to the Type II receptor and recruits Type I, whereby Type II receptor phosphorylates and activates Type I. The Type I receptor, in turn, phosphorylates receptor-activated Smads ( R-Smads: Smad1, Smad2, Smad3, Smad5, and Smad8). Once phosphorylated, R-Smads associate with the co-mediator Smad, Smad4, and the heteromeric complex then translocates into the nucleus. In the nucleus, Smad complexes activate specific genes through cooperative interactions with other DNA-binding and coactivator (or co-repressor) proteins.


description_brief: Axon guidance
systematic_name: M5539
exact_source: hsa04360
external_details_URL: http://www.genome.jp/pathway/hsa04360
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Axon guidance represents a key stage in the formation of neuronal network. Axons are guided by a variety of guidance factors, such as netrins, ephrins, Slits, and semaphorins. These guidance cues are read by growth cone receptors, and signal transduction pathways downstream of these receptors converge onto the Rho GTPases to elicit changes in cytoskeletal organization that determine which way the growth cone will turn.


description_brief: VEGF signaling pathway
systematic_name: M1749
exact_source: hsa04370
external_details_URL: http://www.genome.jp/pathway/hsa04370
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  There is now much evidence that VEGFR-2 is the major mediator of VEGF-driven responses in endothelial cells and it is considered to be a crucial signal transducer in both physiologic and pathologic angiogenesis. The binding of VEGF to VEGFR-2 leads to a cascade of different signaling pathways, resulting in the up-regulation of genes involved in mediating the proliferation and migration of endothelial cells and promoting their survival and vascular permeability. For example, the binding of VEGF to VEGFR-2 leads to dimerization of the receptor, followed by intracellular activation of the PLCgamma;PKC-Raf kinase-MEK-mitogen-activated protein kinase (MAPK) pathway and subsequent initiation of DNA synthesis and cell growth, whereas activation of the phosphatidylinositol 3' -kinase (PI3K)-Akt pathway leads to increased endothelial-cell survival. Activation of PI3K, FAK, and p38 MAPK is implicated in cell migration signaling.


description_brief: Focal adhesion
systematic_name: M7253
exact_source: hsa04510
external_details_URL: http://www.genome.jp/pathway/hsa04510
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Cell-matrix adhesions play essential roles in important biological processes including cell motility, cell proliferation, cell differentiation, regulation of gene expression and cell survival. At the cell-extracellular matrix contact points, specialized structures are formed and termed focal adhesions, where bundles of actin filaments are anchored to transmembrane receptors of the integrin family through a multi-molecular complex of junctional plaque proteins. Some of the constituents of focal adhesions participate in the structural link between membrane receptors and the actin cytoskeleton, while others are signalling molecules, including different protein kinases and phosphatases, their substrates, and various adapter proteins. Integrin signaling is dependent upon the non-receptor tyrosine kinase activities of the FAK and src proteins as well as the adaptor protein functions of FAK, src and Shc to initiate downstream signaling events. These signalling events culminate in reorganization of the actin cytoskeleton; a prerequisite for changes in cell shape and motility, and gene expression. Similar morphological alterations and modulation of gene expression are initiated by the binding of growth factors to their respective receptors, emphasizing the considerable crosstalk between adhesion- and growth factor-mediated signalling.


description_brief: ECM-receptor interaction
systematic_name: M7098
exact_source: hsa04512
external_details_URL: http://www.genome.jp/pathway/hsa04512
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  The extracellular matrix (ECM) consists of a complex mixture of structural and functional macromolecules and serves an important role in tissue and organ morphogenesis and in the maintenance of cell and tissue structure and function. Specific interactions between cells and the ECM are mediated by transmembrane molecules, mainly integrins and perhaps also proteoglycans, CD36, or other cell-surface-associated components. These interactions lead to a direct or indirect control of cellular activities such as adhesion, migration, differentiation, proliferation, and apoptosis. In addition, integrins function as mechanoreceptors and provide a force-transmitting physical link between the ECM and the cytoskeleton. Integrins are a family of glycosylated, heterodimeric transmembrane adhesion receptors that consist of noncovalently bound alpha- and beta-subunits.


description_brief: Cell adhesion molecules (CAMs)
systematic_name: M16476
exact_source: hsa04514
external_details_URL: http://www.genome.jp/pathway/hsa04514
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Cell adhesion molecules are (glyco)proteins expressed on the cell surface and play a critical role in a wide array of biologic processes that include hemostasis, the immune response, inflammation, embryogenesis, and development of neuronal tissue. There are four main groups: the integrin family, the immunoglobulin superfamily, selectins, and cadherins. Membrane proteins that mediate immune cellcell interactions fall into different categories, namely those involved in antigen recognition, costimulation and cellular adhesion. Furthermore cell-cell adhesions are important for brain morphology and highly coordinated brain functions such as memory and learning. During early development of the nervous system, neurons elongate their axons towards their targets and establish and maintain synapses through formation of cell-cell adhesions. Cell-cell adhesions also underpin axon-axon contacts and link neurons with supporting schwann cells and oligodendrocytes.


description_brief: Adherens junction
systematic_name: M638
exact_source: hsa04520
external_details_URL: http://www.genome.jp/pathway/hsa04520
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Cell-cell adherens junctions (AJs), the most common type of intercellular adhesions, are important for maintaining tissue architecture and cell polarity and can limit cell movement and proliferation. At AJs, E-cadherin serves as an essential cell adhesion molecules (CAMs). The cytoplasmic tail binds beta-catenin, which in turn binds alpha-catenin. Alpha-catenin is associated with F-actin bundles directly and indirectly. The integrity of the cadherin-catenin complex is negatively regulated by phosphorylation of beta-catenin by receptor tyrosine kinases (RTKs) and cytoplasmic tyrosine kinases (Fer, Fyn, Yes, and Src), which leads to dissociation of the cadherin-catenin complex. Integrity of this complex is positively regulated by beta -catenin phosphorylation by casein kinase II, and dephosphorylation by protein tyrosine phosphatases. Changes in the phosphorylation state of beta-catenin affect cell-cell adhesion, cell migration and the level of signaling beta-catenin. Wnt signaling acts as a positive regulator of beta-catenin by inhibiting beta-catenin degradation, which stabilizes beta-catenin, and causes its accumulation. Cadherin may acts as a negative regulator of signaling beta-catenin as it binds beta-catenin at the cell surface and thereby sequesters it from the nucleus. Nectins also function as CAMs at AJs, but are more highly concentrated at AJs than E-cadherin. Nectins transduce signals through Cdc42 and Rac, which reorganize the actin cytoskeleton, regulate the formation of AJs, and strengthen cell-cell adhesion.


description_brief: Tight junction
systematic_name: M11355
exact_source: hsa04530
external_details_URL: http://www.genome.jp/pathway/hsa04530
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Epithelial tight junctions (TJs) are composed of at least three types of transmembrane protein -occludin, claudin and junctional adhesion molecules (JAMs)- and a cytoplasmic 'plaque' consisting of many different proteins that form large complexes. The transmembrane proteins mediate cell adhesion and are thought to constitute the intramembrane and paracellular diffusion barriers. The cytoplasmic 'plaque' contains three major multi-protein complexes consisting largely of scaffolding proteins, the ZO protein complex, the CRB3-Pals1-PATJ complex and the PAR-3-aPKC-PAR-6 complex. The ZO protein complex appears to organize the transmembrane proteins and couple them to other cytoplasmic proteins and to actin microfilaments. Two evolutionarily conserved protein complexes, the CRB3 and PAR complexes are involved in the establishment and maintenance of epithelial cell polarity. Besides these three protein complexes which seem to be constitutively associated at TJs, a number of proteins with different functions has been identified at TJs. These include additional scaffolding proteins like MUPP1 and MAGI-1, adaptor proteins, transcription regulators and RNA processing factors, regulatory proteins like small GTPases and G-proteins, kinases and phosphatases, and heat shock proteins. These are proposed to be involved in junction assembly, barrier regulation, gene transcription, and perhaps other, presently undefined pathways.


description_brief: Gap junction
systematic_name: M4013
exact_source: hsa04540
external_details_URL: http://www.genome.jp/pathway/hsa04540
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Gap junctions contain intercellular channels that allow direct communication between the cytosolic compartments of adjacent cells. Each gap junction channel is formed by docking of two 'hemichannels', each containing six connexins, contributed by each neighboring cell. These channels permit the direct transfer of small molecules including ions, amino acids, nucleotides, second messengers and other metabolites between adjacent cells. Gap junctional communication is essential for many physiological events, including embryonic development, electrical coupling, metabolic transport, apoptosis, and tissue homeostasis. Communication through Gap Junction is sensitive to a variety of stimuli, including changes in the level of intracellular Ca2+, pH, transjunctional applied voltage and phosphorylation/dephosphorylation processes. This figure represents the possible activation routes of different protein kinases involved in Cx43 and Cx36 phosphorylation.


description_brief: Complement and coagulation cascades
systematic_name: M16894
exact_source: hsa04610
external_details_URL: http://www.genome.jp/pathway/hsa04610
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Blood coagulation is a series of coordinated and calcium-dependent proenzyme-to-serine protease conversions likely to be localized on the surfaces of activated cells in vivo. It culminates in the formation of thrombin, the enzyme responsible for the conversion of soluble fibrinogen to the insoluble fibrin clot. The kallikrein-kinin system is an endogenous metabolic cascade, triggering of which results in the release of vasoactive kinins (bradykinin-related peptides). Kinin peptides are implicated in many physiological and pathological processes including the regulation of blood pressure and sodium homeostasis, inflammatory processes, and the cardioprotective effects of preconditioning. Complement is a system of plasma proteins that is activated by the presence of pathogens. There are three pathways of complement activation: the classical pathway, the lectin pathway, and the alternative pathway. All of these pathways generate a crucial enzymatic activity that, intern, generates the effector molecules of complement. The three main consequences of complement activation are the opsonization of pathogens, the recruitment of inflammatory and immunocompetent cells, and the direct killing of pathogens.


description_brief: Toll-like receptor signaling pathway
systematic_name: M3261
exact_source: hsa04620
external_details_URL: http://www.genome.jp/pathway/hsa04620
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Specific families of pattern recognition receptors are responsible for detecting microbial pathogens and generating innate immune responses. Toll-like receptors (TLRs) are membrane-bound receptors identified as homologs of Toll in Drosophila. Mammalian TLRs are expressed on innate immune cells, such as macrophages and dendritic cells, and respond to the membrane components of Gram-positive or Gram-negative bacteria. Pathogen recognition by TLRs provokes rapid activation of innate immunity by inducing production of proinflammatory cytokines and upregulation of costimulatory molecules. TLR signaling pathways are separated into two groups: a MyD88-dependent pathway that leads to the production of proinflammatory cytokines with quick activation of NF-{kappa}B and MAPK, and a MyD88-independent pathway associated with the induction of IFN-beta and IFN-inducible genes, and maturation of dendritic cells with slow activation of NF-{kappa}B and MAPK.


description_brief: NOD-like receptor signaling pathway
systematic_name: M15569
exact_source: hsa04621
external_details_URL: http://www.genome.jp/pathway/hsa04621
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Specific families of pattern recognition receptors are responsible for detecting various pathogens and generating innate immune responses. The intracellular NOD-like receptor (NLR) family contains more than 20 members in mammals and plays a pivotal role in the recognition of intracellular ligands. NOD1 and NOD2, two prototypic NLRs, sense the cytosolic presence of the bacterial peptidoglycan fragments that escaped from endosomal compartments, driving the activation of NF-{kappa}B and MAPK, cytokine production and apoptosis. On the other hand, a different set of NLRs induces caspase-1 activation through the assembly of multiprotein complexes called inflammasomes. These NLRs include NALP1, NALP3 and Ipaf. The inflammasomes are critical for generating mature proinflammatory cytokines in concert with Toll-like receptor signaling pathway.


description_brief: RIG-I-like receptor signaling pathway
systematic_name: M15913
exact_source: hsa04622
external_details_URL: http://www.genome.jp/pathway/hsa04622
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Specific families of pattern recognition receptors are responsible for detecting viral pathogens and generating innate immune responses. Non-self RNA appearing in a cell as a result of intracellular viral replication is recognized by a family of cytosolic RNA helicases termed RIG-I-like receptors (RLRs). The RLR proteins include RIG-I, MDA5, and LGP2 and are expressed in both immune and nonimmune cells. Upon recognition of viral nucleic acids, RLRs recruit specific intracellular adaptor proteins to initiate signaling pathways that lead to the synthesis of type I interferon and other inflammatory cytokines, which are important for eliminating viruses.


description_brief: Cytosolic DNA-sensing pathway
systematic_name: M11844
exact_source: hsa04623
external_details_URL: http://www.genome.jp/pathway/hsa04623
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Specific families of pattern recognition receptors are responsible for detecting foreign DNA from invading microbes or host cells and generating innate immune responses. DAI is the first identified sensor of cytosolic DNA which activates the IRF and NF-{kappa}B transcription factors, leading to production of type I interferon and other cytokines. The second type of cytoplasmic DNA sensor is AIM2. Upon sensing DNA, AIM2 triggers the assembly of the inflammasome, culminating in interleukin maturation. In addition to these receptors, there is a mechanism to sense foreign DNA, with the host RNA polymerase III converting the DNA into RNA for recognition by the RNA sensor RIG-I. These pathways provide various means to alert the cell.


description_brief: Jak-STAT signaling pathway
systematic_name: M17411
exact_source: hsa04630
external_details_URL: http://www.genome.jp/pathway/hsa04630
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is one of a handful of pleiotropic cascades used to transduce a multitude of signals for development and homeostasis in animals, from humans to flies. In mammals, the JAK/STAT pathway is the principal signaling mechanism for a wide array of cytokines and growth factors. Following the binding of cytokines to their cognate receptor, STATs are activated by members of the JAK family of tyrosine kinases. Once activated, they dimerize and translocate to the nucleus and modulate the expression of target genes. In addition to the activation of STATs, JAKs mediate the recruitment of other molecules such as the MAP kinases, PI3 kinase etc. These molecules process downstream signals via the Ras-Raf-MAP kinase and PI3 kinase pathways which results in the activation of additional transcription factors.


description_brief: Hematopoietic cell lineage
systematic_name: M6856
exact_source: hsa04640
external_details_URL: http://www.genome.jp/pathway/hsa04640
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Blood-cell development progresses from a hematopoietic stem cell (HSC), which can undergo either self-renewal or differentiation into a multilineage committed progenitor cell: a common lymphoid progenitor (CLP) or a common myeloid progenitor (CMP). A CLP gives rise to the lymphoid lineage of white blood cells or leukocytes-the natural killer (NK) cells and the T and B lymphocytes. A CMP gives rise to the myeloid lineage, which comprises the rest of the leukocytes, the erythrocytes (red blood cells), and the megakaryocytes that produce platelets important in blood clotting. Cells undergoing these differentiation process express a stage- and lineage-specific set of surface markers. Therefore cellular stages are identified by the specific expression patterns of these genes.


description_brief: Natural killer cell mediated cytotoxicity
systematic_name: M5669
exact_source: hsa04650
external_details_URL: http://www.genome.jp/pathway/hsa04650
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Natural killer (NK) cells are lymphocytes of the innate immune system that are involved in early defenses against both allogeneic (nonself) cells and autologous cells undergoing various forms of stress, such as infection with viruses, bacteria, or parasites or malignant transformation. Although NK cells do not express classical antigen receptors of the immunoglobulin gene family, such as the antibodies produced by B cells or the T cell receptor expressed by T cells, they are equipped with various receptors whose engagement allows them to discriminate between target and nontarget cells. Activating receptors bind ligands on the target cell surface and trigger NK cell activation and target cell lysis. However Inhibitory receptors recognize MHC class I molecules (HLA) and inhibit killing by NK cells by overruling the actions of the activating receptors. This inhibitory signal is lost when the target cells do not express MHC class I and perhaps also in cells infected with virus, which might inhibit MHC class I exprssion or alter its conformation. The mechanism of NK cell killing is the same as that used by the cytotoxic T cells generated in an adaptive immune response; cytotoxic granules are released onto the surface of the bound target cell, and the effector proteins they contain penetrate the cell membrane and induce programmed cell death.


description_brief: T cell receptor signaling pathway
systematic_name: M9904
exact_source: hsa04660
external_details_URL: http://www.genome.jp/pathway/hsa04660
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Activation of T lymphocytes is a key event for an efficient response of the immune system. It requires the involvement of the T-cell receptor (TCR) as well as costimulatory molecules such as CD28. Engagement of these receptors through the interaction with a foreign antigen associated with major histocompatibility complex molecules and CD28 counter-receptors B7.1/B7.2, respectively, results in a series of signaling cascades. These cascades comprise an array of protein-tyrosine kinases, phosphatases, GTP-binding proteins and adaptor proteins that regulate generic and specialised functions, leading to T-cell proliferation, cytokine production and differentiation into effector cells.


description_brief: B cell receptor signaling pathway
systematic_name: M5436
exact_source: hsa04662
external_details_URL: http://www.genome.jp/pathway/hsa04662
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  B cells are an important component of adaptive immunity. They produce and secrete millions of different antibody molecules, each of which recognizes a different (foreign) antigen. The B cell receptor (BCR) is an integral membrane protein complex that is composed of two immunoglobulin (Ig) heavy chains, two Ig light chains and two heterodimers of Ig-alpha and Ig-beta. After BCR ligation by antigen, three main protein tyrosine kinases (PTKs) -the SRC-family kinase LYN, SYK and the TEC-family kinase BTK- are activated. Phosphatidylinositol 3-kinase (PI3K) and phospholipase C-gamma 2 (PLC-gamma 2) are important downstream effectors of BCR signalling. This signalling ultimately results in the expression of immediate early genes that further activate the expression of other genes involved in B cell proliferation, differentiation and Ig production as well as other processes.


description_brief: Fc epsilon RI signaling pathway
systematic_name: M11816
exact_source: hsa04664
external_details_URL: http://www.genome.jp/pathway/hsa04664
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Fc epsilon RI-mediated signaling pathways in mast cells are initiated by the interaction of antigen (Ag) with IgE bound to the extracellular domain of the alpha chain of Fc epsilon RI. The activation pathways are regulated both positively and negatively by the interactions of numerous signaling molecules. Mast cells that are thus activated release preformed granules which contain biogenic amines (especially histamines) and proteoglycans (especially heparin). The activation of phospholipase A2 causes the release of membrane lipids followed by development of lipid mediators such as leukotrienes (LTC4, LTD4 and LTE4) and prostaglandins (especially PDG2). There is also secretion of cytokines, the most important of which are TNF-alpha, IL-4 and IL-5. These mediators and cytokines contribute to inflammatory responses.


description_brief: Fc gamma R-mediated phagocytosis
systematic_name: M16121
exact_source: hsa04666
external_details_URL: http://www.genome.jp/pathway/hsa04666
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Phagocytosis plays an essential role in host-defense mechanisms through the uptake and destruction of infectious pathogens. Specialized cell types including macrophages, neutrophils, and monocytes take part in this process in higher organisms. After opsonization with antibodies (IgG), foreign extracellular materials are recognized by Fc gamma receptors. Cross-linking of Fc gamma receptors initiates a variety of signals mediated by tyrosine phosphorylation of multiple proteins, which lead through the actin cytoskeleton rearrangements and membrane remodeling to the formation of phagosomes. Nascent phagosomes undergo a process of maturation that involves fusion with lysosomes. The acquisition of lysosomal proteases and release of reactive oxygen species are crucial for digestion of engulfed materials in phagosomes.


description_brief: Leukocyte transendothelial migration
systematic_name: M2164
exact_source: hsa04670
external_details_URL: http://www.genome.jp/pathway/hsa04670
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Leukocyte migaration from the blood into tissues is vital for immune surveillance and inflammation. During this diapedesis of leukocytes, the leukocytes bind to endothelial cell adhesion molecules (CAM) and then migrate across the vascular endothelium. A leukocyte adherent to CAMs on the endothelial cells moves forward by leading-edge protrusion and retraction of its tail. In this process, alphaL /beta2 integrin activates through Vav1, RhoA, which subsequently activates the kinase p160ROCK. ROCK activation leads to MLC phosphorylation, resulting in retraction of the actin cytoskeleton. Moreover, Leukocytes activate endothelial cell signals that stimulate endothelial cell retraction during localized dissociation of the endothelial cell junctions. ICAM-1-mediated signals activate an endothelial cell calcium flux and PKC, which are required for ICAM-1 dependent leukocyte migration. VCAM-1 is involved in the opening of the endothelial passage through which leukocytes can extravasate. In this regard, VCAM-1 ligation induces NADPH oxidase activation and the production of reactive oxygen species (ROS) in a Rac-mediated manner, with subsequent activation of matrix metallopoteinases and loss of VE-cadherin-mediated adhesion.


description_brief: Intestinal immune network for IgA production
systematic_name: M615
exact_source: hsa04672
external_details_URL: http://www.genome.jp/pathway/hsa04672
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  The intestine is the largest lymphoid tissue in the body. One striking feature of intestinal immunity is its ability to generate great amounts of noninflammatory immunoglobulin A (IgA) antibodies that serve as the first line of defense against microorganisms. The basic map of IgA production includes induction of mucosal B cells in the Peyer's patches, circulation through the bloodstream and homing to intestinal mucosa of IgA-commited plasma cells, and local antibody production for export across the intestinal membranes. Multiple cytokines, including TGF-{beta}, IL-10, IL-4, IL-5, and IL-6, are required to promote IgA class switching and terminal differentiation process of the B cells. Secreted IgA promotes immune exclusion by entrapping dietary antigens and microorganisms in the mucus and functions for neutralization of toxins and pathogenic microbes.


description_brief: Long-term potentiation
systematic_name: M3115
exact_source: hsa04720
external_details_URL: http://www.genome.jp/pathway/hsa04720
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Hippocampal long-term potentiation (LTP), a long-lasting increase in synaptic efficacy, is the molecular basis for learning and memory. Tetanic stimulation of afferents in the CA1 region of the hippocampus induces glutamate release and activation of glutamate receptors in dendritic spines. A large increase in i resulting from influx through NMDA receptors leads to constitutive activation of CaM kinase II (CaM KII). Constitutively active CaM kinase II phosphorylates AMPA receptors, resulting in potentiation of the ionic conductance of AMPA receptors. Early-phase LTP (E-LTP) expression is due, in part, to this phosphorylation of the AMPA receptor. It is hypothesized that postsynaptic Ca2+ increases generated through NMDA receptors activate several signal transduction pathways including the Erk/MAP kinase and cAMP regulatory pathways. The convergence of these pathways at the level of the CREB/CRE transcriptional pathway may increase expression of a family of genes required for late-phase LTP (L-LTP).


description_brief: Neurotrophin signaling pathway
systematic_name: M16763
exact_source: hsa04722
external_details_URL: http://www.genome.jp/pathway/hsa04722
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Neurotrophins are a family of trophic factors involved in differentiation and survival of neural cells. The neurotrophin family consists of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). Neurotrophins exert their functions through engagement of Trk tyrosine kinase receptors or p75 neurotrophin receptor (p75NTR). Neurotrophin/Trk signaling is regulated by connecting a variety of intracellular signaling cascades, which include MAPK pathway, PI-3 kinase pathway, and PLC pathway, transmitting positive signals like enhanced survival and growth. On the other hand, p75NTR transmits both positive and nagative signals. These signals play an important role for neural development and additional higher-order activities such as learning and memory.


description_brief: Long-term depression
systematic_name: M8232
exact_source: hsa04730
external_details_URL: http://www.genome.jp/pathway/hsa04730
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Cerebellar long-term depression (LTD), thought to be a molecular and cellular basis for cerebellar learning, is a process involving a decrease in the synaptic strength between parallel fiber (PF) and Purkinje cells (PCs) induced by the conjunctive activation of PFs and climbing fiber (CF). Multiple signal transduction pathways have been shown to be involved in this process. Activation of PFs terminating on spines in dendritic branchlets leads to glutamate release and activation of both AMPA and mGluRs. Activation of CFs, which make multiple synaptic contacts on proximal dendrites, also via AMPA receptors, opens voltage-gated calcium channels (VGCCs) and causes a generalized influx of calcium. These cellular signals, generated from two different synaptic origins, trigger a cascade of events culminating in a phosphorylation-dependent, long-term reduction in AMPA receptor sensitivity at the PF-PC synapse. This may take place either through receptor internalization and/or through receptor desensitization.


description_brief: Olfactory transduction
systematic_name: M14091
exact_source: hsa04740
external_details_URL: http://www.genome.jp/pathway/hsa04740
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Within the compact cilia of the olfactory receptor neurons (ORNs) a cascade of enzymatic activity transduces the binding of an odorant molecule to a receptor into an electrical signal that can be transmitted to the brain. Odorant molecules bind to a receptor protein (R) coupled to an olfactory specific Gs-protein (G) and activate a type III adenylyl cyclase (AC), increasing intracellular cAMP levels. cAMP targets an olfactory-specific cyclic-nucleotide gated ion channel (CNG), allowing cations, particularly Na and Ca, to flow down their electrochemical gradients into the cell, depolarizing the ORN. Furthermore, the Ca entering the cell is able to activate a Ca-activated Cl channel, which would allow Cl to flow out of the cell, thus further increasing the depolarization. Elevated intracellular Ca causes adaptation by at least two different molecular steps: inhibition of the activity of adenylyl cyclase via CAMKII-dependent phosphorylation and down-regulation of the affinity of the CNG channel to cAMP.Longer exposure to odorants can stimulate particulate guanylyl cyclase in cilia to produce cGMP and activate PKG, leading to a further increase in amount and duration of intracellular cAMP levels, which may serve to convert inactive forms of protein kinase A (PKA2) to active forms (PKA*). As part of a feedback loop, PKA can inhibit the activation of particulate guanylyl cyclase.


description_brief: Insulin signaling pathway
systematic_name: M18155
exact_source: hsa04910
external_details_URL: http://www.genome.jp/pathway/hsa04910
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Insulin binding to its receptor results in the tyrosine phosphorylation of insulin receptor substrates (IRS) by the insulin receptor tyrosine kinase (INSR). This allows association of IRSs with the regulatory subunit of phosphoinositide 3-kinase (PI3K). PI3K activates 3-phosphoinositide-dependent protein kinase 1 (PDK1), which activates Akt, a serine kinase. Akt in turn deactivates glycogen synthase kinase 3 (GSK-3), leading to activation of glycogen synthase (GYS) and thus glycogen synthesis. Activation of Akt also results in the translocation of GLUT4 vesicles from their intracellular pool to the plasma membrane, where they allow uptake of glucose into the cell. Akt also leads to mTOR-mediated activation of protein synthesis by eIF4 and p70S6K. The translocation of GLUT4 protein is also elicited through the CAP/Cbl/TC10 pathway, once Cbl is phosphorylated by INSR. Other signal transduction proteins interact with IRS including GRB2. GRB2 is part of the cascade including SOS, RAS, RAF and MEK that leads to activation of mitogen-activated protein kinase (MAPK) and mitogenic responses in the form of gene transcription. SHC is another substrate of INSR. When tyrosine phosphorylated, SHC associates with GRB2 and can thus activate the RAS/MAPK pathway independently of IRS-1.


description_brief: GnRH signaling pathway
systematic_name: M1979
exact_source: hsa04912
external_details_URL: http://www.genome.jp/pathway/hsa04912
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus acts upon its receptor in the anterior pituitary to regulate the production and release of the gonadotropins, LH and FSH. The GnRHR is coupled to Gq/11 proteins to activate phospholipase C which transmits its signal to diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG activates the intracellular protein kinase C (PKC) pathway and IP3 stimulates release of intracellular calcium. In addition to the classical Gq/11, coupling of Gs is occasionally observed in a cell-specific fashion. Signaling downstream of protein kinase C (PKC) leads to transactivation of the epidermal growth factor (EGF) receptor and activation of mitogen-activated protein kinases (MAPKs), including extracellular-signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and p38 MAPK. Active MAPKs translocate to the nucleus, resulting in activation of transcription factors and rapid induction of early genes.


description_brief: Progesterone-mediated oocyte maturation
systematic_name: M3578
exact_source: hsa04914
external_details_URL: http://www.genome.jp/pathway/hsa04914
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Xenopus oocytes are naturally arrested at G2 of meiosis I. Exposure to either insulin/IGF-1 or the steroid hormone progesterone breaks this arrest and induces resumption of the two meiotic division cycles and maturation of the oocyte into a mature, fertilizable egg. This process is termed oocyte maturation. The transition is accompanied by an increase in maturation promoting factor (MPF or Cdc2/cyclin B) which precedes germinal vesicle breakdown (GVBD). Most reports point towards the Mos-MEK1-ERK2 pathway and the polo-like kinase/CDC25 pathway as responsible for the activation of MPF in meiosis, most likely triggered by a decrease in cAMP.


description_brief: Melanogenesis
systematic_name: M7761
exact_source: hsa04916
external_details_URL: http://www.genome.jp/pathway/hsa04916
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Cutaneous melanin pigment plays a critical role in camouflage, mimicry, social communication, and protection against harmful effects of solar radiation. Melanogenesis is under complex regulatory control by multiple agents. The most important positive regulator of melanogenesis is the MC1 receptor with its ligands melanocortic peptides. MC1R activates the cyclic AMP (cAMP) response-element binding protein (CREB). Increased expression of MITF and its activation by phosphorylation (P) stimulate the transcription of tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), and dopachrome tautomerase (DCT), which produce melanin. Melanin synthesis takes place within specialized intracellular organelles named melanosomes. Melanin-containing melanosomes then move from the perinuclear region to the dendrite tips and are transferred to keratinocytes by a still not well-characterized mechanism.


description_brief: Adipocytokine signaling pathway
systematic_name: M10462
exact_source: hsa04920
external_details_URL: http://www.genome.jp/pathway/hsa04920
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Increased adipocyte volume and number are positively correlated with leptin production, and negatively correlated with production of adiponectin. Leptin is an important regulator of energy intake and metabolic rate primarily by acting at hypothalamic nuclei. Leptin exerts its anorectic effects by modulating the levels of neuropeptides such as NPY, AGRP, and alpha-MSH. This leptin action is through the JAK kinase, STAT3 phosphorylation, and nuclear transcriptional effect. Adiponectin lowers plasma glucose and FFAs. These effects are partly accounted for by adiponectin-induced AMPK activation, which in turn stimulates skeletal muscle fatty acid oxidation and glucose uptake. Furthermore, activation of AMPK by adiponectin suppresses endogenous glucose production, concomitantly with inhibition of PEPCK and G6Pase expression. The proinflammatory cytokine TNFalpha has been implicated as a link between obesity and insulin resistance. TNFalpha interferes with early steps of insulin signaling. Several data have shown that TNFalpha inhibits IRS1 tyrosine phosphorylation by promoting its serine phosphorylation. Among the serine/threonine kinases activated by TNFalpha, JNK, mTOR and IKK have been shown to be involved in this phosphorylation.


description_brief: Type II diabetes mellitus
systematic_name: M19708
exact_source: hsa04930
external_details_URL: http://www.genome.jp/pathway/hsa04930
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Insulin resistance is strongly associated with type II diabetes. Diabetogenic factors including FFA, TNFalpha and cellular stress induce insulin resistance through inhibition of IRS1 functions. Serine/threonine phosphorylation, interaction with SOCS, regulation of the expression, modification of the cellular localization, and degradation represent the molecular mechanisms stimulated by them. Various kinases (ERK, JNK, IKKbeta, PKCzeta, PKCtheta and mTOR) are involved in this process. The development of type II diabetes requires impaired beta-cell function. Chronic hyperglycemia has been shown to induce multiple defects in beta-cells. Hyperglycemia has been proposed to lead to large amounts of reactive oxygen species (ROS) in beta-cells, with subsequent damage to cellular components including PDX-1. Loss of PDX-1, a critical regulator of insulin promoter activity, has also been proposed as an important mechanism leading to beta-cell dysfunction. Although there is little doubt as to the importance of genetic factors in type II diabetes, genetic analysis is difficult due to complex interaction among multiple susceptibility genes and between genetic and environmental factors. Genetic studies have therefore given very diverse results. Kir6.2 and IRS are two of the candidate genes. It is known that Kir6.2 and IRS play central roles in insulin secretion and insulin signal transmission, respectively.


description_brief: Type I diabetes mellitus
systematic_name: M12617
exact_source: hsa04940
external_details_URL: http://www.genome.jp/pathway/hsa04940
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Type I diabetes mellitus is a disease that results from autoimmune destruction of the insulin-producing beta-cells. Certain beta-cell proteins act as autoantigens after being processed by antigen-presenting cell (APC), such as macrophages and dendritic cells, and presented in a complex with MHC-II molecules on the surface of the APC. Then immunogenic signals from APC activate CD4+ T cells, predominantly of the Th1 subset. Antigen-activated Th1 cells produce IL-2 and IFNgamma. They activate macrophages and cytotoxic CD8+ T cells, and these effector cells may kill islet beta-cells by one or both of two types of mechanisms: (1) direct interactions of antigen-specific cytotoxic T cells with a beta-cell autoantigen-MHC-I complex on the beta-cell, and (2) non-specific inflammatory mediators, such as free radicals/oxidants and cytokines (IL-1, TNFalpha, TNFbeta, IFNgamma). Type I diabetes is a polygenic disease. One of the principle determining genetic factors in diabetes incidence is the inheritance of mutant MHC-II alleles. Another plausible candidate gene is the insulin gene.


description_brief: Maturity onset diabetes of the young
systematic_name: M18312
exact_source: hsa04950
external_details_URL: http://www.genome.jp/pathway/hsa04950
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  About 2-5% of type II diabetic patients suffer from a monogenic disease with autosomal dominant inheritance. This monogenic form of type II diabetes is called maturity onset diabetes of the young (MODY). We now know that MODY is caused by heterozygous mutations in at least five genes encoding transcription factors: HNF4alpha (MODY1), HNF1alpha (MODY3), PDX1 (MODY4), HNF1beta (MODY5) and NEUROD1 (MODY6). MODY2, which is so far the only subtype not related to a transcription factor, is caused by mutations in the glucokinase gene. Mutations of MODY transcription factor genes lead to abnormal expression of genes involved in pancreatic islet development and metabolism.


description_brief: Aldosterone-regulated sodium reabsorption
systematic_name: M16473
exact_source: hsa04960
external_details_URL: http://www.genome.jp/pathway/hsa04960
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Sodium transport across the tight epithelia of Na+ reabsorbing tissues such as the distal part of the kidney nephron and colon is the major factor determining total-body Na+ levels, and thus, long-term blood pressure. Aldosterone plays a major role in sodium and potassium metabolism by binding to epithelial mineralocorticoid receptors (MR) in the renal collecting duct cells localized in the distal nephron, promoting sodium resorption and potassium excretion. Aldosterone enters a target cell and binds MR, which translocates into the nucleus and regulates gene transcription. Activation of MR leads to increased expression of Sgk-1, which phosphorylates Nedd4-2, an ubiquitin-ligase which targets ENAC to proteosomal degradation. Phosphorylated Nedd4-2 dissociates from ENAC, increasing its apical membrane abundance. Activation of MR also leads to increased expression of Na+/K+-ATPase, thus causing a net increase in sodium uptake from the renal filtrate. The specificity of MR for aldosterone is provided by 11beta-HSD2 by the rapid conversion of cortisol to cortisone in renal cortical collecting duct cells. Recently, besides genomic effects mediated by activated MR, rapid aldosterone actions that are independent of translation and transcription have been documented.


description_brief: Vasopressin-regulated water reabsorption
systematic_name: M9011
exact_source: hsa04962
external_details_URL: http://www.genome.jp/pathway/hsa04962
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  In the kidney, the antidiuretic hormone vasopressin (AVP) is a critical regulator of water homeostasis by controlling the water movement from lumen to the interstitium for water reabsorption and adjusting the urinary water excretion. In normal physiology, AVP is secreted into the circulation by the posterior pituitary gland, in response to an increase in serum osmolality or a decrease in effective circulating volume. When reaching the kidney, AVP binds to V2 receptors on the basolateral surface of the collecting duct epithelium, triggering a G-protein-linked signaling cascade, which leads to water channel aquaporin-2 (AQP2) vesicle insertion into the apical plasma membrane. This results in higher water permeability in the collecting duct and, driven by an osmotic gradient, pro-urinary water then passes the membrane through AQP2 and leaves the cell on the basolateral side via AQP3 and AQP4 water channels, which are constitutively expressed on the basolateral side of these cells. When isotonicity is restored, reduced blood AVP levels results in AQP2 internalization, leaving the apical membrane watertight again.


description_brief: Alzheimer's disease
systematic_name: M16024
exact_source: hsa05010
external_details_URL: http://www.genome.jp/pathway/hsa05010
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Alzheimer's disease (AD) is a chronic disorder that slowly destroys neurons and causes serious cognitive disability. AD is associated with senile plaques and neurofibrillary tangles (NFTs). Amyloid-beta (Abeta), a major component of senile plaques, has various pathological effects on cell and organelle function. The extracellular Abeta oligomers may activate caspases through activation of cell surface death receptors. Alternatively, intracellular Abeta may contribute to pathology by facilitating tau hyper-phosphorylation, disrupting mitochondria function, and triggering calcium dysfunction. To date genetic studies have revealed four genes that may be linked to autosomal dominant or familial early onset AD (FAD). These four genes include: amyloid precursor protein (APP), presenilin 1 (PS1), presenilin 2 (PS2) and apolipoprotein E (ApoE). All mutations associated with APP and PS proteins can lead to an increase in the production of Abeta peptides, specifically the more amyloidogenic form, Abeta42. FAD-linked PS1 mutation downregulates the unfolded protein response and leads to vulnerability to ER stress.


description_brief: Parkinson's disease
systematic_name: M7272
exact_source: hsa05012
external_details_URL: http://www.genome.jp/pathway/hsa05012
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Parkinson's disease (PD) is a progressive neurodegenerative movement disorder that results primarily from the death of dopaminergic neurons in the substantia nigra. Mutations in alpha-synuclein, UCHL1 (a ubiquitin carboxy-terminal hydrolase L1), parkin, DJ1 (a parkin-associated protein involved with oxidative stress), and PINK1 (a putative serine threonine kinase) are known to cause early-onset PD. Mutations or altered expression of these proteins contributes to PD pathogenesis through common mechanisms that result in proteasome dysfunction, mitochondrial impairment, and oxidative stress. Point mutations in alpha-synuclein and the recently described Iowan functional duplication of alpha-synuclein lead to excessive intracellular accumulation and protofibril formation. Decrease in the amount of soluble alpha-synuclein tends to increase free cytoplasmic dopamine and the formation of reactive oxygen species (ROS). Indeed, formation of protofibrils or aggregates and Lewy bodies (LBs) diminishes the availability of the physiological forms of alpha-synuclein, favoring an increase in TH (tyrosine hydroxylase) and DAT (dopamine transporter), but diminishes vesicles formation and neuronal plasticity. Modification of parkin and UCHL1 are associated with the ubiquitin-proteasome system pathway and may increase proteotoxic stress. Mutations in parkin, DJ1, and PINK1 may alter mitochondiral activity, potentially impairing proteasomal function. Environmental toxins such as N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and rotenone can cause mitochondrial dysfunction and oxidative stress.


description_brief: Amyotrophic lateral sclerosis (ALS)
systematic_name: M3812
exact_source: hsa05014
external_details_URL: http://www.genome.jp/pathway/hsa05014
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Amyotrophic lateral sclerosis (ALS) is a progressive, lethal, degenerative disorder of motor neurons. The hallmark of this disease is the selective death of motor neurons in the brain and spinal cord, leading to paralysis of voluntary muscles. Mutant superoxide dismutase 1 (SOD1), as seen in some familial amyotrophic lateral sclerosis (FALS) cases, may be toxic because it is unstable, forming aggregates in the motor neuron cytoplasm, axoplasm and mitochondria. Within mitochondria, mutant SOD1 may interfere with the anti-apoptotic function of Bcl-2, affect mitochondrial import by interfering with the translocation machinery (TOM/TIM), and generate toxic free radicals (ROS) via aberrant superoxide chemistry. These changes may then result in abnormal mitochondrial energy metabolism, Ca2+ handling, and release of pro-apoptotic factors. Reactive oxygen species (ROS), produced within mitochondria, inhibit the function of EAAT2, the main glial glutamate transporter protein, responsible for most of the reuptake of synaptically released glutamate. Glutamate excess causes neurotoxicity by increasing intracellular calcium, which enhances oxidative stress and mitochondrial damage. Mutant SOD1 can also trigger oxidative reactions by various means including by increasing levels of peroxynitrite, which can then cause damage through the formation of hydroxyl radicals or via nitration of tyrosine residues on proteins. Nitration may target neurofilament proteins, disrupting their phosphorylation and affecting axonal transport. Collectively, these mechanisms (or a combination thereof) are predicted to disturb cellular homeostasis (within glial and/or motor neurons), ultimately triggering motor neuron death.


description_brief: Huntington's disease
systematic_name: M13486
exact_source: hsa05016
external_details_URL: http://www.genome.jp/pathway/hsa05016
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Huntington disease (HD) is an autosomal-dominant neurodegenerative disorder that primarily affects medium spiny striatal neurons (MSN). HD is caused by a CAG repeat expansion in the IT15 gene, which results in a long stretch of polyglutamine close to the amino-terminus of the HD protein huntingtin (Htt). Mutant Htt (mHtt) has effects both in the cytoplasm and in the nucleus. In the cytoplasm, full-length mHtt can interfere with BDNF vesicular transport on microtubules. This mutant protein also may lead to abnormal endocytosis and secretion in neurons, because normal Htt form a complex with the proteins Hip1, clathrin and AP2 that are involved in endocytosis. In addition, mHtt affects Ca2+ signaling by sensitizing InsP3R1 to activation by InsP3, stimulating NR2B/NR1 NMDAR activity, and destabilizing mitochondrial Ca2+ handling. As a result, stimulation of glutamate receptors leads to supranormal Ca2+ responses in HD MSN and mitochondrial Ca2+ overload. The mHtt translocates to the nucleus, where it forms intranuclear inclusions, though they are not primarily responsible for toxicity. Nuclear toxicity is believed to be caused by interference with gene transcription, leading to loss of transcription of neuroprotective molecules such as BDNF. While mHtt binds to p53 and upregulates levels of nuclear p53 as well as p53 transcriptional activity. Augmented p53 mediates mitochondrial dysfunction.


description_brief: Prion diseases
systematic_name: M13036
exact_source: hsa05020
external_details_URL: http://www.genome.jp/pathway/hsa05020
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Prion diseases, also termed transmissible spongiform encephalopathies (TSEs), are a group of fatal neurodegenerative diseases that affect humans and a number of other animal species. The etiology of these diseases is thought to be associated with the conversion of a normal protein, PrPC, into an infectious, pathogenic form, PrPSc. The conversion is induced by prion infections (for example, variant Creutzfeldt-Jakob disease (vCJD), iatrogenic CJD, Kuru), mutations (familial CJD, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia (FFI)) or unknown factors (sporadic CJD (sCJD)), and is thought to occur after PrPC has reached the plasma membrane or is re-internalized for degradation. The PrPSc form shows greater protease resistance than PrPC and accumulates in affected individuals, often in the form of extracellular plaques. Pathways that may lead to neuronal death comprise oxidative stress, regulated activation of complement, ubiquitin-proteasome and endosomal-lysosomal systems, synaptic alterations and dendritic atrophy, corticosteroid response, and endoplasmic reticulum stress. In addition, the conformational transition could lead to the lost of a beneficial activity of the natively folded protein, PrPC.


description_brief: Vibrio cholerae infection
systematic_name: M17906
exact_source: hsa05110
external_details_URL: http://www.genome.jp/pathway/hsa05110
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Cholera toxin (CTX) is one of the main virulence factors of Vibrio cholerae. Once secreted, CTX B-chain (CTXB) binds to ganglioside GM1 on the surface of the host's cells. After binding takes place, the entire CTX complex is carried from plasma membrane (PM) to endoplasmic reticulum (ER). In the ER, the A-chain (CTXA) is recognized by protein disulfide isomerase (PDI), unfolded, and delivered to the membrane where the membrane-associated ER-oxidase, Ero1, oxidizes PDI to release the CTXA into the protein-conducting channel, Sec61. CTXA is then retro-translocated to the cytosol and induces water and electrolyte secretion by increasing cAMP levels via adenylate cyclase (AC) to exert toxicity. Other than CTX, Vibrio cholerae generates several toxins that are perilous to eukaryotic cells. Zonula occludens toxin (ZOT) causes tight junction disruption through protein kinase C-dependent actin polymerization. RTX toxin (RtxA) causes actin depolymerization by covalently cross-linking actin monomers into dimers, trimers, and higher multimers. Vibrio cholerae cytolysin (VCC) is an important pore-forming toxin. The assembly of VCC anion channels in cells cause vacuolization and lysis.


description_brief: Epithelial cell signaling in Helicobacter pylori infection
systematic_name: M16848
exact_source: hsa05120
external_details_URL: http://www.genome.jp/pathway/hsa05120
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Two major virulence factors of H. pylori are the vacuolating cytotoxin (VacA) and the cag type-IV secretion system (T4SS) and its translocated effector protein, cytotoxin-associated antigen A (CagA). VacA binds to lipid rafts and glycosylphosphatidylinositol-anchored proteins (GPI-APs) of the target cell membrane. After insertion into the plasma membrane, VacA channels are endocytosed and eventually reach late endosomal compartments, increasing their permeability to anions with enhancement of the electrogenic vacuolar ATPase (v-ATPase) proton pump. In the presence of weak bases, osmotically active acidotropic ions will accumulate in the endosomes. This leads to water influx and vesicle swelling, an essential step in vacuole formation. In addition, it is reported that the VacA cleavage product binds to the tyrosine phosphatase receptor zeta (Ptprz) on epithelial cells and the induced signaling leads to the phosphorylation of the G protein-coupled receptor kinase-interactor 1 (Git1) and induces ulcerogenesis in mice. The other virulence factor cag T4SS mediates the translocation of the effector protein CagA, which is subsequently phosphorylated by a Src kinase. Phosphorylated CagA interacts with the protein tyrosine phosphatase SHP-2, thus stimulating its phosphatase activity. Activated SHP-2 is able to induce MAPK signalling through Ras/Raf-dependent and -independent mechanisms. Deregulation of this pathway by CagA may lead to abnormal proliferation and movement of gastric epithelial cells.


