Canonical JAK-STAT cytokine signaling pathwaySignaling Pathwayjak_stat_signaling
cell surface receptor signaling pathway via JAK-STATGO:0007259
cytokine-mediated signaling pathwayGO:0019221
Connections
Receptor reorganization juxtaposes the receptor-associated JAKs, enabling their trans-activation.
Activated JAKs phosphorylate the receptor cytoplasmic tails.
Receptor phosphotyrosines provide the SH2 docking sites that recruit STATs.
Phosphorylated STATs dimerize and are imported into the nucleus.
Nuclear STAT dimers bind GAS/ISRE elements to activate transcription.
SHP1 (PTPN6), SHP2 (PTPN11) and PTPN2 dephosphorylate JAKs and receptors, resetting JAK activation. (SOCS inhibition of JAK is the separate socs_feedback connection below.)
PTPN2 (TC-PTP) dephosphorylates nuclear STATs, restraining STAT transcriptional output.
PIAS SUMO E3 ligases bind activated nuclear STAT dimers and restrain their transcriptional activity.
STAT-driven transcription induces SOCS/CIS genes, closing the negative-feedback loop.
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).
PMID:9202126A new protein containing an SH2 domain that inhibits JAK kinases.
JAB/SOCS1 binds the JAK JH1 domain and inhibits JAK kinase activity and downstream STAT activation.
Interaction of JAB with Jak1, Jak2 or Jak3 markedly reduces their tyrosine-kinase activity and suppresses the tyrosine-phosphorylation and activation of STATs.
PMID:9202125A family of cytokine-inducible inhibitors of signalling.
SOCS genes are rapidly transcribed in response to cytokine, forming a negative feedback loop.
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.
Receptor phosphotyrosines recruit GRB2/SHC and fork into the Ras-MAPK sidecar (MODULE:erk_cascade).
Receptor/IRS phosphotyrosines recruit class I PI3K and fork into the PI3K-AKT sidecar (MODULE:pi3k_akt_mtor).
ERK serine-phosphorylates STATs (e.g. Ser727), converging back to tune STAT transcriptional output.
RTK/Src/GPCR tyrosine kinases can phosphorylate STATs independently of cytokine-receptor JAKs.
Part 1: ligand binding and receptor reorganization
Cytokine binding and receptor reorganizationRegulatory Stepligand_receptor_engagement
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.
Annotons
Cytokine/hormone ligand
cytokine_ligand
Participant: Any With Function: cytokine receptor binding
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.
Extracellular agonist that initiates the pathway.
Single-pass cytokine receptor chain(s)
cytokine_receptor
Participant: Any With Function: cytokine receptor activity
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
Locations
Ligand-binding scaffold that juxtaposes its associated JAKs upon cytokine engagement; provides the tyrosines that become STAT docks.
PMID:8197455Cytokine receptors lacking intrinsic catalytic activity signal by recruiting JAK tyrosine kinases following ligand binding.
Part 2: JAK juxtaposition and trans-activation
Receptor-associated JAK activationReactionjak_activation
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.
non-membrane spanning protein tyrosine kinase activityGO:0004715
Annotons
Janus kinase catalytic role
jak_kinase_role
Participant: Family: Janus kinase (JAK) family
Family:
Janus kinase (JAK) family 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.
Function
non-membrane spanning protein tyrosine kinase activityGO:0004715
Targets:
partner JAK activation-loop tyrosines
receptor cytoplasmic tail tyrosines
STAT tyrosine residues
Locations
cytosolic side of the plasma membrane
Receptor-proximal catalytic engine of the pathway; activated by trans-phosphorylation and in turn phosphorylates the receptor and STATs.
PMID:25587654JAKs are constitutively receptor-associated tyrosine kinases that trans-activate upon ligand-induced receptor dimerization and then phosphorylate receptor and STAT tyrosines.
Variant set: Receptor-class-determined JAK usage by receptor class (Exactly One)
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.
Type I interferon receptor (JAK1 + TYK2)Reactiontype1_ifn_jak
IFN-alpha/beta via IFNAR1 (TYK2) and IFNAR2 (JAK1).
Annotons
JAK1 at IFNAR2
type1_ifn_jak1
Participant: Gene Product: JAK1
TYK2 at IFNAR1
type1_ifn_tyk2
Participant: Gene Product: TYK2
Type II interferon receptor (JAK1 + JAK2)Reactiontype2_ifn_jak
IFN-gamma via IFNGR1 (JAK1) and IFNGR2 (JAK2).
PMID:14525967IFN-gamma signaling uses JAK1 and JAK2 to activate STAT1.
Annotons
JAK1 at IFNGR1
type2_ifn_jak1
Participant: Gene Product: JAK1
JAK2 at IFNGR2
type2_ifn_jak2
Participant: Gene Product: JAK2
gp130/IL-6-family receptor (JAK1/JAK2/TYK2)Reactiongp130_jak
IL-6, IL-11, LIF, OSM, etc. via the shared gp130/IL6ST signal transducer, predominantly using JAK1 with JAK2 and TYK2.
Annotons
JAK1 at gp130 (dominant)
gp130_jak1
Participant: Gene Product: JAK1
Common gamma-chain receptor (JAK1 + JAK3)Reactiongammac_jak
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
JAK1 at the cytokine-specific chain
gammac_jak1
Participant: Gene Product: JAK1
JAK3 at the common gamma chain
gammac_jak3
Participant: Gene: JAK3
Gene:
JAK3 Tyrosine-protein kinase JAK3 (UniProtKB:P52333), hematopoietic-restricted, binds the common gamma chain (IL2RG); loss-of-function causes T-B+NK- SCID.
Homodimeric hormone receptor (JAK2 only)Reactionhomodimeric_jak2
Single-chain homodimeric receptors EPOR, MPL/TPOR, GHR, PRLR, G-CSFR, and leptin receptor signal predominantly through JAK2.
Annotons
JAK2 at homodimeric receptor
homodimeric_jak2_unit
Participant: Gene Product: JAK2
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.
Part 3: receptor tyrosine phosphorylation creating STAT docking sites
Receptor tail phosphorylation and STAT docking-site creationReactionreceptor_phosphorylation
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
JAK-mediated receptor tyrosine phosphorylation
receptor_tyr_phosphorylation
Participant: Family: Janus kinase (JAK) family
Family:
Janus kinase (JAK) family The same JAKs activated in the prior step act on the receptor tails.
Function
non-membrane spanning protein tyrosine kinase activityGO:0004715
Targets:
cytokine receptor cytoplasmic tyrosines
Generates phosphotyrosine docking motifs that confer STAT specificity on the receptor.
Part 4: STAT recruitment and tyrosine phosphorylation
STAT recruitment and phosphorylationReactionstat_recruitment_phosphorylation
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).
tyrosine phosphorylation of STAT proteinGO:0007260
Annotons
STAT recruitment via SH2 and phosphorylation
stat_substrate_role
Participant: Family: STAT transcription factor family
Family:
STAT transcription factor family 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.
Function
SH2 domain bindingGO:0042169 STAT SH2 domains recognize receptor phosphotyrosine motifs for recruitment, and later recognize the reciprocal STAT phosphotyrosine for dimerization. Processes
tyrosine phosphorylation of STAT proteinGO:0007260 Latent signal-carrying substrate: docks onto the activated receptor and is converted by JAK phosphorylation into an active, dimerization-competent form.
PMID:8197455STAT proteins are recruited to activated receptors and tyrosine phosphorylated, converting them from latent cytoplasmic factors to active transcriptional regulators.
Variant set: Receptor-determined STAT usage by receptor class (One Or More)
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.
STAT1/STAT2 (interferon responses)Reactionstat1_stat2_variant
Annotons
STAT1
stat1_unit
Participant: Gene Product: STAT1
STAT2
stat2_unit
Participant: Gene Product: STAT2
STAT3 (IL-6/gp130, IL-10, IL-21)Reactionstat3_variant
Annotons
STAT3
stat3_unit
Participant: Gene Product: STAT3
STAT4 (IL-12/IL-23, Th1/IFN-gamma production)Reactionstat4_variant
Annotons
STAT4
stat4_unit
Participant: Gene Product: STAT4
STAT5A/STAT5B (gammac cytokines, EPO, GH, prolactin)Reactionstat5_variant
Annotons
STAT5B
stat5b_unit
Participant: Gene Product: STAT5B
STAT5A
stat5a_unit
Participant: Gene: STAT5A
Gene:
STAT5A Signal transducer and activator of transcription 5A (UniProtKB:P42229); largely redundant with STAT5B for gammac/prolactin/GH responses.
STAT6 (IL-4/IL-13, Th2 responses)Reactionstat6_variant
Annotons
STAT6
stat6_unit
Participant: Gene: STAT6
Gene:
STAT6 Signal transducer and activator of transcription 6 (UniProtKB:P42226); the dedicated STAT for IL-4/IL-13 signaling and Th2 differentiation.
Part 5: STAT dimerization and nuclear translocation
STAT dimerization and nuclear importTransport Stepstat_dimerization_import
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).
positive regulation of tyrosine phosphorylation of STAT proteinGO:0042531
Connections
The phospho-STAT dimer is the cargo of the import cycle.
Part 1: STAT release and dimerization
STAT release and dimerizationRegulatory Stepstat_dimerization
Phosphorylated STATs leave the receptor docking sites and pair through reciprocal SH2-phosphotyrosine contacts. No other gene product is needed for this step.
Annotons
STAT dimer formation
stat_dimer_import
Participant: Family: phospho-STAT dimer
Family:
phospho-STAT dimer A parallel STAT homo- or heterodimer joined by reciprocal SH2-phosphotyrosine contacts.
Function
SH2 domain bindingGO:0042169 Reciprocal SH2-phosphotyrosine binding holds the activated STAT dimer together. Locations
Converts the receptor-released phospho-STAT into a dimer that the import machinery recognizes and that can bind DNA.
Part 2: STAT nuclear import
STAT nuclear importTransport Stepstat_nuclear_import
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.
Realized by module
karyopherin_nuclear_protein_import
PMID:9384585Extracellular signal-dependent nuclear import of Stat1 is mediated by nuclear pore-targeting complex formation with NPI-1, but not Rch1.
IFN-gamma-induced import of tyrosine-phosphorylated STAT1 depends on importin-beta1 and the NPI-1 (importin-alpha5) adaptor.
Antibodies against NPI-1 or beta subunit consistently inhibited the IFN-gamma-dependent nuclear import of Stat1 in living cells
PMID:15919823STAT3 nuclear import is independent of tyrosine phosphorylation and mediated by importin-alpha3.
STAT3 import is constitutive and uses importin-alpha3.
nuclear import takes place constitutively and independently of tyrosine phosphorylation
Part 6: STAT-dependent transcription of cytokine-response genes
STAT-dependent transcriptionRegulatory Stepstat_transcription
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.
DNA-binding transcription factor activity, RNA polymerase II-specificGO:0000981
Annotons
STAT dimer transcriptional activation
stat_transcriptional_activation
Participant: Family: nuclear phospho-STAT dimer / ISGF3
Family:
nuclear phospho-STAT dimer / ISGF3 STAT homodimers, STAT heterodimers, or the ISGF3 (STAT1/STAT2/IRF9) complex bound at GAS/ISRE elements.
Function
DNA-binding transcription factor activity, RNA polymerase II-specificGO:0000981 Processes
positive regulation of transcription by RNA polymerase IIGO:0045944 Locations
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).
PMID:28323260STAT dimers recognize GAS and ISRE elements with paralog-specific preferences and drive the transcriptional output of cytokine signaling.
Part 7: negative regulation and signal termination
Negative regulation of JAK-STAT signalingRegulatory Stepjak_stat_negative_regulation
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.
negative regulation of receptor signaling pathway via JAK-STATGO:0046426
Part 1: SOCS/CIS feedback inhibition
SOCS/CIS negative feedbackRegulatory Stepsocs_feedback
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
SOCS/CIS feedback inhibitor
socs_inhibitor_role
Participant: Family: SOCS/CIS family
Family:
SOCS/CIS family SH2-domain, SOCS-box feedback inhibitors (SOCS1-7, CISH). SOCS1 and SOCS3 are the most potent direct JAK inhibitors.
Function
protein kinase inhibitor activityGO:0004860
Targets:
JAK kinases
cytokine receptor docking sites
Processes
negative regulation of receptor signaling pathway via JAK-STATGO:0046426 Cytokine-inducible negative-feedback brake that terminates and limits the duration of JAK-STAT signaling.
PMID:17525754SOCS proteins are cytokine-inducible inhibitors that suppress JAK-STAT signaling via JAK inhibition, receptor competition, and SOCS-box-mediated ubiquitination.
Part 2: phosphatase-mediated dephosphorylation
Protein tyrosine phosphatase dephosphorylationReactionptp_dephosphorylation
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
JAK/STAT tyrosine phosphatase
ptp_role
Participant: Any With Function: protein tyrosine phosphatase activity
SHP1/PTPN6, SHP2/PTPN11, PTPN2/TC-PTP.
Function
protein tyrosine phosphatase activityGO:0004725
Targets:
phospho-JAK
phospho-receptor
phospho-STAT
Processes
negative regulation of receptor signaling pathway via JAK-STATGO:0046426 Removes activating phosphotyrosines to terminate signaling.
Part 3: PIAS nuclear restraint
PIAS SUMO-ligase restraint of nuclear STATsRegulatory Steppias_restraint
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
PIAS negative regulator
pias_role
Participant: Family: PIAS family
Family:
PIAS family PIAS1, PIAS2, PIAS3, PIAS4 SUMO E3 ligases that inhibit activated STATs.
Processes
negative regulation of receptor signaling pathway via JAK-STATGO:0046426 Restrains nuclear STAT activity, adding a nuclear layer of negative control.
Part 8: branch-point interfaces and cross-talk (sidecar pathways) (optional)
Branch-point interfaces to parallel pathwaysRegulatory Stepjak_stat_branch_interfaces
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.
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).
Part 1: Ras-MAPK fork off the activated receptor
Ras-MAPK branch interfaceRegulatory Stepmapk_branch_interface
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.
Annotons
ERK serine phosphorylation of STATs
erk_stat_serine_feedback
Participant: Any With Function: MAP kinase activity
ERK1/ERK2 (and other Ser kinases) acting on STAT C-terminal serine.
Function
MAP kinase activity toward STAT C-terminal serine sitesGO:0004707
Targets:
STAT C-terminal serine (e.g. STAT1/STAT3 Ser727)
Processes
Convergent input that tunes STAT transcriptional output.
Part 2: PI3K-AKT fork off the activated receptor
PI3K-AKT-mTOR branch interfaceRegulatory Steppi3k_branch_interface
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.
phosphatidylinositol 3-kinase/protein kinase B signal transductionGO:0043491
Annotons
PI3K recruitment at the cytokine receptor
pi3k_branch_recruitment
Participant: Family: class I PI3K (p110/p85) with IRS adaptors
Family:
class I PI3K (p110/p85) with IRS adaptors PI3K recruited to receptor/IRS phosphotyrosines downstream of JAK activation.
Function
Couples the activated cytokine receptor to the PI3K-AKT sidecar.
Part 3: alternative (JAK-independent) inputs into STAT activation