id: MODULE:jak_stat_signaling title: Canonical JAK-STAT cytokine signaling pathway module description: >- A taxon-neutral decomposition of the canonical JAK-STAT signal transduction pathway, the principal route by which type I/II cytokines and many hormones convert an extracellular signal into a direct change in gene transcription. The module is phrased as an ordered set of functions rather than a fixed gene list so it can represent the many receptor/JAK/STAT combinations that share the same mechanistic core: (1) a cytokine ligand binds and reorganizes a single-pass transmembrane receptor so that its intracellular domains are brought together; (2) receptor-associated Janus kinases (JAK1, JAK2, JAK3, TYK2) are juxtaposed and trans-activate by reciprocal tyrosine phosphorylation; (3) activated JAKs phosphorylate tyrosines on the receptor tails, creating phosphotyrosine docking sites; (4) latent cytoplasmic STAT transcription factors (STAT1-4, STAT5A, STAT5B, STAT6) are recruited via their SH2 domains and phosphorylated by the JAKs; (5) phosphorylated STATs dimerize through reciprocal SH2-phosphotyrosine contacts and translocate to the nucleus; (6) STAT dimers bind GAS/ISRE elements and drive transcription of cytokine-response genes; and (7) the response is terminated and tuned by SOCS/CIS proteins, protein tyrosine phosphatases (SHP1/SHP2, PTPN2), and PIAS SUMO ligases. Which JAKs and STATs are used is set by the receptor, captured here as variant sets along a receptor-class axis. The pathway is grounded in GO:0007259 (cell surface receptor signaling pathway via JAK-STAT). status: DRAFT evidence: - source_id: GO:0007259 title: cell surface receptor signaling pathway via JAK-STAT statement: >- The module is grounded in the GO biological process term for JAK-STAT signaling, the series of molecular signals initiated by a cytokine binding its receptor and culminating in STAT-dependent transcription. - source_id: PMID:8197455 title: "Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins" statement: >- Foundational description of the JAK-STAT paradigm: receptor-associated JAK tyrosine kinases phosphorylate STAT factors that then translocate to the nucleus and activate transcription, linking cytokine receptors directly to gene expression. - source_id: PMID:25587654 title: "The JAK-STAT pathway: impact on human disease and therapeutic intervention" statement: >- Comprehensive review of the four mammalian JAKs and seven STATs, their pairing with specific cytokine receptors, the activation cascade, negative regulation, and the disease relevance that underlies JAK-inhibitor therapy. - source_id: PMID:28323260 title: "Mechanisms and consequences of Jak-STAT signaling in the immune system" statement: >- Reviews receptor/JAK/STAT pairing rules, STAT dimerization and DNA-element (GAS/ISRE) specificity, and the negative regulators (SOCS, phosphatases, PIAS) that shape immune cytokine responses. - source_id: PMID:17525754 title: "SOCS proteins, cytokine signalling and immune regulation" statement: >- Establishes SOCS/CIS proteins as cytokine-inducible negative-feedback inhibitors of JAK-STAT signaling acting via JAK/kinase inhibition, receptor competition, and SOCS-box-mediated ubiquitination. - source_id: PMID:14525967 title: "Interferon-gamma: an overview of signals, mechanisms and functions" statement: >- Describes the IFN-gamma receptor signaling module in which JAK1 and JAK2 activate STAT1 homodimers that bind GAS elements, an exemplar realization of this generic module. - source_id: PMID:24058787 title: Evolution of the JAK-STAT pathway. statement: >- Taxon scope: the canonical receptor-JAK-STAT pathway was assembled in Bilateria, before the protostome-deuterostome split; Drosophila Domeless-Hopscotch-STAT92E is the invertebrate exemplar. supporting_text: >- These came together to form the canonical JAK-STAT signaling pathway prior to the divergence of protostomia - source_id: PMID:24058787 title: Evolution of the JAK-STAT pathway. statement: >- The ancestral bilaterian pathway had one JAK, one STAT and one SHP and three SOCS proteins; the multiple JAKs and STATs that the receptor-class variant sets choose among are later, vertebrate expansions. supporting_text: >- At the time of the emergence of bilateria, archetypal members of each of the JAK-STAT pathway components had been generated, including a single JAK, STAT and SHP, and three SOCS proteins. - source_id: PMID:24058748 title: Comparative evolutionary genomics of the STAT family of transcription factors. statement: >- The vertebrate STAT1-6 set arose by the two early-vertebrate whole-genome duplications. supporting_text: >- the core of STAT gene regulatory networks, comprising stat1 through 4, stat5 and stat6, arose early in vertebrate evolution, probably through the two whole genome duplication events - source_id: PANTHER:PTN001562978 title: PAINT Janus kinase ancestral node statement: >- Local PAINT IBD seed rows place curated JAK1/JAK2/TYK2 exemplars in PTHR45807 node PTN001562978 with non-membrane spanning protein tyrosine kinase activity, cytokine-mediated signaling, and JAK-STAT pathway terms. - source_id: PANTHER:PTN000210451 title: PAINT STAT cytokine-signaling node statement: >- Local PAINT IBD seed rows place curated STAT exemplars in PTHR11801 node PTN000210451 with cytokine-mediated signaling pathway participation. notes: >- This module is intentionally mechanism-centric and taxon/receptor-neutral. The ordered parts capture the invariant logic shared by every JAK-STAT receptor; the receptor-specific identity of the JAKs and STATs is represented as variant sets along a "receptor class" axis rather than baked into the trunk. Concrete realizations (e.g. the IFN-alpha/beta, IFN-gamma, IL-6/gp130, or common gamma-chain modules) specialize these variant sets and add the specific ligand, receptor chains, cell types, and target genes. Non-canonical and cross-talk features (unphosphorylated-STAT signaling, mitochondrial STAT3, serine phosphorylation, receptor-tyrosine-kinase- or GPCR-driven STAT activation) are out of scope for the canonical trunk and are noted where relevant. GO term ids in descriptors were checked against curated gene reviews in this repository; where no precise GO molecular function exists, only a preferred_term and description are given. Pathway evolution and taxon scope follow Liongue and Ward 2013 (PMID:24058787): the components are older than the pathway, and their coupling into a receptor-JAK-STAT cascade is bilaterian. Pre-bilaterian STATs and JAK-like proteins, and lineages whose STATs act without JAK, are outside this module's scope. A cross-gene briefing on JAK-STAT taxon scope is at https://claude.ai/artifact/4MLfbbbWWnLchDvspwdPuM. module: id: jak_stat_signaling label: Canonical JAK-STAT cytokine signaling pathway module_type: SIGNALING_PATHWAY concepts: - preferred_term: cell surface receptor signaling pathway via JAK-STAT term: id: GO:0007259 label: cell surface receptor signaling pathway via JAK-STAT description: >- The series of molecular signals from cytokine-receptor engagement through JAK activation, STAT phosphorylation, and STAT-dependent transcription. - preferred_term: cytokine-mediated signaling pathway term: id: GO:0019221 label: cytokine-mediated signaling pathway description: >- Most JAK-STAT inputs are type I/II cytokines; the JAK-STAT cascade is the dominant proximal mechanism of cytokine-mediated signaling. context: taxa: - preferred_term: bilaterians term: id: NCBITaxon:33213 label: Bilateria description: >- The canonical receptor/JAK/STAT cassette was assembled in the bilaterian ancestor; sponges have only a JAK-like kinase, while STATs are much older (PMID:24058787). Mammals encode four JAKs and seven STATs. Invertebrates use a reduced set (e.g. a single Hopscotch JAK and STAT92E in Drosophila). Caenorhabditis elegans has no JAK, and its STATs act in JAK-independent pathways (MODULE:c_elegans_jak_independent_stat_signaling). Dictyostelium also has STATs but no JAK; they are activated by tyrosine kinase-like kinases and the cAMP receptor cAR1 (MODULE:dicty_jak_independent_stat_signaling). cellular_components: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane - preferred_term: cytosol term: id: GO:0005829 label: cytosol - preferred_term: nucleus term: id: GO:0005634 label: nucleus parts: - order: 1 role: ligand binding and receptor reorganization node: id: ligand_receptor_engagement label: Cytokine binding and receptor reorganization module_type: REGULATORY_STEP description: >- A cytokine (or hormone) ligand binds the extracellular domains of one or more single-pass transmembrane receptor chains, driving dimerization or a conformational change that repositions the receptor intracellular tails and their associated JAKs. The receptors themselves have no intrinsic catalytic activity; they act as scaffolds that present JAKs. concepts: - preferred_term: cytokine receptor activity term: id: GO:0004896 label: cytokine receptor activity annotons: - id: cytokine_ligand label: Cytokine/hormone ligand participant: selector_type: ANY_WITH_FUNCTION required_function: preferred_term: cytokine receptor binding term: id: GO:0005126 label: cytokine receptor binding description: >- The activating ligand: type I cytokines (e.g. IL-2/4/6/7 family, EPO, GH, leptin, GM-CSF), type II cytokines (interferons, IL-10 family), or hormones signaling through JAK-STAT. role_description: Extracellular agonist that initiates the pathway. - id: cytokine_receptor label: Single-pass cytokine receptor chain(s) participant: selector_type: ANY_WITH_FUNCTION required_function: preferred_term: cytokine receptor activity term: id: GO:0004896 label: cytokine receptor activity description: >- One or more transmembrane receptor chains (e.g. IFNAR1/2, IFNGR1/2, gp130/IL6ST, common gamma chain IL2RG, betac CSF2RB, EPOR, GHR) that lack intrinsic kinase activity and constitutively associate with JAKs via their box1/box2 membrane-proximal motifs. function: preferred_term: cytokine receptor activity term: id: GO:0004896 label: cytokine receptor activity locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Ligand-binding scaffold that juxtaposes its associated JAKs upon cytokine engagement; provides the tyrosines that become STAT docks. evidence: - source_id: PMID:8197455 statement: >- Cytokine receptors lacking intrinsic catalytic activity signal by recruiting JAK tyrosine kinases following ligand binding. - order: 2 role: JAK juxtaposition and trans-activation node: id: jak_activation label: Receptor-associated JAK activation gocam_associations: - model: gomodel:5f46c3b700002685 activity: gomodel:5f46c3b700002685/5f46c3b700002801 title: IL6:sIL6R Trans-signaling pathway (Human) notes: JAK1 activity in this model. - model: gomodel:5fadbcf000001962 activity: gomodel:5fadbcf000001962/5fadbcf000001990 title: T-helper 17 cell lineage commitment by IL6 cluster (Human) notes: JAK1 activity in this model. - model: gomodel:61f34dd300000787 activity: gomodel:61f34dd300000787/62183af000000016 title: IL23 signaling pathway (Human) notes: JAK2 activity in this model. - model: gomodel:6205c24300001663 activity: gomodel:6205c24300001663/6205c24300001744 title: IL2 signaling pathway (Human) notes: JAK1 activity in this model. - model: gomodel:6205c24300001663 activity: gomodel:6205c24300001663/6205c24300001751 title: IL2 signaling pathway (Human) notes: JAK3 activity in this model. - model: gomodel:623d156d00000290 activity: gomodel:623d156d00000290/623d156d00000305 title: IL4-mediated signaling pathway (human) notes: JAK1 activity in this model. - model: gomodel:623d156d00000290 activity: gomodel:623d156d00000290/623d156d00000309 title: IL4-mediated signaling pathway (human) notes: JAK3 activity in this model. - model: gomodel:623d156d00000340 activity: gomodel:623d156d00000340/623d156d00000369 title: IL3-mediated signaling pathway (Human) notes: JAK2 activity in this model. - model: gomodel:6246724f00000675 activity: gomodel:6246724f00000675/6246724f00000717 title: IL7-mediated signaling pathway (Human) notes: JAK3 activity in this model. - model: gomodel:6246724f00000675 activity: gomodel:6246724f00000675/6246724f00000731 title: IL7-mediated signaling pathway (Human) notes: JAK1 activity in this model. - model: gomodel:6246724f00000763 activity: gomodel:6246724f00000763/6246724f00000779 title: TSLP-mediated signaling pathway (Human) notes: JAK1 activity in this model. - model: gomodel:6246724f00000763 activity: gomodel:6246724f00000763/6246724f00000782 title: TSLP-mediated signaling pathway (Human) notes: JAK2 activity in this model. - model: gomodel:626b20c100000025 activity: gomodel:626b20c100000025/626b20c100000040 title: IL9-mediated signaling pathway (Human) notes: JAK1 activity in this model. - model: gomodel:626b20c100000025 activity: gomodel:626b20c100000025/626b20c100000044 title: IL9-mediated signaling pathway (Human) notes: JAK3 activity in this model. - model: gomodel:626b20c100000681 activity: gomodel:626b20c100000681/626b20c100000712 title: IL10-mediated signaling pathway (Human) notes: JAK1 activity in this model. - model: gomodel:626b20c100001212 activity: gomodel:626b20c100001212/626b20c100001633 title: IL11-mediated signaling pathway (Human) notes: JAK1 activity in this model. - model: gomodel:627d95ee00000024 activity: gomodel:627d95ee00000024/62900b6400000205 title: IL12-mediated signaling pathway (Human) notes: JAK2 activity in this model. - model: gomodel:627d95ee00000472 activity: gomodel:627d95ee00000472/627d95ee00000530 title: IL15 signaling pathway (Human) notes: JAK3 activity in this model. - model: gomodel:62900b6400000999 activity: gomodel:62900b6400000999/62900b6400001652 title: IL19-mediated signaling pathway notes: JAK1 activity in this model. - model: gomodel:62b4ffe300003747 activity: gomodel:62b4ffe300003747/62b4ffe300003944 title: Response to IFN-beta, leading to JAK-STAT activation (Human) notes: TYK2 activity in this model. - model: gomodel:62b4ffe300003747 activity: gomodel:62b4ffe300003747/62b4ffe300004047 title: Response to IFN-beta, leading to JAK-STAT activation (Human) notes: JAK1 activity in this model. - model: gomodel:62b4ffe300003747 activity: gomodel:62b4ffe300003747/62b4ffe300004140 title: Response to IFN-beta, leading to JAK-STAT activation (Human) notes: TYK2 activity in this model. - model: gomodel:653b0ce600000016 activity: gomodel:653b0ce600000016/653b0ce600000033 title: Regulation of T-helper 17 cell lineage commitment by acetylation and deacetylation of STAT3 (Human) notes: JAK1 activity in this model. - model: gomodel:6606056e00000282 activity: gomodel:6606056e00000282/6606056e00000290 title: LGALS1-CD69 pair involved in negative regulation of T-helper 17 cell lineage (Human) notes: JAK3 activity in this model. - model: gomodel:68d5ebd600002260 activity: gomodel:68d5ebd600002260/68d5ebd600002375 title: CRLF-CLCF1 signaling pathway involving CNTFR-IL6ST-LIFR complex via JAK-STAT (human) notes: JAK1 activity in this model. - model: gomodel:68fac5ed00000166 activity: gomodel:68fac5ed00000166/68fac5ed00000196 title: CNTF signaling pathway involving CNTFR-IL6ST-LIFR complex via JAK-STAT (human) notes: JAK1 activity in this model. - model: gomodel:68fac5ed00000166 activity: gomodel:68fac5ed00000166/68fac5ed00000205 title: CNTF signaling pathway involving CNTFR-IL6ST-LIFR complex via JAK-STAT (human) notes: JAK2 activity in this model. - model: gomodel:6918f23700003265 activity: gomodel:6918f23700003265/6918f23700003500 title: LIF signaling pathway involving IL6ST-LIFR (human) notes: JAK1 activity in this model. - model: gomodel:6918f23700003265 activity: gomodel:6918f23700003265/6918f23700003735 title: LIF signaling pathway involving IL6ST-LIFR (human) notes: JAK2 activity in this model. - model: gomodel:696022cd00002138 activity: gomodel:696022cd00002138/696022cd00002169 title: OSM signaling pathway involving IL6ST-LIFR receptor complex (human) notes: JAK1 activity in this model. - model: gomodel:696022cd00002138 activity: gomodel:696022cd00002138/696022cd00002190 title: OSM signaling pathway involving IL6ST-LIFR receptor complex (human) notes: JAK2 activity in this model. - model: gomodel:696022cd00002481 activity: gomodel:696022cd00002481/696022cd00002510 title: OSM signaling pathway involving IL6ST-OSMR receptor complex (human) notes: JAK1 activity in this model. - model: gomodel:696022cd00002481 activity: gomodel:696022cd00002481/696022cd00002521 title: OSM signaling pathway involving IL6ST-OSMR receptor complex (human) notes: JAK2 activity in this model. - model: gomodel:696022cd00002619 activity: gomodel:696022cd00002619/696022cd00002634 title: IL31 signaling pathway involving IL31RA-OSMR (human) notes: JAK1 activity in this model. - model: gomodel:69729a3800000296 activity: gomodel:69729a3800000296/69729a3800000311 title: CTF1 signaling pathway involving IL6ST-LIFR receptor complex (human) notes: JAK1 activity in this model. - model: gomodel:69729a3800000296 activity: gomodel:69729a3800000296/69729a3800000320 title: CTF1 signaling pathway involving IL6ST-LIFR receptor complex (human) notes: JAK2 activity in this model. module_type: REACTION description: >- Ligand-induced receptor reorganization brings two receptor-bound Janus kinases into proximity. The kinases relieve pseudokinase-domain autoinhibition and trans-phosphorylate each other on activation-loop tyrosines, switching on their catalytic kinase domains. Which JAKs are used is dictated by the receptor (see variant set). JAKs are non-receptor (non-membrane-spanning) protein tyrosine kinases anchored to the receptor by their N-terminal FERM and SH2-like domains. concepts: - preferred_term: non-membrane spanning protein tyrosine kinase activity term: id: GO:0004715 label: non-membrane spanning protein tyrosine kinase activity annotons: - id: jak_kinase_role label: Janus kinase catalytic role participant: selector_type: FAMILY family: preferred_term: Janus kinase (JAK) family description: >- The four mammalian Janus kinases JAK1, JAK2, JAK3, and TYK2, each with a tandem pseudokinase (JH2) and active kinase (JH1) domain plus FERM and SH2-like receptor-binding domains. representative_members: - preferred_term: JAK1 term: id: UniProtKB:P23458 label: Tyrosine-protein kinase JAK1 - preferred_term: JAK2 term: id: UniProtKB:O60674 label: Tyrosine-protein kinase JAK2 - preferred_term: TYK2 term: id: UniProtKB:P29597 label: Non-receptor tyrosine-protein kinase TYK2 function: preferred_term: non-membrane spanning protein tyrosine kinase activity term: id: GO:0004715 label: non-membrane spanning protein tyrosine kinase activity targets: - preferred_term: partner JAK activation-loop tyrosines - preferred_term: receptor cytoplasmic tail tyrosines - preferred_term: STAT tyrosine residues locations: - preferred_term: cytosolic side of the plasma membrane description: JAKs are anchored to the receptor cytoplasmic tails at the inner membrane face. role_description: >- Receptor-proximal catalytic engine of the pathway; activated by trans-phosphorylation and in turn phosphorylates the receptor and STATs. evidence: - source_id: PMID:25587654 statement: >- JAKs are constitutively receptor-associated tyrosine kinases that trans-activate upon ligand-induced receptor dimerization and then phosphorylate receptor and STAT tyrosines. variant_sets: - id: receptor_jak_pairing label: Receptor-class-determined JAK usage axis: receptor class selection: EXACTLY_ONE notes: >- Each cytokine receptor recruits a characteristic pair (or, for some homodimeric hormone receptors, a single species) of JAKs. This variant set enumerates the canonical pairings; a concrete module selects the one matching its receptor. variants: - id: type1_ifn_jak label: Type I interferon receptor (JAK1 + TYK2) module_type: REACTION description: IFN-alpha/beta via IFNAR1 (TYK2) and IFNAR2 (JAK1). annotons: - id: type1_ifn_jak1 label: JAK1 at IFNAR2 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: JAK1 term: id: UniProtKB:P23458 label: Tyrosine-protein kinase JAK1 - id: type1_ifn_tyk2 label: TYK2 at IFNAR1 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: TYK2 term: id: UniProtKB:P29597 label: Non-receptor tyrosine-protein kinase TYK2 - id: type2_ifn_jak label: Type II interferon receptor (JAK1 + JAK2) module_type: REACTION description: IFN-gamma via IFNGR1 (JAK1) and IFNGR2 (JAK2). annotons: - id: type2_ifn_jak1 label: JAK1 at IFNGR1 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: JAK1 term: id: UniProtKB:P23458 label: Tyrosine-protein kinase JAK1 - id: type2_ifn_jak2 label: JAK2 at IFNGR2 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: JAK2 term: id: UniProtKB:O60674 label: Tyrosine-protein kinase JAK2 evidence: - source_id: PMID:14525967 statement: IFN-gamma signaling uses JAK1 and JAK2 to activate STAT1. - id: gp130_jak label: gp130/IL-6-family receptor (JAK1/JAK2/TYK2) module_type: REACTION description: >- IL-6, IL-11, LIF, OSM, etc. via the shared gp130/IL6ST signal transducer, predominantly using JAK1 with JAK2 and TYK2. annotons: - id: gp130_jak1 label: JAK1 at gp130 (dominant) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: JAK1 term: id: UniProtKB:P23458 label: Tyrosine-protein kinase JAK1 - id: gammac_jak label: Common gamma-chain receptor (JAK1 + JAK3) module_type: REACTION description: >- IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 via the common gamma chain (IL2RG, bound by JAK3) paired with a cytokine-specific chain (bound by JAK1). annotons: - id: gammac_jak1 label: JAK1 at the cytokine-specific chain participant: selector_type: GENE_PRODUCT gene_product: preferred_term: JAK1 term: id: UniProtKB:P23458 label: Tyrosine-protein kinase JAK1 - id: gammac_jak3 label: JAK3 at the common gamma chain participant: selector_type: GENE gene: preferred_term: JAK3 description: >- Tyrosine-protein kinase JAK3 (UniProtKB:P52333), hematopoietic-restricted, binds the common gamma chain (IL2RG); loss-of-function causes T-B+NK- SCID. - id: homodimeric_jak2 label: Homodimeric hormone receptor (JAK2 only) module_type: REACTION description: >- Single-chain homodimeric receptors EPOR, MPL/TPOR, GHR, PRLR, G-CSFR, and leptin receptor signal predominantly through JAK2. annotons: - id: homodimeric_jak2_unit label: JAK2 at homodimeric receptor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: JAK2 term: id: UniProtKB:O60674 label: Tyrosine-protein kinase JAK2 role_description: >- JAK2 is the obligate kinase for erythropoietin, thrombopoietin, growth hormone, prolactin and GM-CSF/IL-3/IL-5 betac receptors; the JAK2 V617F mutation drives myeloproliferative neoplasms. - order: 3 role: receptor tyrosine phosphorylation creating STAT docking sites node: id: receptor_phosphorylation label: Receptor tail phosphorylation and STAT docking-site creation module_type: REACTION description: >- Activated JAKs phosphorylate specific tyrosine residues on the receptor cytoplasmic tails. The resulting phosphotyrosine motifs are recognized by the SH2 domains of latent STATs, recruiting them to the receptor and determining which STATs are engaged. annotons: - id: receptor_tyr_phosphorylation label: JAK-mediated receptor tyrosine phosphorylation participant: selector_type: FAMILY family: preferred_term: Janus kinase (JAK) family description: The same JAKs activated in the prior step act on the receptor tails. function: preferred_term: non-membrane spanning protein tyrosine kinase activity term: id: GO:0004715 label: non-membrane spanning protein tyrosine kinase activity targets: - preferred_term: cytokine receptor cytoplasmic tyrosines role_description: >- Generates phosphotyrosine docking motifs that confer STAT specificity on the receptor. - order: 4 role: STAT recruitment and tyrosine phosphorylation node: id: stat_recruitment_phosphorylation label: STAT recruitment and phosphorylation module_type: REACTION description: >- Latent cytoplasmic STATs are recruited to receptor phosphotyrosines via their SH2 domains and are then phosphorylated by the JAKs on a single conserved C-terminal tyrosine. Which STAT is engaged depends on the receptor docking site (variant set). concepts: - preferred_term: tyrosine phosphorylation of STAT protein term: id: GO:0007260 label: tyrosine phosphorylation of STAT protein annotons: - id: stat_substrate_role label: STAT recruitment via SH2 and phosphorylation participant: selector_type: FAMILY family: preferred_term: STAT transcription factor family description: >- The seven mammalian STATs (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6), each with an SH2 domain that both docks onto the receptor and mediates reciprocal dimerization. representative_members: - preferred_term: STAT1 term: id: UniProtKB:P42224 label: Signal transducer and activator of transcription 1-alpha/beta - preferred_term: STAT3 term: id: UniProtKB:P40763 label: Signal transducer and activator of transcription 3 - preferred_term: STAT5B term: id: UniProtKB:P51692 label: Signal transducer and activator of transcription 5B function: preferred_term: SH2 domain binding term: id: GO:0042169 label: SH2 domain binding description: >- STAT SH2 domains recognize receptor phosphotyrosine motifs for recruitment, and later recognize the reciprocal STAT phosphotyrosine for dimerization. processes: - preferred_term: tyrosine phosphorylation of STAT protein term: id: GO:0007260 label: tyrosine phosphorylation of STAT protein role_description: >- Latent signal-carrying substrate: docks onto the activated receptor and is converted by JAK phosphorylation into an active, dimerization-competent form. evidence: - source_id: PMID:8197455 statement: >- STAT proteins are recruited to activated receptors and tyrosine phosphorylated, converting them from latent cytoplasmic factors to active transcriptional regulators. variant_sets: - id: stat_paralog_usage label: Receptor-determined STAT usage axis: receptor class selection: ONE_OR_MORE notes: >- Receptors select characteristic STATs. Common pairings: type I IFN -> STAT1+STAT2 (with IRF9); IFN-gamma -> STAT1; IL-6/gp130 -> STAT3; IL-12/IL-23 -> STAT4; gammac (IL-2/7/15), EPO, GH, prolactin -> STAT5A/STAT5B; IL-4/IL-13 -> STAT6. variants: - id: stat1_stat2_variant label: STAT1/STAT2 (interferon responses) module_type: REACTION annotons: - id: stat1_unit label: STAT1 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: STAT1 term: id: UniProtKB:P42224 label: Signal transducer and activator of transcription 1-alpha/beta - id: stat2_unit label: STAT2 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: STAT2 term: id: UniProtKB:P52630 label: Signal transducer and activator of transcription 2 - id: stat3_variant label: STAT3 (IL-6/gp130, IL-10, IL-21) module_type: REACTION annotons: - id: stat3_unit label: STAT3 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: STAT3 term: id: UniProtKB:P40763 label: Signal transducer and activator of transcription 3 - id: stat4_variant label: STAT4 (IL-12/IL-23, Th1/IFN-gamma production) module_type: REACTION annotons: - id: stat4_unit label: STAT4 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: STAT4 term: id: UniProtKB:Q14765 label: Signal transducer and activator of transcription 4 - id: stat5_variant label: STAT5A/STAT5B (gammac cytokines, EPO, GH, prolactin) module_type: REACTION annotons: - id: stat5b_unit label: STAT5B participant: selector_type: GENE_PRODUCT gene_product: preferred_term: STAT5B term: id: UniProtKB:P51692 label: Signal transducer and activator of transcription 5B - id: stat5a_unit label: STAT5A participant: selector_type: GENE gene: preferred_term: STAT5A description: >- Signal transducer and activator of transcription 5A (UniProtKB:P42229); largely redundant with STAT5B for gammac/prolactin/GH responses. - id: stat6_variant label: STAT6 (IL-4/IL-13, Th2 responses) module_type: REACTION annotons: - id: stat6_unit label: STAT6 participant: selector_type: GENE gene: preferred_term: STAT6 description: >- Signal transducer and activator of transcription 6 (UniProtKB:P42226); the dedicated STAT for IL-4/IL-13 signaling and Th2 differentiation. - order: 5 role: STAT dimerization and nuclear translocation node: id: stat_dimerization_import label: STAT dimerization and nuclear import module_type: TRANSPORT_STEP description: >- Phosphorylated STATs release from the receptor and form parallel dimers through reciprocal SH2-domain/phosphotyrosine interactions, then enter the nucleus through the karyopherin import cycle. This is the step that GO-CAM models compress into a single edge from a plasma-membrane JAK to a nuclear STAT transcription factor activity (see projects/GOCAM_COMPARTMENTS.md). Release and dimerization are changes of state of the STATs themselves; import uses other gene products (importins and the Ran system), included here by reference. Type I IFN forms the ISGF3 trimer (STAT1-STAT2-IRF9). concepts: - preferred_term: positive regulation of tyrosine phosphorylation of STAT protein term: id: GO:0042531 label: positive regulation of tyrosine phosphorylation of STAT protein parts: - order: 1 role: STAT release and dimerization node: id: stat_dimerization label: STAT release and dimerization module_type: REGULATORY_STEP description: >- Phosphorylated STATs leave the receptor docking sites and pair through reciprocal SH2-phosphotyrosine contacts. No other gene product is needed for this step. annotons: - id: stat_dimer_import label: STAT dimer formation participant: selector_type: FAMILY family: preferred_term: phospho-STAT dimer description: A parallel STAT homo- or heterodimer joined by reciprocal SH2-phosphotyrosine contacts. function: preferred_term: SH2 domain binding term: id: GO:0042169 label: SH2 domain binding description: Reciprocal SH2-phosphotyrosine binding holds the activated STAT dimer together. locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Converts the receptor-released phospho-STAT into a dimer that the import machinery recognizes and that can bind DNA. - order: 2 role: STAT nuclear import node: id: stat_nuclear_import label: STAT nuclear import module_type: TRANSPORT_STEP description: >- The STAT dimer is carried into the nucleus by the importin-alpha/ importin-beta1 route: tyrosine-phosphorylated STAT1 through importin-alpha5 (KPNA1), STAT3 through importin-alpha3 (KPNA4). STAT3 also enters the nucleus without tyrosine phosphorylation, so for STAT3 the signal mainly governs DNA binding and nuclear retention, not entry. module_ref: karyopherin_nuclear_protein_import evidence: - source_id: PMID:9384585 title: Extracellular signal-dependent nuclear import of Stat1 is mediated by nuclear pore-targeting complex formation with NPI-1, but not Rch1. statement: IFN-gamma-induced import of tyrosine-phosphorylated STAT1 depends on importin-beta1 and the NPI-1 (importin-alpha5) adaptor. supporting_text: >- Antibodies against NPI-1 or beta subunit consistently inhibited the IFN-gamma-dependent nuclear import of Stat1 in living cells - source_id: PMID:15919823 title: STAT3 nuclear import is independent of tyrosine phosphorylation and mediated by importin-alpha3. statement: STAT3 import is constitutive and uses importin-alpha3. supporting_text: >- nuclear import takes place constitutively and independently of tyrosine phosphorylation connections: - source: stat_dimerization target: stat_nuclear_import connection_type: PRECEDES description: The phospho-STAT dimer is the cargo of the import cycle. - order: 6 role: STAT-dependent transcription of cytokine-response genes node: id: stat_transcription label: STAT-dependent transcription activation_logic: # Transcription needs the nuclear STAT dimer and is restrained by PTPN2 # and PIAS. The default rule would also let ERK alone switch it on. all_of: - element: stat_dimerization_import - none_of: - element: ptp_dephosphorylation - element: pias_restraint omitted_regulators: # ERK serine phosphorylation (STAT1/STAT3 Ser727) tunes maximal # transcription of an already-active STAT dimer; it neither drives nor # is required for transcription, which a Boolean rule cannot express. - mapk_branch_interface module_type: REGULATORY_STEP description: >- Nuclear STAT dimers bind specific DNA elements - GAS (gamma-activated sequence, TTCnnnGAA) for STAT homodimers, or ISRE (interferon-stimulated response element) for the STAT1-STAT2-IRF9 ISGF3 complex - and recruit coactivators (CBP/p300) to activate transcription of cytokine-response genes. This is the terminal output that defines a JAK-STAT response. concepts: - preferred_term: DNA-binding transcription factor activity, RNA polymerase II-specific term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific annotons: - id: stat_transcriptional_activation label: STAT dimer transcriptional activation gocam_associations: - model: gomodel:5f46c3b700002685 activity: gomodel:5f46c3b700002685/5f46c3b700002806 title: IL6:sIL6R Trans-signaling pathway (Human) notes: STAT3 activity in this model. - model: gomodel:5fadbcf000001962 activity: gomodel:5fadbcf000001962/5fadbcf000001997 title: T-helper 17 cell lineage commitment by IL6 cluster (Human) notes: STAT3 activity in this model. - model: gomodel:61f34dd300000787 activity: gomodel:61f34dd300000787/62183af000000030 title: IL23 signaling pathway (Human) notes: STAT3 activity in this model. - model: gomodel:6205c24300001663 activity: gomodel:6205c24300001663/6205c24300001760 title: IL2 signaling pathway (Human) notes: STAT5A activity in this model. - model: gomodel:6205c24300001663 activity: gomodel:6205c24300001663/627d95ee00000553 title: IL2 signaling pathway (Human) notes: STAT3 activity in this model. - model: gomodel:623d156d00000290 activity: gomodel:623d156d00000290/623d156d00000325 title: IL4-mediated signaling pathway (human) notes: STAT6 activity in this model. - model: gomodel:623d156d00000290 activity: gomodel:623d156d00000290/626b20c100000122 title: IL4-mediated signaling pathway (human) notes: STAT5A activity in this model. - model: gomodel:623d156d00000340 activity: gomodel:623d156d00000340/623d156d00000374 title: IL3-mediated signaling pathway (Human) notes: STAT5A activity in this model. - model: gomodel:6246724f00000675 activity: gomodel:6246724f00000675/6246724f00000751 title: IL7-mediated signaling pathway (Human) notes: STAT5A activity in this model. - model: gomodel:6246724f00000675 activity: gomodel:6246724f00000675/65d7e4ac00000418 title: IL7-mediated signaling pathway (Human) notes: STAT1 activity in this model. - model: gomodel:6246724f00000763 activity: gomodel:6246724f00000763/6246724f00000785 title: TSLP-mediated signaling pathway (Human) notes: STAT5A activity in this model. - model: gomodel:626b20c100000025 activity: gomodel:626b20c100000025/626b20c100000048 title: IL9-mediated signaling pathway (Human) notes: STAT5A activity in this model. - model: gomodel:626b20c100000025 activity: gomodel:626b20c100000025/626b20c100000052 title: IL9-mediated signaling pathway (Human) notes: STAT1 activity in this model. - model: gomodel:626b20c100000025 activity: gomodel:626b20c100000025/626b20c100000056 title: IL9-mediated signaling pathway (Human) notes: STAT3 activity in this model. - model: gomodel:626b20c100000681 activity: gomodel:626b20c100000681/626b20c100000721 title: IL10-mediated signaling pathway (Human) notes: STAT3 activity in this model. - model: gomodel:626b20c100001212 activity: gomodel:626b20c100001212/626b20c100001653 title: IL11-mediated signaling pathway (Human) notes: STAT3 activity in this model. - model: gomodel:627d95ee00000024 activity: gomodel:627d95ee00000024/62900b6400000213 title: IL12-mediated signaling pathway (Human) notes: STAT4 activity in this model. - model: gomodel:627d95ee00000472 activity: gomodel:627d95ee00000472/627d95ee00000566 title: IL15 signaling pathway (Human) notes: STAT5A activity in this model. - model: gomodel:62900b6400000999 activity: gomodel:62900b6400000999/62900b6400001658 title: IL19-mediated signaling pathway notes: STAT3 activity in this model. - model: gomodel:62b4ffe300003747 activity: gomodel:62b4ffe300003747/62b4ffe300004006 title: Response to IFN-beta, leading to JAK-STAT activation (Human) notes: STAT1 activity in this model. - model: gomodel:62b4ffe300003747 activity: gomodel:62b4ffe300003747/62b4ffe300004187 title: Response to IFN-beta, leading to JAK-STAT activation (Human) notes: STAT2 activity in this model. - model: gomodel:653b0ce600000016 activity: gomodel:653b0ce600000016/653b0ce600000036 title: Regulation of T-helper 17 cell lineage commitment by acetylation and deacetylation of STAT3 (Human) notes: STAT3 activity in this model. - model: gomodel:6606056e00000282 activity: gomodel:6606056e00000282/6606056e00000301 title: LGALS1-CD69 pair involved in negative regulation of T-helper 17 cell lineage (Human) notes: STAT5A activity in this model. - model: gomodel:68d5ebd600002260 activity: gomodel:68d5ebd600002260/68d5ebd600002393 title: CRLF-CLCF1 signaling pathway involving CNTFR-IL6ST-LIFR complex via JAK-STAT (human) notes: STAT3 activity in this model. - model: gomodel:68fac5ed00000166 activity: gomodel:68fac5ed00000166/68fac5ed00000214 title: CNTF signaling pathway involving CNTFR-IL6ST-LIFR complex via JAK-STAT (human) notes: STAT3 activity in this model. - model: gomodel:6918f23700003265 activity: gomodel:6918f23700003265/6918f23700003289 title: LIF signaling pathway involving IL6ST-LIFR (human) notes: STAT3 activity in this model. - model: gomodel:696022cd00002138 activity: gomodel:696022cd00002138/696022cd00002148 title: OSM signaling pathway involving IL6ST-LIFR receptor complex (human) notes: STAT3 activity in this model. - model: gomodel:696022cd00002481 activity: gomodel:696022cd00002481/696022cd00002489 title: OSM signaling pathway involving IL6ST-OSMR receptor complex (human) notes: STAT3 activity in this model. - model: gomodel:696022cd00002619 activity: gomodel:696022cd00002619/696022cd00002627 title: IL31 signaling pathway involving IL31RA-OSMR (human) notes: STAT3 activity in this model. - model: gomodel:69729a3800000296 activity: gomodel:69729a3800000296/69729a3800000304 title: CTF1 signaling pathway involving IL6ST-LIFR receptor complex (human) notes: STAT3 activity in this model. participant: selector_type: FAMILY family: preferred_term: nuclear phospho-STAT dimer / ISGF3 description: STAT homodimers, STAT heterodimers, or the ISGF3 (STAT1/STAT2/IRF9) complex bound at GAS/ISRE elements. function: preferred_term: DNA-binding transcription factor activity, RNA polymerase II-specific term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific processes: - preferred_term: positive regulation of transcription by RNA polymerase II term: id: GO:0045944 label: positive regulation of transcription by RNA polymerase II locations: - preferred_term: nucleus term: id: GO:0005634 label: nucleus role_description: >- Sequence-specific transcriptional activator that converts the cytokine signal into a defined gene-expression program (e.g. interferon-stimulated genes, acute-phase genes, lineage-commitment genes). evidence: - source_id: PMID:28323260 statement: >- STAT dimers recognize GAS and ISRE elements with paralog-specific preferences and drive the transcriptional output of cytokine signaling. - order: 7 role: negative regulation and signal termination optional: false node: id: jak_stat_negative_regulation label: Negative regulation of JAK-STAT signaling module_type: REGULATORY_STEP description: >- The response is self-limiting and tuned by multiple negative regulators acting at different steps: cytokine-inducible SOCS/CIS proteins (feedback inhibition of JAKs/receptors and SOCS-box-dependent degradation), protein tyrosine phosphatases that dephosphorylate JAKs, receptors and STATs (SHP1/PTPN6, SHP2/PTPN11, PTPN2/TC-PTP), and PIAS SUMO E3 ligases that restrain nuclear STAT activity. concepts: - preferred_term: negative regulation of receptor signaling pathway via JAK-STAT term: id: GO:0046426 label: negative regulation of receptor signaling pathway via JAK-STAT parts: - order: 1 role: SOCS/CIS feedback inhibition node: id: socs_feedback label: SOCS/CIS negative feedback module_type: REGULATORY_STEP description: >- STAT-induced SOCS/CIS proteins bind phospho-receptors/JAKs via their SH2 domains, inhibit JAK catalysis (SOCS1/SOCS3 via the kinase-inhibitory region) or compete for receptor docking sites (CIS), and target bound components for proteasomal degradation via the SOCS box/elongin-cullin ubiquitin ligase. annotons: - id: socs_inhibitor_role label: SOCS/CIS feedback inhibitor participant: selector_type: FAMILY family: preferred_term: SOCS/CIS family description: >- SH2-domain, SOCS-box feedback inhibitors (SOCS1-7, CISH). SOCS1 and SOCS3 are the most potent direct JAK inhibitors. representative_members: - preferred_term: SOCS1 term: id: UniProtKB:O15524 label: Suppressor of cytokine signaling 1 - preferred_term: SOCS3 term: id: UniProtKB:O14543 label: Suppressor of cytokine signaling 3 function: preferred_term: protein kinase inhibitor activity term: id: GO:0004860 label: protein kinase inhibitor activity targets: - preferred_term: JAK kinases - preferred_term: cytokine receptor docking sites processes: - preferred_term: negative regulation of receptor signaling pathway via JAK-STAT term: id: GO:0046426 label: negative regulation of receptor signaling pathway via JAK-STAT role_description: >- Cytokine-inducible negative-feedback brake that terminates and limits the duration of JAK-STAT signaling. evidence: - source_id: PMID:17525754 statement: >- SOCS proteins are cytokine-inducible inhibitors that suppress JAK-STAT signaling via JAK inhibition, receptor competition, and SOCS-box-mediated ubiquitination. - order: 2 role: phosphatase-mediated dephosphorylation node: id: ptp_dephosphorylation label: Protein tyrosine phosphatase dephosphorylation module_type: REACTION description: >- Protein tyrosine phosphatases reverse the activating phosphorylations: SHP1 (PTPN6) and SHP2 (PTPN11) act at the receptor/JAK level, and PTPN2 (TC-PTP) dephosphorylates JAKs and nuclear STATs, resetting the pathway. annotons: - id: ptp_role label: JAK/STAT tyrosine phosphatase participant: selector_type: ANY_WITH_FUNCTION required_function: preferred_term: protein tyrosine phosphatase activity term: id: GO:0004725 label: protein tyrosine phosphatase activity description: SHP1/PTPN6, SHP2/PTPN11, PTPN2/TC-PTP. function: preferred_term: protein tyrosine phosphatase activity term: id: GO:0004725 label: protein tyrosine phosphatase activity targets: - preferred_term: phospho-JAK - preferred_term: phospho-receptor - preferred_term: phospho-STAT processes: - preferred_term: negative regulation of receptor signaling pathway via JAK-STAT term: id: GO:0046426 label: negative regulation of receptor signaling pathway via JAK-STAT role_description: Removes activating phosphotyrosines to terminate signaling. - order: 3 role: PIAS nuclear restraint node: id: pias_restraint label: PIAS SUMO-ligase restraint of nuclear STATs module_type: REGULATORY_STEP description: >- PIAS (protein inhibitor of activated STAT) SUMO E3 ligases bind activated nuclear STAT dimers and restrain their transcriptional activity by blocking DNA binding, recruiting corepressors, or promoting SUMOylation. annotons: - id: pias_role label: PIAS negative regulator participant: selector_type: FAMILY family: preferred_term: PIAS family description: PIAS1, PIAS2, PIAS3, PIAS4 SUMO E3 ligases that inhibit activated STATs. processes: - preferred_term: negative regulation of receptor signaling pathway via JAK-STAT term: id: GO:0046426 label: negative regulation of receptor signaling pathway via JAK-STAT role_description: Restrains nuclear STAT activity, adding a nuclear layer of negative control. - order: 8 role: branch-point interfaces and cross-talk (sidecar pathways) optional: true node: id: jak_stat_branch_interfaces label: Branch-point interfaces to parallel pathways module_type: REGULATORY_STEP description: >- The same ligand-activated receptor/JAK complex that drives STAT activation also branches into parallel "sidecar" pathways, and the STATs receive convergent inputs from them. These interfaces are not part of the canonical STAT trunk; each forks off the activated receptor and is curated as its own reusable module. Modeled here as interface nodes plus connections so the cross-talk is explicit without inlining the sidecar mechanisms. notes: >- Sidecar modules: MODULE:erk_cascade and MODULE:pi3k_akt_mtor. Both are reusable and are deployed by many other receptor systems (RTKs, GPCRs, integrins), which is why they are separate module documents rather than parts of this pathway. Additional non-canonical interfaces noted but not separately moduled: receptor-tyrosine-kinase- / Src- / GPCR-driven STAT activation that bypasses cytokine receptors, and non-canonical STAT outputs (unphosphorylated-STAT signaling, STAT3-NF-kB cross-talk, mitochondrial STAT3). parts: - order: 1 role: Ras-MAPK fork off the activated receptor node: id: mapk_branch_interface label: Ras-MAPK branch interface module_type: REGULATORY_STEP description: >- JAK-phosphorylated receptor tyrosines recruit GRB2/SHC adaptors and fork into the Ras-RAF-MEK-ERK cascade in parallel with STAT activation. ERK additionally converges back onto the STATs by phosphorylating their C-terminal serine (e.g. STAT1/STAT3 Ser727) to modulate maximal transcriptional activity. See MODULE:erk_cascade. concepts: - preferred_term: MAPK cascade term: id: GO:0000165 label: MAPK cascade description: Reusable Ras-RAF-MEK-ERK cascade; curated as MODULE:erk_cascade. annotons: - id: erk_stat_serine_feedback label: ERK serine phosphorylation of STATs participant: selector_type: ANY_WITH_FUNCTION required_function: preferred_term: MAP kinase activity term: id: GO:0004707 label: MAP kinase activity description: ERK1/ERK2 (and other Ser kinases) acting on STAT C-terminal serine. function: preferred_term: MAP kinase activity toward STAT C-terminal serine sites term: id: GO:0004707 label: MAP kinase activity targets: - preferred_term: STAT C-terminal serine (e.g. STAT1/STAT3 Ser727) processes: - preferred_term: peptidyl-serine phosphorylation term: id: GO:0018105 label: peptidyl-serine phosphorylation role_description: Convergent input that tunes STAT transcriptional output. - order: 2 role: PI3K-AKT fork off the activated receptor node: id: pi3k_branch_interface label: PI3K-AKT-mTOR branch interface module_type: REGULATORY_STEP description: >- JAK-phosphorylated receptor tyrosines (frequently via IRS-1/IRS-2 adaptors, e.g. for IL-4 and growth-hormone receptors) recruit class I PI3K and fork into the PI3K-AKT-mTOR survival/growth axis in parallel with STAT activation. See MODULE:pi3k_akt_mtor. concepts: - preferred_term: phosphatidylinositol 3-kinase/protein kinase B signal transduction term: id: GO:0043491 label: phosphatidylinositol 3-kinase/protein kinase B signal transduction description: Reusable PI3K-AKT-mTOR axis; curated as MODULE:pi3k_akt_mtor. annotons: - id: pi3k_branch_recruitment label: PI3K recruitment at the cytokine receptor participant: selector_type: FAMILY family: preferred_term: class I PI3K (p110/p85) with IRS adaptors description: PI3K recruited to receptor/IRS phosphotyrosines downstream of JAK activation. function: preferred_term: insulin receptor substrate binding term: id: GO:0043560 label: insulin receptor substrate binding role_description: Couples the activated cytokine receptor to the PI3K-AKT sidecar. - order: 3 role: alternative (JAK-independent) inputs into STAT activation node: id: alt_stat_inputs label: RTK / Src / GPCR inputs into STATs module_type: REGULATORY_STEP description: >- STATs (especially STAT3 and STAT5) can be tyrosine-phosphorylated independently of cytokine-receptor JAKs by receptor tyrosine kinases (EGFR, PDGFR), non-receptor kinases (c-Src, BCR-ABL), and downstream of GPCRs - a major route of STAT activation in cancer. Represented as an alternative input interface, not part of the canonical cytokine-receptor trunk. annotons: - id: rtk_src_stat_input label: RTK/Src tyrosine phosphorylation of STATs participant: selector_type: ANY_WITH_FUNCTION required_function: preferred_term: protein tyrosine kinase activity term: id: GO:0004713 label: protein tyrosine kinase activity description: EGFR/PDGFR (RTKs) and c-Src/BCR-ABL (non-receptor) tyrosine kinases. processes: - preferred_term: tyrosine phosphorylation of STAT protein term: id: GO:0007260 label: tyrosine phosphorylation of STAT protein role_description: JAK-independent activation of STATs, converging on the same STAT trunk. connections: - source: ligand_receptor_engagement target: jak_activation connection_type: PROVIDES_INPUT_FOR description: Receptor reorganization juxtaposes the receptor-associated JAKs, enabling their trans-activation. - source: jak_activation target: receptor_phosphorylation connection_type: PRECEDES description: Activated JAKs phosphorylate the receptor cytoplasmic tails. - source: receptor_phosphorylation target: stat_recruitment_phosphorylation connection_type: PROVIDES_INPUT_FOR description: Receptor phosphotyrosines provide the SH2 docking sites that recruit STATs. - source: stat_recruitment_phosphorylation target: stat_dimerization_import connection_type: PRECEDES description: Phosphorylated STATs dimerize and are imported into the nucleus. - source: stat_dimerization_import target: stat_transcription connection_type: PROVIDES_INPUT_FOR description: Nuclear STAT dimers bind GAS/ISRE elements to activate transcription. - source: ptp_dephosphorylation target: jak_activation connection_type: NEGATIVELY_REGULATES description: >- SHP1 (PTPN6), SHP2 (PTPN11) and PTPN2 dephosphorylate JAKs and receptors, resetting JAK activation. (SOCS inhibition of JAK is the separate socs_feedback connection below.) - source: ptp_dephosphorylation target: stat_transcription connection_type: NEGATIVELY_REGULATES description: PTPN2 (TC-PTP) dephosphorylates nuclear STATs, restraining STAT transcriptional output. - source: pias_restraint target: stat_transcription connection_type: NEGATIVELY_REGULATES description: >- PIAS SUMO E3 ligases bind activated nuclear STAT dimers and restrain their transcriptional activity. - source: stat_transcription target: socs_feedback connection_type: CAUSES description: STAT-driven transcription induces SOCS/CIS genes, closing the negative-feedback loop. - source: socs_feedback target: jak_activation connection_type: NEGATIVELY_REGULATES description: >- STAT-induced SOCS/CIS proteins bind JAKs and phospho-receptors and inhibit JAK catalysis, closing the classic negative feedback loop (STAT transcription -> SOCS -> JAK inhibition). evidence: - source_id: PMID:9202126 title: A new protein containing an SH2 domain that inhibits JAK kinases. statement: JAB/SOCS1 binds the JAK JH1 domain and inhibits JAK kinase activity and downstream STAT activation. supporting_text: Interaction of JAB with Jak1, Jak2 or Jak3 markedly reduces their tyrosine-kinase activity and suppresses the tyrosine-phosphorylation and activation of STATs. - source_id: PMID:9202125 title: A family of cytokine-inducible inhibitors of signalling. statement: SOCS genes are rapidly transcribed in response to cytokine, forming a negative feedback loop. supporting_text: Transcription of all four SOCS genes is increased rapidly in response to interleukin-6, in vitro and in vivo, suggesting they may act in a classic negative feedback loop to regulate cytokine signal transduction. - source: receptor_phosphorylation target: mapk_branch_interface connection_type: PROVIDES_INPUT_FOR description: Receptor phosphotyrosines recruit GRB2/SHC and fork into the Ras-MAPK sidecar (MODULE:erk_cascade). - source: receptor_phosphorylation target: pi3k_branch_interface connection_type: PROVIDES_INPUT_FOR description: Receptor/IRS phosphotyrosines recruit class I PI3K and fork into the PI3K-AKT sidecar (MODULE:pi3k_akt_mtor). - source: mapk_branch_interface target: stat_transcription connection_type: POSITIVELY_REGULATES description: ERK serine-phosphorylates STATs (e.g. Ser727), converging back to tune STAT transcriptional output. - source: alt_stat_inputs target: stat_recruitment_phosphorylation connection_type: PROVIDES_INPUT_FOR description: RTK/Src/GPCR tyrosine kinases can phosphorylate STATs independently of cytokine-receptor JAKs. executable_models: - id: jak_stat_signaling_boolean title: JAK-STAT signaling as a Boolean network model_type: BOOLEAN derivation: DERIVED_FROM_MODULE description: >- The module's connections read as a signed regulatory graph and translated by ai-gene-review module-to-bnet. Each negative regulator is wired where the module says it acts: SOCS and the phosphatases on JAK, the phosphatases and PIAS on nuclear STATs. STAT transcription carries activation_logic because ERK serine phosphorylation of STATs only tunes maximal transcription, so it is declared an omitted regulator. In every scenario the phosphatase, PIAS and JAK-independent STAT inputs are held off unless stated. scenarios: - id: unstimulated label: No cytokine description: No ligand engagement; the pathway rests with every step off. settings: - element: ligand_receptor_engagement active: false - element: ptp_dephosphorylation active: false - element: pias_restraint active: false - element: alt_stat_inputs active: false expected_attractor_kind: FIXED_POINT expected_attractor_count: 1 expected_inactive: - jak_activation - stat_transcription - id: sustained_cytokine label: Sustained cytokine description: >- Ligand engagement held on. STAT-driven transcription induces SOCS, which inhibits JAK, so there is no steady state with STAT transcription on: the single attractor is cyclic, which in a Boolean model reads as a transient (pulsed or adapting) response rather than literal oscillation. settings: - element: ligand_receptor_engagement active: true - element: ptp_dephosphorylation active: false - element: pias_restraint active: false - element: alt_stat_inputs active: false expected_attractor_kind: CYCLIC expected_attractor_count: 1 expected_oscillating: - jak_activation - stat_transcription - socs_feedback evidence: - source_id: PMID:9202125 statement: >- SOCS genes are cytokine-induced and proposed to act in a classic negative feedback loop on cytokine signalling. supporting_text: >- Transcription of all four SOCS genes is increased rapidly in response to interleukin-6, in vitro and in vivo, suggesting they may act in a classic negative feedback loop to regulate cytokine signal transduction. - id: socs_lost label: SOCS knocked out description: >- SOCS held off under sustained cytokine. With nothing else wired to terminate JAK, the pathway locks on with STAT transcription sustained: in this module SOCS is the only loop that makes the response transient. settings: - element: ligand_receptor_engagement active: true - element: ptp_dephosphorylation active: false - element: pias_restraint active: false - element: alt_stat_inputs active: false - element: socs_feedback active: false expected_attractor_kind: FIXED_POINT expected_attractor_count: 1 expected_active: - jak_activation - stat_transcription evidence: - source_id: PMID:9202125 statement: SOCS-1 inhibits receptor phosphorylation and STAT activation. supporting_text: >- Expression of SOCS-1 inhibited both interleukin-6-induced receptor phosphorylation and STAT activation. - id: jak_inhibited label: JAK inhibited description: >- JAK held off, as by a JAK inhibitor. Receptor and STAT phosphorylation cannot occur and STAT transcription stays off. settings: - element: ligand_receptor_engagement active: true - element: ptp_dephosphorylation active: false - element: pias_restraint active: false - element: alt_stat_inputs active: false - element: jak_activation active: false expected_attractor_kind: FIXED_POINT expected_attractor_count: 1 expected_inactive: - receptor_phosphorylation - stat_transcription - id: pias_restraint label: PIAS active description: >- PIAS held on under sustained cytokine. STATs are still activated and imported, but nuclear transcription is blocked; because SOCS is then never induced, JAK stays on. The nuclear brake stops the output without terminating the upstream signal. settings: - element: ligand_receptor_engagement active: true - element: ptp_dephosphorylation active: false - element: pias_restraint active: true - element: alt_stat_inputs active: false expected_attractor_kind: FIXED_POINT expected_attractor_count: 1 expected_active: - jak_activation - stat_nuclear_import expected_inactive: - stat_transcription - socs_feedback - id: jak_independent_input label: JAK-independent STAT input description: >- No cytokine, but STATs phosphorylated by a JAK-independent kinase (RTK, Src). STAT transcription comes on and induces SOCS, but SOCS acts only on JAK, so in this wiring it cannot terminate the response. A property of the module's wiring, not a curated biological claim. settings: - element: ligand_receptor_engagement active: false - element: ptp_dephosphorylation active: false - element: pias_restraint active: false - element: alt_stat_inputs active: true expected_attractor_kind: FIXED_POINT expected_attractor_count: 1 expected_active: - stat_transcription - socs_feedback expected_inactive: - jak_activation