family_id: PANTHER:PTHR45807 family_name: TYROSINE-PROTEIN KINASE HOPSCOTCH preferred_name: Janus kinases (JAK1, JAK2, JAK3, TYK2, Drosophila Hopscotch) summary: >- Janus kinases are cytoplasmic (non-membrane-spanning) protein tyrosine kinases. They are the catalytic partners of cytokine receptors that have no kinase domain of their own. Each JAK has an N-terminal FERM domain and an SH2-like domain that together bind the membrane-proximal box1/box2 region of a receptor tail, a JH2 pseudokinase domain that holds the kinase off until ligand binds, and a C-terminal JH1 tyrosine kinase domain. When a cytokine brings two receptor chains together, the attached JAKs trans-phosphorylate each other's activation loops. They then phosphorylate receptor tyrosines, which become docking sites for STAT SH2 domains, and finally the STATs themselves, which dimerize and move to the nucleus. Vertebrates have four paralogs that arose by duplication near the root of Euteleostomi, each used by a different set of receptors. JAK1 serves class II (interferon, IL-10 family), gamma-c and gp130 receptors. JAK2 serves the homodimeric hormone-like receptors (erythropoietin, thrombopoietin, growth hormone) and IFN-gamma, and is required for definitive erythropoiesis. JAK3 binds only the common gamma chain of the IL-2, -4, -7, -9, -15 and -21 receptors. TYK2 pairs with JAK1 or JAK2 on the type I IFN, IL-10, IL-12 and IL-23 receptors. Insects have a single JAK, Hopscotch, which signals from the Upd/Domeless receptor to Stat92E in segmentation, hematopoiesis and immunity. A canonical JAK, with both the pseudokinase and the kinase domain, is a bilaterian feature. A sponge protein with FERM, SH2 and a single JAK-related kinase domain marks the earliest JAK-like architecture. Nematodes have STATs but no JAK, and Dictyostelium, whose STATs are activated by tyrosine kinase-like kinases, has no JAK either. No bona fide JAK is known outside Metazoa. functional_coherence: COHERENT coherence_reason: >- Every characterized member, the four vertebrate paralogs and Drosophila Hopscotch, is a receptor-associated non-receptor tyrosine kinase that drives STAT activation. The JH1 catalytic lysine, HRD aspartate and the tyrosine-kinase catalytic-loop arginine (HRDLAARN/HRDLATRN) are conserved in all of them. The family has no catalytically inactive lineage. The JH2 pseudokinase is a regulatory domain present in every full-length member, and in JAK2 it even has weak dual-specificity kinase activity. It is not a subfamily-level pseudoenzyme. The divergence between paralogs is in which receptors they serve, not in what they do. So the kinase activity, cytokine-receptor binding and JAK-STAT signaling are family-wide, while each named cytokine pathway is paralog-specific (see term assessments). Two caveats concern membership, not function. (1) The pre-bilaterian members under the family root (sponge, placozoan, cnidarian) are uncharacterized, and PAINT correctly places the family terms one node lower, at Bilateria. (2) The PANTHER HMM also catches short kinase-domain fragments in nematodes and a few fungi. These are not JAKs: a 203-residue Panagrolaimus fragment carries a Ser/Thr-type catalytic loop. Through TreeGrafter they pick up the family's IEA terms. reference_protein: id: UniProtKB:P23458 label: Tyrosine-protein kinase JAK1 gene_symbol: JAK1 organism: Homo sapiens gene_review: genes/human/JAK1/JAK1-ai-review.yaml subfamilies: - subfamily_id: PANTHER:PTHR45807:SF5 clade_node_id: PANTHER:PTN002910265 label: TYROSINE-PROTEIN KINASE JAK1 description: >- Euteleostome JAK1 (fish to mammals). It is broadly expressed and is the non-redundant JAK for class II cytokine receptors (type I/II IFN, IL-10 family), gamma-c receptors (with JAK3) and gp130 receptors (IL-6, LIF, CNTF, OSM). Jak1-null mice die perinatally. representative_members: - id: UniProtKB:P23458 label: Tyrosine-protein kinase JAK1 gene_symbol: JAK1 organism: Homo sapiens gene_review: genes/human/JAK1/JAK1-ai-review.yaml - id: UniProtKB:P52332 label: Tyrosine-protein kinase JAK1 gene_symbol: Jak1 organism: Mus musculus gene_review: genes/mouse/Jak1/Jak1-ai-review.yaml - id: UniProtKB:O12990 label: Tyrosine-protein kinase JAK1 gene_symbol: jak1 organism: Danio rerio diverged_from_family: false - subfamily_id: PANTHER:PTHR45807:SF1 clade_node_id: PANTHER:PTN002910276 label: TYROSINE-PROTEIN KINASE JAK2 description: >- Euteleostome JAK2. It is the kinase for the homodimeric hormone-like receptors (EPOR, MPL, GHR, PRLR) and for IFN-gamma (with JAK1), IL-3/GM-CSF and IL-23 (with TYK2). Jak2-null embryos lack definitive erythropoiesis. The SF1 clade node also contains the teleost duplication that gives rise to SF2. representative_members: - id: UniProtKB:O60674 label: Tyrosine-protein kinase JAK2 gene_symbol: JAK2 organism: Homo sapiens - id: UniProtKB:Q62120 label: Tyrosine-protein kinase JAK2 gene_symbol: Jak2 organism: Mus musculus diverged_from_family: false - subfamily_id: PANTHER:PTHR45807:SF2 clade_node_id: PANTHER:PTN000758072 label: TYROSINE-PROTEIN KINASE description: >- Teleost JAK2 paralog (zebrafish jak2a, also called jak4, and its medaka ortholog), from the teleost duplication PTN002521573 inside the JAK2 clade. PANTHER's generic name hides that it is a JAK2. Zebrafish jak2a is a PAINT seed for erythrocyte differentiation and JAK-STAT signaling. Every JAK2-scoped term should include SF2. representative_members: - id: UniProtKB:O93596 label: Tyrosine-protein kinase gene_symbol: jak2a organism: Danio rerio diverged_from_family: false - subfamily_id: PANTHER:PTHR45807:SF3 clade_node_id: PANTHER:PTN008462070 label: TYROSINE-PROTEIN KINASE JAK3 description: >- Euteleostome JAK3. It is expressed mainly in hematopoietic cells and binds only the common gamma chain (IL2RG) of the IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 receptors. Loss of JAK3 causes T-B+NK- SCID. representative_members: - id: UniProtKB:P52333 label: Tyrosine-protein kinase JAK3 gene_symbol: JAK3 organism: Homo sapiens - id: UniProtKB:Q62137 label: Tyrosine-protein kinase JAK3 gene_symbol: Jak3 organism: Mus musculus diverged_from_family: false - subfamily_id: PANTHER:PTHR45807:SF6 clade_node_id: PANTHER:PTN002910252 label: NON-RECEPTOR TYROSINE-PROTEIN KINASE TYK2 description: >- Euteleostome TYK2. It pairs with JAK1 on the type I IFN and IL-10-family receptors and with JAK2 on the IL-12 and IL-23 receptors. It binds and phosphorylates IFNAR1. Human TYK2 deficiency abolishes type I IFN, IL-6, IL-10, IL-12 and IL-23 signaling. PAINT carries a negated IRD for GO:0007259 on this clade, which this review judges to be wrong. representative_members: - id: UniProtKB:P29597 label: Non-receptor tyrosine-protein kinase TYK2 gene_symbol: TYK2 organism: Homo sapiens - id: UniProtKB:Q9R117 label: Non-receptor tyrosine-protein kinase TYK2 gene_symbol: Tyk2 organism: Mus musculus diverged_from_family: false - subfamily_id: PANTHER:PTHR45807:SF7 clade_node_id: PANTHER:PTN001975446 label: TYROSINE-PROTEIN KINASE HOPSCOTCH description: >- PANTHER's default subfamily, assigned at the family root (PTN001975446, Eumetazoa). It collects every member not placed in a vertebrate paralog subfamily: Drosophila Hopscotch and other arthropod JAKs, the single JAKs of sea urchin, amphioxus and Ciona, the placozoan, cnidarian and sponge JAK-like proteins (for example Ephydatia EfPTK30, which has FERM, SH2 and a single kinase domain), and the HMM-captured kinase-domain fragments from nematodes and fungi. It is phylogenetically heterogeneous. The bilaterian members (hop and the invertebrate deuterostome JAKs) share the family function, but the pre-bilaterian members are untested and the fragments are not JAKs. representative_members: - id: UniProtKB:Q24592 label: Tyrosine-protein kinase hopscotch gene_symbol: hop organism: Drosophila melanogaster - id: UniProtKB:Q9Y1Y4 label: Tyrosine-protein kinase gene_symbol: EfPTK30 organism: Ephydatia fluviatilis diverged_from_family: false node_assessments: - node_id: PANTHER:PTN001562978 asserted_term: id: GO:0005829 label: cytosol evidence: IBD node_taxon: id: NCBITaxon:33213 label: Bilateria paint_snapshot: '20250413' seeds: - id: FB:FBgn0004864 label: hop organism: Drosophila melanogaster - id: MGI:MGI:96629 label: Jak2 organism: Mus musculus assessment: SOUND assessment_reason: >- PTN001562978 is the Bilateria speciation node in the PANTHER 19 tree. It sits one step below the family root (PTN001975446, labelled Eumetazoa, which also holds the Trichoplax member) and covers the deuterostome JAKs (sea urchin, amphioxus, Ciona and the four vertebrate paralogs) and the Hexapoda-Crustacea branch (Drosophila hop, Daphnia). JAKs have no transmembrane segment. They are cytoplasmic and bind the cytoplasmic tails of cytokine receptors through their FERM-SH2 region. Seeds from the fly (hop) and mouse (Jak2) bracket the node. Cytosol is a correct, if incomplete, location. The receptor-bound pool at the cytoplasmic face of the plasma membrane is the site of action. supported_by: - reference_id: PMID:8343952 supporting_text: "Here we identify JAK2, a nonreceptor tyrosine kinase, as a GHR-associated tyrosine kinase." - node_id: PANTHER:PTN001562978 asserted_term: id: GO:0004715 label: non-membrane spanning protein tyrosine kinase activity evidence: IBD node_taxon: id: NCBITaxon:33213 label: Bilateria paint_snapshot: '20250413' seeds: - id: FB:FBgn0004864 label: hop organism: Drosophila melanogaster - id: MGI:MGI:96629 label: Jak2 organism: Mus musculus - id: UniProtKB:O60674 label: JAK2 organism: Homo sapiens - id: UniProtKB:P23458 label: JAK1 organism: Homo sapiens - id: UniProtKB:P29597 label: TYK2 organism: Homo sapiens assessment: SOUND assessment_reason: >- The seeds are hop and mouse Jak2 plus human JAK1, JAK2 and TYK2, which span both bilaterian branches below this node. Hop was identified as a JAK by its tandem kinase domains. The gain-of-function hopTum-l allele raises Hop tyrosine autophosphorylation in cells. TYK2, JAK1 and JAK2 phosphorylate receptor and STAT tyrosines directly. Every full-length member checked here (JAK1, JAK2, JAK3, TYK2, hop) keeps the JH1 catalytic lysine, the HRD aspartate and the tyrosine-kinase-specific catalytic-loop arginine (site jh1_ptk_catalytic). The pre-bilaterian members outside this node (sponge, placozoan, cnidarian) do not inherit the term. That is conservative but correct, since none has been tested. supported_by: - reference_id: PMID:7796812 supporting_text: "We conclude that hopTum-l encodes a hyperactive Hop kinase" - reference_id: PMID:7526154 supporting_text: "the p135tyk2 tyrosine kinase directly binds and tyrosine phosphorylates this receptor subunit" - reference_id: PMID:8343951 supporting_text: "EPO induces tyrosine phosphorylation of JAK2 kinase and activates its in vitro autophosphorylation" - node_id: PANTHER:PTN001562978 asserted_term: id: GO:0005126 label: cytokine receptor binding evidence: IBD node_taxon: id: NCBITaxon:33213 label: Bilateria paint_snapshot: '20260530' seeds: - id: FB:FBgn0004864 label: hop organism: Drosophila melanogaster - id: MGI:MGI:96628 label: Jak1 organism: Mus musculus - id: MGI:MGI:96629 label: Jak2 organism: Mus musculus - id: RGD:2939 label: Jak2 organism: Rattus norvegicus - id: RGD:69056 label: Jak1 organism: Rattus norvegicus - id: UniProtKB:P29597 label: TYK2 organism: Homo sapiens assessment: SOUND assessment_reason: >- The seeds are hop, mouse Jak1 and Jak2, rat Jak2 and Jak1, and human TYK2. In vertebrates the FERM-SH2 module binds the box1/box2 region of class I and class II cytokine receptors (EPOR and GHR for JAK2, IFNAR1 for TYK2). In the fly, Hop is the JAK for the Upd/Domeless cytokine-receptor system. A bilaterian placement is the lowest node that covers both the fly and the vertebrate seeds. supported_by: - reference_id: PMID:8343951 supporting_text: "JAK2 physically associates with a membrane-proximal region of the EPOR cytoplasmic domain that is required for biological activity" - reference_id: PMID:7973659 supporting_text: "Jak3-negative fibroblasts expressing reconstituted IL-2R became responsive to IL-2 after the additional expression of Jak3 complementary DNA" - reference_id: PMID:24058787 supporting_text: "the association of the prototypal JAK with a membrane-bound receptor that lacked intracellular tyrosine kinase activity" - node_id: PANTHER:PTN001562978 asserted_term: id: GO:0007259 label: cell surface receptor signaling pathway via JAK-STAT evidence: IBD node_taxon: id: NCBITaxon:33213 label: Bilateria paint_snapshot: '20260828' seeds: - id: FB:FBgn0004864 label: hop organism: Drosophila melanogaster - id: MGI:MGI:96628 label: Jak1 organism: Mus musculus - id: MGI:MGI:96629 label: Jak2 organism: Mus musculus - id: RGD:2939 label: Jak2 organism: Rattus norvegicus - id: UniProtKB:O60674 label: JAK2 organism: Homo sapiens - id: UniProtKB:P23458 label: JAK1 organism: Homo sapiens - id: UniProtKB:P29597 label: TYK2 organism: Homo sapiens - id: ZFIN:ZDB-GENE-980526-481 label: jak2a (jak4) organism: Danio rerio assessment: SOUND assessment_reason: >- The defining process of the family. Seeds come from both bilaterian branches: fly hop and zebrafish jak2a, mouse Jak1/Jak2/rat Jak2, and human JAK1, JAK2 and TYK2. Hop acts upstream of the STAT Marelle/Stat92E, which shows an invertebrate JAK/STAT system. The Upd ligand activates the pathway through Hop. No nematode or Dictyostelium protein sits in the PANTHER 19 tree for this family, and C. elegans has no JAK homolog. So this node does not deliver the JAK-STAT term to any organism that lacks the pathway. The worm and slime-mould GO:0007259 IBAs come from the STAT family (PTHR11801 node PTN000927860), not from here. The one route by which a nematode protein gets this term from PTHR45807 is TreeGrafter IEA onto kinase-domain fragments (see the member exception on the GO:0007259 term assessment). The TYK2-node IRD that blocks descent of this term to TYK2 is assessed separately and judged wrong. The Bilateria placement matches the evolutionary record: the canonical JAK architecture with a JH2 pseudokinase, and the assembly of JAK, STAT, SHP and SOCS into a working pathway, are both dated to Bilateria, while the only older JAK-like protein is a sponge FERM-SH2-kinase protein without JH2 (PMID:24058787; quotes on the GO:0007259 term assessment). supported_by: - reference_id: PMID:24058787 supporting_text: "the association of the prototypal JAK with a membrane-bound receptor that lacked intracellular tyrosine kinase activity" - reference_id: PMID:24058787 supporting_text: "These came together to form the canonical JAK-STAT signaling pathway prior to the divergence of protostomia" - reference_id: PMID:8608595 supporting_text: "Our results demonstrate the existence of an invertebrate JAK/STAT system." - node_id: PANTHER:PTN001562978 asserted_term: id: GO:0019221 label: cytokine-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:33213 label: Bilateria paint_snapshot: '20260828' seeds: - id: MGI:MGI:96628 label: Jak1 organism: Mus musculus - id: MGI:MGI:96629 label: Jak2 organism: Mus musculus - id: MGI:MGI:99928 label: Jak3 organism: Mus musculus - id: RGD:2939 label: Jak2 organism: Rattus norvegicus - id: RGD:2940 label: Jak3 organism: Rattus norvegicus - id: UniProtKB:K7GSE8 label: JAK3 organism: Sus scrofa - id: UniProtKB:O60674 label: JAK2 organism: Homo sapiens - id: UniProtKB:P23458 label: JAK1 organism: Homo sapiens - id: UniProtKB:P29597 label: TYK2 organism: Homo sapiens - id: UniProtKB:P52333 label: JAK3 organism: Homo sapiens assessment: SOUND assessment_reason: >- All ten seeds are vertebrate (mouse, rat, pig and human JAK1, JAK2, JAK3 and TYK2), so the extension to the insect branch relies on homology, not on a fly seed. That extension is reasonable. Drosophila Upd is a secreted ligand that activates the JAK pathway, and Domeless is a cytokine-receptor-like protein, so Hop takes part in cytokine-type signaling. The term is a parent-like companion of GO:0007259 and is safe wherever GO:0007259 is. supported_by: - reference_id: PMID:9590173 supporting_text: "Jak2 plays a critical, nonredundant role in the function of a specific group of cytokines receptors" - node_id: PANTHER:PTN001562978 asserted_term: id: GO:0030154 label: cell differentiation evidence: IBD node_taxon: id: NCBITaxon:33213 label: Bilateria paint_snapshot: '20230112' seeds: - id: FB:FBgn0004864 label: hop organism: Drosophila melanogaster - id: MGI:MGI:96629 label: Jak2 organism: Mus musculus - id: MGI:MGI:99928 label: Jak3 organism: Mus musculus - id: RGD:2939 label: Jak2 organism: Rattus norvegicus - id: ZFIN:ZDB-GENE-070725-4 label: jak3 organism: Danio rerio - id: ZFIN:ZDB-GENE-980526-142 label: jak1 organism: Danio rerio - id: ZFIN:ZDB-GENE-980526-481 label: jak2a (jak4) organism: Danio rerio assessment: SOUND assessment_reason: >- The placement follows from the seeds (fly hop, mouse Jak2 and Jak3, rat Jak2, zebrafish jak1, jak2a and jak3). JAK signaling drives differentiation decisions such as definitive erythropoiesis (Jak2), lymphoid development (Jak3) and pair-rule patterning and blood cell fate (hop). The term is very broad, and the JAK's direct role is signal transduction upstream of the transcriptional programs that carry out differentiation. Gene reviews should keep it as non-core, not as a core function. - node_id: PANTHER:PTN001562978 asserted_term: id: GO:0035556 label: intracellular signal transduction evidence: IBD node_taxon: id: NCBITaxon:33213 label: Bilateria paint_snapshot: '20240801' seeds: - id: MGI:MGI:96628 label: Jak1 organism: Mus musculus - id: MGI:MGI:96629 label: Jak2 organism: Mus musculus - id: MGI:MGI:99928 label: Jak3 organism: Mus musculus - id: RGD:2939 label: Jak2 organism: Rattus norvegicus assessment: SOUND assessment_reason: >- The seeds are mouse Jak1, Jak2, Jak3 and rat Jak2. Intracellular signal transduction is a generic parent of what JAKs do once the receptor is engaged. It is correct but uninformative next to GO:0007259, and it is non-core for every member. - node_id: PANTHER:PTN002521566 asserted_term: id: GO:0005131 label: growth hormone receptor binding evidence: IBD paint_snapshot: '20260530' seeds: - id: MGI:MGI:96628 label: Jak1 organism: Mus musculus - id: RGD:2939 label: Jak2 organism: Rattus norvegicus - id: RGD:69056 label: Jak1 organism: Rattus norvegicus - id: UniProtKB:P29597 label: TYK2 organism: Homo sapiens assessment: NEEDS_PRUNING assessment_reason: >- PAINT records no taxon. In the PANTHER 19 tree PTN002521566 is the euteleostome duplication node, and it is a four-way polytomy over the TYK2 (SF6), JAK1 (SF5), JAK2 (SF1, with the teleost SF2 below it) and JAK3 (SF3) clades. With seeds from JAK1 (mouse, rat), JAK2 (rat) and TYK2 (human), the polytomy forces the assertion onto the duplication node, so JAK3 inherits it with no evidence of its own. JAK2 is the physiological GH-receptor kinase: it was identified as the GHR-associated tyrosine kinase, and GH responses depend on it. JAK1 and TYK2 binding is supported only by the seed annotations and should be non-core. JAK3 associates selectively with the common gamma chain of the IL-2-family receptors. Nothing places it on the GH receptor. An IRD on the JAK3 clade (PTN008462070) is recommended. JAK3 also currently receives GO:0060397 from this node (QuickGO, P52333). affected_subfamilies: - id: PANTHER:PTHR45807:SF3 label: TYROSINE-PROTEIN KINASE JAK3 supported_by: - reference_id: PMID:8343952 supporting_text: "Here we identify JAK2, a nonreceptor tyrosine kinase, as a GHR-associated tyrosine kinase." - node_id: PANTHER:PTN002521566 asserted_term: id: GO:0060333 label: type II interferon-mediated signaling pathway evidence: IBD paint_snapshot: '20260728' seeds: - id: RGD:2939 label: Jak2 organism: Rattus norvegicus - id: UniProtKB:P23458 label: JAK1 organism: Homo sapiens - id: UniProtKB:P29597 label: TYK2 organism: Homo sapiens assessment: NEEDS_PRUNING assessment_reason: >- Same polytomy as for GO:0005131. The seeds are rat Jak2, human JAK1 and human TYK2. The IFN-gamma receptor works through JAK1 and JAK2. JAK1-deficient cells lose both type I and type II IFN responses, and Jak2-deficient fibroblasts do not respond to IFN-gamma. TYK2 is a curator seed and is kept as non-core. JAK3 has no role in IFN-gamma signaling: it is restricted to gamma-c cytokines and expressed mainly in hematopoietic cells. An IRD on PTN008462070 is recommended. affected_subfamilies: - id: PANTHER:PTHR45807:SF3 label: TYROSINE-PROTEIN KINASE JAK3 supported_by: - reference_id: PMID:8232552 supporting_text: "establishing the requirement for JAK1 in both the interferon-alpha/beta and -gamma signal transduction pathways" - reference_id: PMID:9590173 supporting_text: "Jak2-deficient fibroblasts failed to respond to interferon gamma (IFNgamma), although the responses to IFNalpha/beta and IL-6 were unaffected." - node_id: PANTHER:PTN002521566 asserted_term: id: GO:0060397 label: growth hormone receptor signaling pathway via JAK-STAT evidence: IBD paint_snapshot: '20241121' seeds: - id: MGI:MGI:96629 label: Jak2 organism: Mus musculus - id: RGD:2939 label: Jak2 organism: Rattus norvegicus - id: UniProtKB:O60674 label: JAK2 organism: Homo sapiens assessment: TOO_DEEP assessment_reason: >- All three seeds are JAK2 (mouse Jak2, rat Jak2, human JAK2), so the lowest node that covers them is the JAK2 clade node PTN002910276, not the euteleostome duplication polytomy. As placed, JAK1, TYK2 and JAK3 all inherit GH-receptor JAK-STAT signaling. JAK1 and TYK2 have separate support for GH-receptor association (they are seeds for GO:0005131 at this node), so their inheritance can be kept as non-core. The JAK1 gene reviews already do this. JAK3 has none. The recommended fix is to move the IBD to PTN002910276 and, if JAK1/TYK2 participation is wanted, add it through their own experimental annotations. affected_subfamilies: - id: PANTHER:PTHR45807:SF3 label: TYROSINE-PROTEIN KINASE JAK3 supported_by: - reference_id: PMID:8343952 supporting_text: "Immunological approaches were used to establish GH-dependent complex formation between JAK2 and GHR" - node_id: PANTHER:PTN002910252 asserted_term: id: GO:0007259 label: cell surface receptor signaling pathway via JAK-STAT node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260828' seeds: - id: PANTHER:PTN001562978 label: PTN001562978 (Bilateria node; IRD source) evidence: IRD negated: true assessment: LOSS_CONTRADICTED assessment_reason: >- This row is a negated IRD (dated 2026-08-28, the same day the Bilateria GO:0007259 IBD was refreshed). It asserts that the euteleostome TYK2 clade (SF6) has diverged so far that it no longer takes part in receptor JAK-STAT signaling, and its effect is that human and mouse TYK2 get no GO:0007259 IBA (confirmed in QuickGO). The evidence points the other way. TYK2 was identified by complementing an IFN-alpha-unresponsive cell line and links the IFN-alpha/beta receptor to ISGF3. It binds and phosphorylates IFNAR1, creating the STAT2 docking site. Human TYK2 deficiency abolishes type I IFN, IL-6, IL-10, IL-12 and IL-23 signaling. Human TYK2 carries five IDA GO:0007259 annotations in GOA. TYK2 is also a seed for GO:0004715 and GO:0005126 at the Bilateria node, and PAINT places three TYK2-specific cytokine-pathway IBDs on this same node. No affected subfamily is listed, because the error is the negation itself. The IRD should be retracted so that TYK2 inherits GO:0007259 like the other three paralogs. supported_by: - reference_id: PMID:1386289 supporting_text: "This finding shows that tyk2 links the interferon alpha/beta receptor to the cytoplasmic transcription factor that mediates activation of interferon-responsive genes." - reference_id: PMID:7526154 supporting_text: "the p135tyk2 tyrosine kinase directly binds and tyrosine phosphorylates this receptor subunit" - node_id: PANTHER:PTN002910252 asserted_term: id: GO:0038155 label: interleukin-23-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: UniProtKB:P29597 label: TYK2 organism: Homo sapiens assessment: SOUND assessment_reason: >- PTN002910252 is the euteleostome TYK2 node (SF6). The seed is human TYK2. TYK2-deficient patient cells fail to respond to IL-23 (and IL-12), and the IL-23 receptor complex pairs TYK2 with JAK2. The node is the lowest that holds TYK2 orthologs from fish to mammals. Teleost IL-23 signaling is less well characterized, which is acceptable for a paralog-specific term. - node_id: PANTHER:PTN002910252 asserted_term: id: GO:0060337 label: type I interferon-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: UniProtKB:P29597 label: TYK2 organism: Homo sapiens assessment: SOUND assessment_reason: >- The paradigm TYK2 function. TYK2 was cloned by complementing an IFN-alpha-unresponsive mutant line, and it binds and phosphorylates IFNAR1. The seed is human TYK2. The same term is placed separately on the JAK1 node, which matches the JAK1-TYK2 pairing on the type I IFN receptor. supported_by: - reference_id: PMID:1386289 supporting_text: "This finding shows that tyk2 links the interferon alpha/beta receptor to the cytoplasmic transcription factor that mediates activation of interferon-responsive genes." - reference_id: PMID:8232552 supporting_text: "establishing the requirement for JAK1 in both the interferon-alpha/beta and -gamma signal transduction pathways" - reference_id: PMID:9590174 supporting_text: "In contrast to IFNalpha stimulation, Jak2-/- cells do not respond to IFNgamma." - node_id: PANTHER:PTN002910252 asserted_term: id: GO:0140105 label: interleukin-10-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: UniProtKB:P29597 label: TYK2 organism: Homo sapiens assessment: SOUND assessment_reason: >- The seed is human TYK2. TYK2-deficient patient cells are defective in IL-10 signaling. The IL-10 receptor uses JAK1 and TYK2, and the same term is placed on the JAK1 node. - node_id: PANTHER:PTN002910265 asserted_term: id: GO:0035723 label: interleukin-15-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: UniProtKB:P23458 label: JAK1 organism: Homo sapiens assessment: SOUND assessment_reason: >- PTN002910265 is the euteleostome JAK1 node (SF5). The seed is human JAK1. IL-15 signals through IL-2R beta and gamma-c, which pair with JAK1 and JAK3. Jak1-deficient cells lose responses to the gamma-c receptor family. The same term is placed on the JAK3 node. - node_id: PANTHER:PTN002910265 asserted_term: id: GO:0035771 label: interleukin-4-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: UniProtKB:P23458 label: JAK1 organism: Homo sapiens assessment: SOUND assessment_reason: >- The seed is human JAK1. IL-4 receptor alpha binds JAK1 in both the type I (gamma-c) and type II (IL-13R alpha1) IL-4 receptors. A paralog-specific placement is appropriate. - node_id: PANTHER:PTN002910265 asserted_term: id: GO:0038110 label: interleukin-2-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: UniProtKB:P23458 label: JAK1 organism: Homo sapiens assessment: SOUND assessment_reason: >- The seed is human JAK1. JAK1 binds the serine-rich region of IL-2R beta, and IL-2 activates JAK1 and JAK3. Jak1-deficient cells fail gamma-c cytokine responses. supported_by: - reference_id: PMID:7973659 supporting_text: "Stimulation with IL-2 induces the tyrosine phosphorylation and activation of the Janus kinases Jak1 and Jak3." - node_id: PANTHER:PTN002910265 asserted_term: id: GO:0038113 label: interleukin-9-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: UniProtKB:P23458 label: JAK1 organism: Homo sapiens assessment: SOUND assessment_reason: >- The seed is human JAK1. IL-9 receptor alpha with gamma-c signals through JAK1 and JAK3, as the other gamma-c cytokines do. - node_id: PANTHER:PTN002910265 asserted_term: id: GO:0038165 label: oncostatin-M-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: UniProtKB:P23458 label: JAK1 organism: Homo sapiens assessment: SOUND assessment_reason: >- The seed is human JAK1. Oncostatin M signals through gp130-containing receptors, and the Jak1 knockout shows that the gp130 family depends on Jak1. Placement on the JAK1 node only is a conservative choice. JAK2 and TYK2 also associate with gp130-family receptors, but PAINT has not extended the term to them, which is acceptable. - node_id: PANTHER:PTN002910265 asserted_term: id: GO:0048861 label: leukemia inhibitory factor signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: UniProtKB:P23458 label: JAK1 organism: Homo sapiens assessment: SOUND assessment_reason: >- The seed is human JAK1. LIF uses gp130 and LIFR, and Jak1-deficient cells lose gp130-family responses. Jak2-deficient ES cells remain LIF-competent, which fits JAK1 being the non-redundant kinase. LIF is also asserted at the JAK2 node, which is weaker (see that row). - node_id: PANTHER:PTN002910265 asserted_term: id: GO:0060337 label: type I interferon-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: UniProtKB:P23458 label: JAK1 organism: Homo sapiens assessment: SOUND assessment_reason: >- The seed is human JAK1. JAK1 is needed for both IFN-alpha/beta and IFN-gamma signal transduction (complementation of a JAK1-null cell line), and it pairs with TYK2 on IFNAR. supported_by: - reference_id: PMID:1386289 supporting_text: "This finding shows that tyk2 links the interferon alpha/beta receptor to the cytoplasmic transcription factor that mediates activation of interferon-responsive genes." - reference_id: PMID:8232552 supporting_text: "establishing the requirement for JAK1 in both the interferon-alpha/beta and -gamma signal transduction pathways" - reference_id: PMID:9590174 supporting_text: "In contrast to IFNalpha stimulation, Jak2-/- cells do not respond to IFNgamma." - node_id: PANTHER:PTN002910265 asserted_term: id: GO:0070120 label: ciliary neurotrophic factor-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: UniProtKB:P23458 label: JAK1 organism: Homo sapiens assessment: SOUND assessment_reason: >- The seed is human JAK1. CNTF signals through gp130, LIFR and CNTFR alpha. The gp130-family dependence on Jak1 covers it. - node_id: PANTHER:PTN002910265 asserted_term: id: GO:0140105 label: interleukin-10-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: UniProtKB:P23458 label: JAK1 organism: Homo sapiens assessment: SOUND assessment_reason: >- The seed is human JAK1. The IL-10 receptor alpha chain binds JAK1. The same term is on the TYK2 node, which matches the JAK1/TYK2 pairing. - node_id: PANTHER:PTN002910276 asserted_term: id: GO:0030218 label: erythrocyte differentiation evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: MGI:MGI:96629 label: Jak2 organism: Mus musculus - id: ZFIN:ZDB-GENE-980526-481 label: jak2a (jak4) organism: Danio rerio assessment: SOUND assessment_reason: >- PTN002910276 is the euteleostome JAK2 node (SF1). It contains the teleost duplication PTN002521573, which gives rise to SF2 (zebrafish jak2a/jak4 and medaka) and a jak2b clade. The seeds are mouse Jak2 and zebrafish jak2a, so the node is the lowest that covers them, and SF2 correctly inherits. Jak2-null embryos lack definitive erythropoiesis and die around E12.5, the strongest single phenotype in the family. This term is a downstream developmental outcome (EPO-receptor signaling), and gene reviews should treat it as non-core. supported_by: - reference_id: PMID:9590174 supporting_text: "Jak2 has pivotal functions for signal transduction of a set of cytokine receptors required in definitive erythropoiesis" - node_id: PANTHER:PTN002910276 asserted_term: id: GO:0033209 label: tumor necrosis factor-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: UniProtKB:O60674 label: JAK2 organism: Homo sapiens assessment: UNRESOLVED assessment_reason: >- The single seed is human JAK2. TNF receptors are not cytokine receptors of the JAK-binding class I/II type, and none of the cached primary papers places JAK2 in the TNF receptor complex. TNF-induced JAK2 activation has been reported, but this review has not checked the seed paper, so it cannot say whether that reflects participation or a secondary, autocrine effect. The node placement is mechanically consistent with the seed. - node_id: PANTHER:PTN002910276 asserted_term: id: GO:0038155 label: interleukin-23-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: UniProtKB:O60674 label: JAK2 organism: Homo sapiens assessment: SOUND assessment_reason: >- The seed is human JAK2. The IL-23 receptor pairs JAK2 (IL-23R) with TYK2 (IL-12R beta1), and the term is placed on both paralog nodes, which is consistent. - node_id: PANTHER:PTN002910276 asserted_term: id: GO:0038163 label: thrombopoietin-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: UniProtKB:O60674 label: JAK2 organism: Homo sapiens assessment: SOUND assessment_reason: >- The seed is human JAK2. Jak2-deficient fetal liver progenitors fail to respond to thrombopoietin, along with EPO, IL-3 and GM-CSF. The MPL receptor is a JAK2-specific homodimeric receptor. supported_by: - reference_id: PMID:9590173 supporting_text: "fail to respond to erythropoietin, thrombopoietin, interleukin-3 (IL-3), or granulocyte/macrophage colony-stimulating factor" - node_id: PANTHER:PTN002910276 asserted_term: id: GO:0042981 label: regulation of apoptotic process evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: MGI:MGI:96629 label: Jak2 organism: Mus musculus - id: RGD:2939 label: Jak2 organism: Rattus norvegicus assessment: SOUND assessment_reason: >- The seeds are mouse and rat Jak2. JAK2-STAT5 signaling downstream of EPOR promotes erythroid progenitor survival. This is a broad regulation term and should be non-core, but the placement follows from the seeds. - node_id: PANTHER:PTN002910276 asserted_term: id: GO:0048861 label: leukemia inhibitory factor signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: UniProtKB:O60674 label: JAK2 organism: Homo sapiens assessment: SOUND assessment_reason: >- The single seed is human JAK2. LIF receptors can engage JAK2 as well as JAK1 and TYK2, but Jak2-null ES cells keep LIF signaling, so JAK2 contributes to LIF signaling without being required for it. The placement follows from the seed. Gene reviews should keep it non-core for JAK2. - node_id: PANTHER:PTN002910276 asserted_term: id: GO:0070120 label: ciliary neurotrophic factor-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: UniProtKB:O60674 label: JAK2 organism: Homo sapiens assessment: SOUND assessment_reason: >- The single seed is human JAK2. CNTF uses the gp130/LIFR pair, which can engage JAK2. As for LIF, this is a contributing, non-core paralog role. The placement follows from the seed. - node_id: PANTHER:PTN008462070 asserted_term: id: GO:0035723 label: interleukin-15-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: UniProtKB:P52333 label: JAK3 organism: Homo sapiens assessment: SOUND assessment_reason: >- PTN008462070 is the euteleostome JAK3 node (SF3). The seed is human JAK3. JAK3 binds the common gamma chain shared by the IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 receptors, and adding back JAK3 restores IL-2 responsiveness to JAK3-negative fibroblasts. This holds for every gamma-c cytokine term at this node. - node_id: PANTHER:PTN008462070 asserted_term: id: GO:0035771 label: interleukin-4-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: UniProtKB:K7GSE8 label: JAK3 organism: Sus scrofa - id: UniProtKB:P52333 label: JAK3 organism: Homo sapiens assessment: SOUND assessment_reason: >- The seeds are human JAK3 and pig JAK3 (K7GSE8). IL-4 signals through the type I receptor (IL-4R alpha with gamma-c), which uses JAK3. - node_id: PANTHER:PTN008462070 asserted_term: id: GO:0038110 label: interleukin-2-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: UniProtKB:P52333 label: JAK3 organism: Homo sapiens assessment: SOUND assessment_reason: >- The seed is human JAK3. This is the founding JAK3 activity. IL-2 activates JAK1 and JAK3, which bind IL-2R beta and gamma-c respectively, and JAK3 re-expression restores IL-2 responses. supported_by: - reference_id: PMID:7973659 supporting_text: "Stimulation with IL-2 induces the tyrosine phosphorylation and activation of the Janus kinases Jak1 and Jak3." - node_id: PANTHER:PTN008462070 asserted_term: id: GO:0038111 label: interleukin-7-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: UniProtKB:P52333 label: JAK3 organism: Homo sapiens assessment: SOUND assessment_reason: >- The seed is human JAK3. The IL-7 receptor (IL-7R alpha with gamma-c) uses JAK1 and JAK3, and loss of the IL-7/gamma-c/JAK3 axis is the basis of JAK3 SCID. supported_by: - reference_id: PMID:9590172 supporting_text: "cytokine receptors that utilize the gamma(c) subunit for signaling" - node_id: PANTHER:PTN008462070 asserted_term: id: GO:0038113 label: interleukin-9-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: UniProtKB:P52333 label: JAK3 organism: Homo sapiens assessment: SOUND assessment_reason: The seed is human JAK3. The IL-9 receptor uses gamma-c and therefore JAK3. - node_id: PANTHER:PTN008462070 asserted_term: id: GO:0042981 label: regulation of apoptotic process evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: MGI:MGI:99928 label: Jak3 organism: Mus musculus assessment: SOUND assessment_reason: >- The seed is mouse Jak3. Gamma-c/JAK3 signaling supports lymphocyte survival. This is a broad regulation term and is non-core. PAINT places the same term separately on the JAK2 node, not on the duplication node, which keeps it away from JAK1 and TYK2. residue_sites: - site_id: jh1_ptk_catalytic label: JH1 tyrosine-kinase catalytic residues description: >- Three catalytic residues of the C-terminal JH1 kinase domain of JAK1, from UniProt features and the catalytic-loop sequence. K908 is the ATP-binding lysine (UniProt binding site). D1003 is the HRD catalytic base (UniProt active site, proton acceptor). R1007 is the arginine of the HRDLAARN catalytic loop, a tyrosine-kinase hallmark: serine/threonine kinases carry HRDLKPEN, with the basic residue two positions earlier and an acidic residue here. The same three residues are present in JAK2 (K882, D976, R980; loop HRDLATRN), JAK3 (K855, D949, R953), TYK2 (K930, D1023, R1027) and Drosophila Hopscotch (K926, D1014, R1018), checked against UniProt canonical sequences. The JH2 pseudokinase domain is deliberately not used. It is a regulatory domain present in every full-length member, and JAK2 JH2 has weak dual-specificity activity on S523 and Y570, so no member-level GO claim depends on it. The negative control is a sequence-level one, not an experimentally tested one. It is the 203-residue Panagrolaimus superbus fragment A0A914YCL6, which PANTHER places in SF7 and which TreeGrafter annotates with the family's tyrosine-kinase and JAK-STAT terms. Its catalytic loop reads HCDLKASN, a Ser/Thr-type loop (InterPro IPR008271) with S171 at the position of JAK1 R1007. anchor: id: UniProtKB:P23458 label: Tyrosine-protein kinase JAK1 gene_symbol: JAK1 organism: Homo sapiens anchor_sequence_version: 2 site_source: UNIPROT_FEATURE residues: - position: 908 expected: - K role: ATP-binding lysine (beta3) - position: 1003 expected: - D role: catalytic base (HRD motif, proton acceptor) - position: 1007 expected: - R role: tyrosine-kinase-specific catalytic-loop arginine (HRDLAARN) required_for: - term: id: GO:0004715 label: non-membrane spanning protein tyrosine kinase activity strength: CONTRIBUTES rationale: >- Phosphotransfer in the JH1 domain needs the beta3 lysine to position ATP and the HRD aspartate as the catalytic base. The catalytic-loop arginine of the HRDLAARN loop is what distinguishes tyrosine kinases from serine/threonine kinases, so its replacement flags a kinase domain that is unlikely to phosphorylate tyrosine. The site is recorded as CONTRIBUTES, not REQUIRED, because no full-length family member lacks it and the only negative control is a sequence fragment, not a tested protein. supported_by: - reference_id: PMID:8314084 supporting_text: >- The hop gene encodes a putative nonreceptor tyrosine kinase of the Janus kinase family, based on an internal duplication of the catalytic domain. - reference_id: PMID:21841788 supporting_text: >- Here we show that JH2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in JAK2 positive_controls: - id: UniProtKB:O60674 label: Tyrosine-protein kinase JAK2 gene_symbol: JAK2 organism: Homo sapiens control_position: 980 control_residue: R - id: UniProtKB:P52333 label: Tyrosine-protein kinase JAK3 gene_symbol: JAK3 organism: Homo sapiens control_position: 953 control_residue: R - id: UniProtKB:P29597 label: Non-receptor tyrosine-protein kinase TYK2 gene_symbol: TYK2 organism: Homo sapiens control_position: 1027 control_residue: R - id: UniProtKB:Q24592 label: Tyrosine-protein kinase hopscotch gene_symbol: hop organism: Drosophila melanogaster control_position: 1018 control_residue: R negative_controls: - id: UniProtKB:A0A914YCL6 label: Serine/threonine-protein (fragment) organism: Panagrolaimus superbus control_position: 171 control_residue: S term_assessments: - assessed_term: id: GO:0004715 label: non-membrane spanning protein tyrosine kinase activity scope: FAMILY_WIDE scope_reason: >- Shown directly for JAK1, JAK2, JAK3, TYK2 and Hopscotch. The JH1 catalytic site (jh1_ptk_catalytic) is intact in every full-length member checked, so it is core for all four vertebrate subfamilies, the teleost SF2 and hop. It does not apply to the short kinase-domain fragments the HMM also captures in nematodes and fungi. These are not JAKs, and the residue site shows what one of them looks like. supported_by: - reference_id: PMID:7796812 supporting_text: We conclude that hopTum-l encodes a hyperactive Hop kinase - reference_id: PMID:7526154 supporting_text: >- the p135tyk2 tyrosine kinase directly binds and tyrosine phosphorylates this receptor subunit - reference_id: PMID:8343951 supporting_text: >- EPO induces tyrosine phosphorylation of JAK2 kinase and activates its in vitro autophosphorylation - assessed_term: id: GO:0005126 label: cytokine receptor binding scope: FAMILY_WIDE scope_reason: >- Receptor binding through the FERM-SH2 module is the mechanism that defines the family. It is shown for JAK2 (EPOR, GHR), TYK2 (IFNAR1), JAK1 and JAK3 (IL-2R beta and gamma-c), and for hop through the Upd/Domeless system. It is core for all bilaterian members. supported_by: - reference_id: PMID:8343951 supporting_text: >- JAK2 physically associates with a membrane-proximal region of the EPOR cytoplasmic domain that is required for biological activity - reference_id: PMID:7973659 supporting_text: >- Jak3-negative fibroblasts expressing reconstituted IL-2R became responsive to IL-2 after the additional expression of Jak3 complementary DNA - reference_id: PMID:24058787 supporting_text: >- the association of the prototypal JAK with a membrane-bound receptor that lacked intracellular tyrosine kinase activity - assessed_term: id: GO:0007259 label: cell surface receptor signaling pathway via JAK-STAT scope: FAMILY_WIDE scope_reason: >- It is the defining process for every full-length bilaterian member. It is shown for all four vertebrate paralogs and for Drosophila hop, which acts upstream of the STAT Marelle. It applies to TYK2 in particular, despite the PAINT IRD on the TYK2 node, which this review judges wrong. Pre-bilaterian JAK-like members sit outside the PAINT node and are untested. The term must not reach nematode proteins. Nematodes have no JAK, so the only nematode members are kinase-domain fragments that the HMM captures. One of these receives the term by TreeGrafter IEA and is excepted below. TreeGrafter also gives GO:0007259 as IEA to 13 fungal (mostly Glomeromycota), 2 plant and 1 bacterial protein that the family HMM matches (QuickGO, October 2026). Those deserve the same scrutiny, but whether they are assembly contaminants, horizontal transfers or mis-scored kinases was not resolved here, so they are not listed as exceptions. member_exceptions: - member: id: UniProtKB:A0A914YCL6 label: Serine/threonine-protein (fragment) organism: Panagrolaimus superbus exception_reason: >- A 203-residue nematode fragment that has only a protein kinase domain (no FERM, SH2 or JH2) with a Ser/Thr-type catalytic loop (HCDLKASN). PANTHER places it in SF7, and TreeGrafter then grafts it under the Bilateria node PTN001562978, so it receives GO:0007259, GO:0019221, GO:0004715 and GO:0005126 as IEA. It is not a JAK ortholog, and nematodes have no JAK. C. elegans has no JAK homolog, the PANTHER 19 reference tree has no nematode member, and across all nematode proteomes the family HMM matches only five fragments of 99-430 residues. The PAINT node is sound for real JAKs, so no pruned node is named. The error is in the HMM/TreeGrafter placement of a fragment. supported_by: - reference_id: PMID:28874466 supporting_text: There is no conserved homolog of the JAK kinases in C. elegans - reference_id: PMID:24058787 supporting_text: >- The canonical JAK domain architecture inclusive of a pseudo-kinase domain appears to be unique within bilateria supported_by: - reference_id: PMID:8608595 supporting_text: Our results demonstrate the existence of an invertebrate JAK/STAT system. - reference_id: PMID:9784499 supporting_text: >- Upd is a secreted protein, associated with the extracellular matrix, that activates the JAK pathway. - reference_id: PMID:1386289 supporting_text: >- This finding shows that tyk2 links the interferon alpha/beta receptor to the cytoplasmic transcription factor that mediates activation of interferon-responsive genes. - reference_id: PMID:9590172 supporting_text: >- they fail to manifest biologic responses to cytokines that bind to three distinct families of cytokine receptors - reference_id: PMID:24058787 supporting_text: >- These came together to form the canonical JAK-STAT signaling pathway prior to the divergence of protostomia - reference_id: PMID:24058787 supporting_text: The first bona fide JAK-like protein is represented in the basal metazoan porifera lineage - assessed_term: id: GO:0019221 label: cytokine-mediated signaling pathway scope: FAMILY_WIDE scope_reason: >- It goes with GO:0007259. All PAINT seeds are vertebrate, but Drosophila Upd is a secreted cytokine-like ligand that signals through Hop, so the term is safe for bilaterian members. The same caveat about nematode fragments applies. supported_by: - reference_id: PMID:9590173 supporting_text: >- Jak2 plays a critical, nonredundant role in the function of a specific group of cytokines receptors - assessed_term: id: GO:0005829 label: cytosol scope: FAMILY_WIDE scope_reason: >- JAKs are soluble cytoplasmic kinases with no transmembrane segment, and they are recruited to receptor tails at the cytoplasmic face of the plasma membrane. Cytosol is correct for all members. It is not the whole picture, but it is not wrong. supported_by: - reference_id: PMID:8343952 supporting_text: Here we identify JAK2, a nonreceptor tyrosine kinase, as a GHR-associated tyrosine kinase. - assessed_term: id: GO:0005131 label: growth hormone receptor binding scope: SUBFAMILY_ONLY applicable_subfamilies: - id: PANTHER:PTHR45807:SF1 label: TYROSINE-PROTEIN KINASE JAK2 - id: PANTHER:PTHR45807:SF2 label: TYROSINE-PROTEIN KINASE - id: PANTHER:PTHR45807:SF5 label: TYROSINE-PROTEIN KINASE JAK1 - id: PANTHER:PTHR45807:SF6 label: NON-RECEPTOR TYROSINE-PROTEIN KINASE TYK2 scope_reason: >- JAK2 (SF1 and the teleost SF2) is the GH-receptor kinase and the term is core there. JAK1 (SF5) and TYK2 (SF6) have curator-recorded GHR binding (they are PAINT seeds) and should keep it as non-core. JAK3 (SF3) inherits it only because the euteleostome duplication node is a polytomy. JAK3 binds the gamma-c chain, not GHR, so it should not carry the term. supported_by: - reference_id: PMID:8343952 supporting_text: Here we identify JAK2, a nonreceptor tyrosine kinase, as a GHR-associated tyrosine kinase. - assessed_term: id: GO:0060397 label: growth hormone receptor signaling pathway via JAK-STAT scope: SUBFAMILY_ONLY applicable_subfamilies: - id: PANTHER:PTHR45807:SF1 label: TYROSINE-PROTEIN KINASE JAK2 - id: PANTHER:PTHR45807:SF2 label: TYROSINE-PROTEIN KINASE - id: PANTHER:PTHR45807:SF5 label: TYROSINE-PROTEIN KINASE JAK1 - id: PANTHER:PTHR45807:SF6 label: NON-RECEPTOR TYROSINE-PROTEIN KINASE TYK2 scope_reason: >- All PAINT seeds are JAK2, so the term is core for SF1/SF2. JAK1 and TYK2 have independent evidence of GH-receptor association and may keep it as non-core. The in-repo JAK1 reviews do this. JAK3 has no GH-receptor role. The IBD as placed is too deep (see the PTN002521566 node assessment). supported_by: - reference_id: PMID:8343952 supporting_text: >- Immunological approaches were used to establish GH-dependent complex formation between JAK2 and GHR - assessed_term: id: GO:0060333 label: type II interferon-mediated signaling pathway scope: SUBFAMILY_ONLY applicable_subfamilies: - id: PANTHER:PTHR45807:SF1 label: TYROSINE-PROTEIN KINASE JAK2 - id: PANTHER:PTHR45807:SF2 label: TYROSINE-PROTEIN KINASE - id: PANTHER:PTHR45807:SF5 label: TYROSINE-PROTEIN KINASE JAK1 - id: PANTHER:PTHR45807:SF6 label: NON-RECEPTOR TYROSINE-PROTEIN KINASE TYK2 scope_reason: >- The IFN-gamma receptor signals through JAK1 and JAK2. Both knockouts lose IFN-gamma responses while JAK3 has no part in the pathway. TYK2 is a PAINT seed and may be kept as non-core. supported_by: - reference_id: PMID:8232552 supporting_text: >- establishing the requirement for JAK1 in both the interferon-alpha/beta and -gamma signal transduction pathways - reference_id: PMID:9590173 supporting_text: >- Jak2-deficient fibroblasts failed to respond to interferon gamma (IFNgamma), although the responses to IFNalpha/beta and IL-6 were unaffected. - assessed_term: id: GO:0060337 label: type I interferon-mediated signaling pathway scope: SUBFAMILY_ONLY applicable_subfamilies: - id: PANTHER:PTHR45807:SF5 label: TYROSINE-PROTEIN KINASE JAK1 - id: PANTHER:PTHR45807:SF6 label: NON-RECEPTOR TYROSINE-PROTEIN KINASE TYK2 scope_reason: >- The type I IFN receptor uses TYK2 (on IFNAR1) and JAK1 (on IFNAR2). JAK2 is dispensable for IFN-alpha/beta responses, and JAK3 has no role. supported_by: - reference_id: PMID:1386289 supporting_text: >- This finding shows that tyk2 links the interferon alpha/beta receptor to the cytoplasmic transcription factor that mediates activation of interferon-responsive genes. - reference_id: PMID:8232552 supporting_text: >- establishing the requirement for JAK1 in both the interferon-alpha/beta and -gamma signal transduction pathways - reference_id: PMID:9590174 supporting_text: In contrast to IFNalpha stimulation, Jak2-/- cells do not respond to IFNgamma. - assessed_term: id: GO:0038110 label: interleukin-2-mediated signaling pathway scope: SUBFAMILY_ONLY applicable_subfamilies: - id: PANTHER:PTHR45807:SF3 label: TYROSINE-PROTEIN KINASE JAK3 - id: PANTHER:PTHR45807:SF5 label: TYROSINE-PROTEIN KINASE JAK1 scope_reason: >- The IL-2 receptor uses JAK1 (on IL-2R beta) and JAK3 (on gamma-c). This also stands in for the other gamma-c cytokine terms PAINT places on the JAK1 and JAK3 nodes (IL-4, IL-7, IL-9, IL-15), which share the same JAK1/JAK3 scope. supported_by: - reference_id: PMID:7973659 supporting_text: >- Stimulation with IL-2 induces the tyrosine phosphorylation and activation of the Janus kinases Jak1 and Jak3. - assessed_term: id: GO:0038111 label: interleukin-7-mediated signaling pathway scope: SUBFAMILY_ONLY applicable_subfamilies: - id: PANTHER:PTHR45807:SF3 label: TYROSINE-PROTEIN KINASE JAK3 - id: PANTHER:PTHR45807:SF5 label: TYROSINE-PROTEIN KINASE JAK1 scope_reason: >- The IL-7 receptor (IL-7R alpha with gamma-c) uses JAK1 and JAK3. PAINT places the IBD only on the JAK3 node. JAK1's participation rests on its own experimental annotation (JAK1 gene review) and on the gamma-c defect of Jak1-null cells. supported_by: - reference_id: PMID:9590172 supporting_text: cytokine receptors that utilize the gamma(c) subunit for signaling - assessed_term: id: GO:0038163 label: thrombopoietin-mediated signaling pathway scope: SUBFAMILY_ONLY applicable_subfamilies: - id: PANTHER:PTHR45807:SF1 label: TYROSINE-PROTEIN KINASE JAK2 - id: PANTHER:PTHR45807:SF2 label: TYROSINE-PROTEIN KINASE scope_reason: >- Thrombopoietin acts through the homodimeric MPL receptor, which uses JAK2 only. Jak2-deficient progenitors do not respond to thrombopoietin. supported_by: - reference_id: PMID:9590173 supporting_text: >- fail to respond to erythropoietin, thrombopoietin, interleukin-3 (IL-3), or granulocyte/macrophage colony-stimulating factor - assessed_term: id: GO:0030218 label: erythrocyte differentiation scope: SUBFAMILY_ONLY applicable_subfamilies: - id: PANTHER:PTHR45807:SF1 label: TYROSINE-PROTEIN KINASE JAK2 - id: PANTHER:PTHR45807:SF2 label: TYROSINE-PROTEIN KINASE scope_reason: >- Definitive erythropoiesis requires JAK2 downstream of EPOR. The PAINT seeds are mouse Jak2 and zebrafish jak2a (SF2). This is a developmental outcome of JAK2 signaling and should be non-core even within SF1/SF2. supported_by: - reference_id: PMID:9590174 supporting_text: >- Jak2 has pivotal functions for signal transduction of a set of cytokine receptors required in definitive erythropoiesis references: - id: PMID:28874466 title: An Alternative STAT Signaling Pathway Acts in Viral Immunity in Caenorhabditis elegans. - id: PMID:24058787 title: Evolution of the JAK-STAT pathway. - id: PMID:16596165 title: The dictyostelium kinome--analysis of the protein kinases from a simple model organism. - id: PMID:22699506 title: >- Identification of the kinase that activates a nonmetazoan STAT gives insights into the evolution of phosphotyrosine-SH2 domain signaling. - id: PMID:25143406 title: >- Two Dictyostelium tyrosine kinase-like kinases function in parallel, stress-induced STAT activation pathways. - id: PMID:1386289 title: A protein tyrosine kinase in the interferon alpha/beta signaling pathway. - id: PMID:7526154 title: >- Direct binding to and tyrosine phosphorylation of the alpha subunit of the type I interferon receptor by p135tyk2 tyrosine kinase. - id: PMID:8605876 title: >- Phosphorylated interferon-alpha receptor 1 subunit (IFNaR1) acts as a docking site for the latent form of the 113 kDa STAT2 protein. - id: PMID:17088085 title: >- Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. - id: PMID:8232552 title: >- The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction. - id: PMID:9590172 title: >- Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. - id: PMID:9590173 title: Jak2 is essential for signaling through a variety of cytokine receptors. - id: PMID:9590174 title: Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. - id: PMID:8343952 title: Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase. - id: PMID:8343951 title: >- JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. - id: PMID:7973659 title: >- Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits. - id: PMID:8608595 title: >- Marelle acts downstream of the Drosophila HOP/JAK kinase and encodes a protein similar to the mammalian STATs. - id: PMID:7796812 title: >- Activation of a Drosophila Janus kinase (JAK) causes hematopoietic neoplasia and developmental defects. - id: PMID:8314084 title: >- Stripe-specific regulation of pair-rule genes by hopscotch, a putative Jak family tyrosine kinase in Drosophila. - id: PMID:9784499 title: Drosophila unpaired encodes a secreted protein that activates the JAK signaling pathway. - id: PMID:21841788 title: >- The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling. - id: file:interpro/panther/panther.obo title: PANTHER official family and subfamily vocabulary review_status: COMPLETE reviewed_by: claude-code review_date: '2026-10-04' notes: >- Tree topology, subfamily assignments and PTN positions come from the PANTHER 19 treeinfo service (family=PTHR45807). The filtered and unfiltered views gave the same 91-leaf tree. The root PTN001975446 (labelled Eumetazoa, SF7) has two children: the Trichoplax leaf and the Bilateria node PTN001562978. The Bilateria node splits into Deuterostomia (sea urchin, then amphioxus, then a Ciona duplication, then the euteleostome four-way duplication polytomy PTN002521566 over SF6, SF5, SF1 and SF3) and Hexapoda-Crustacea (Drosophila hop, Daphnia). The tree contains no nematode, amoebozoan, fungal or plant leaf. InterPro matches of the HMM outside Metazoa are few (40 fungal, 29 of them arbuscular-mycorrhizal Glomeromycota, all 47-876 residues; 2 plant; 1 choanoflagellate; 0 amoebozoan). Nematode matches are 5 fragments of 99-430 residues. The choanoflagellate match, Monosiga A9UPS2, is a FERM-SH2-dual-kinase protein whose kinase domain groups with SYK, not JAK (PMID:24058787). PAINT seed identities were resolved from the tree (MGI:96628 Jak1, MGI:96629 Jak2, MGI:99928 Jak3, RGD:69056 Jak1, RGD:2939 Jak2, RGD:2940 Jak3; ZFIN:ZDB-GENE-980526-481 is zebrafish jak2a/jak4 in SF2) and from UniProt (K7GSE8 pig JAK3). Findings for PAINT. (1) The negated IRD for GO:0007259 on the TYK2 node PTN002910252 is contradicted by TYK2's own experimental record and should be retracted. Human and mouse TYK2 currently get no GO:0007259 IBA because of it. (2) The GH-receptor IBDs on the euteleostome duplication polytomy reach JAK3. GO:0060397 has only JAK2 seeds and belongs on PTN002910276. GO:0005131 and GO:0060333 need an IRD on the JAK3 clade. (3) The worm and Dictyostelium GO:0007259 IBAs do not come from this family. They come from the STAT family node PTN000927860 (PTHR11801). This family's tree confirms that those organisms have no JAK, which is the basis for the taxon-constraint proposals made alongside this review. The older free-text PTHR45807-review.md and the Falcon deep research (which framed the family as under-annotated and did not address nematodes or Dictyostelium) were read. Neither changes the node verdicts. The Falcon JH1 residue numbering (catalytic lysines K908/K882/K855/K930 and activation-loop tyrosines Y1034/Y1007/Y980/Y1054 for JAK1/JAK2/JAK3/TYK2) was checked against UniProt canonical sequences and is correct. JAK origin and distribution (sponge JAK-like protein as the earliest bona fide JAK-like architecture, canonical JAK and pathway assembly in Bilateria, and the choanoflagellate JAK-like protein grouping with SYK, so that no bona fide JAK is known outside Metazoa) follow the Liongue and Ward 2013 evolutionary review (PMID:24058787). A cross-gene briefing on JAK-STAT taxon scope across the STAT, JAK and PIAS families and the C. elegans and Dictyostelium STAT modules is at https://claude.ai/artifact/4MLfbbbWWnLchDvspwdPuM.