family_id: PANTHER:PTHR11801 family_name: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION preferred_name: STAT family of SH2-domain transcription factors (vertebrate STAT1-6, invertebrate and Dictyostelium STATs, plant STAT-type linker-SH2 proteins) summary: >- Signal transducers and activators of transcription (STATs) are latent cytoplasmic transcription factors that are activated by tyrosine phosphorylation, dimerize through reciprocal SH2-phosphotyrosine contacts, move to the nucleus and bind specific promoter elements. The family core is a DNA-binding domain with an immunoglobulin-like fold, a helical linker and an SH2 domain. Metazoan STATs add an N-terminal oligomerization domain and a C-terminal transactivation domain; Dictyostelium STATs lack both and C. elegans STA-1 lacks the N-terminal domain. In Bilateria with JAK kinases (vertebrates, Drosophila Stat92E/Hopscotch) STATs are the transcriptional arm of receptor-JAK-STAT signalling. Vertebrates have seven paralogs from whole-genome and later duplications, each tied to particular cytokine and hormone receptors: STAT1 and STAT2 for interferons (with IRF9 forming ISGF3), STAT3 for IL-6-family cytokines, leptin and growth factors, STAT4 for IL-12, STAT5A/STAT5B for IL-2-family cytokines, growth hormone and prolactin, and STAT6 for IL-4/IL-13. STATs are older than JAK: the four Dictyostelium STATs are activated through serpentine receptors and tyrosine kinase-like kinases, and the two C. elegans STATs act without JAK in immunity and development (STA-2 in the epidermis via SNF-12 and p38 MAPK, STA-1 in antiviral repression via SID-3). Plants have STAT-type linker-SH2 proteins (Arabidopsis SHA and SHB) that lack the STAT DNA-binding domain and whose function is unknown. functional_coherence: MOSTLY_COHERENT coherence_reason: >- Signal-dependent DNA-binding transcription factor activity at RNA polymerase II promoters, with nuclear-cytoplasmic shuttling, is shared by every lineage that keeps the STAT DNA-binding domain: vertebrates, arthropods, nematodes and Dictyostelium. Three boundaries matter for annotation. (1) Upstream coupling: receptor-JAK signalling is bilaterian and is absent from Dictyostelium (SF65, SF50, dstD in SF43) and from nematodes (SF49, SF68, sta-1 in SF43), so the JAK-STAT IBD on the Unikonts node PTN000927860 is too deep. (2) Domain loss: the Viridiplantae STATL clade (Arabidopsis SHA/SHB, in SF43) has no STAT DNA-binding domain, so the root-level transcription factor IBDs should not reach it; SHA and SHB are recorded as member exceptions. (3) Paralog specialisation: the vertebrate cytokine- and hormone-specific pathway terms belong to single paralog subfamilies, and one of them (growth hormone signalling) is placed above the STAT5/STAT6 split. reference_protein: id: UniProtKB:P42224 label: Signal transducer and activator of transcription 1-alpha/beta gene_symbol: STAT1 organism: Homo sapiens gene_review: genes/human/STAT1/STAT1-ai-review.yaml subfamilies: - subfamily_id: PANTHER:PTHR11801:SF43 clade_node_id: PANTHER:PTN000210448 label: SIGNAL TRANSDUCER AND TRANSCRIPTION ACTIVATOR description: >- PANTHER's default subfamily, assigned at the family root (PTN000210448, Eukaryota), so it collects every member not placed in a more specific subfamily and is phylogenetically heterogeneous. It holds the arthropod STATs (Drosophila Stat92E, Anopheles, Tribolium, Daphnia, Ixodes), leech, cnidarian (Nematostella) and placozoan (Trichoplax) STATs, invertebrate deuterostome STATs (sea urchin, Ciona, amphioxus), C. elegans STA-1 and its nematode orthologs, Dictyostelium dstD, and the whole Viridiplantae STAT-type linker-SH2 clade (Arabidopsis SHA/SHB and orthologs, which lack a STAT DNA-binding domain). It is not a functional group, so no subfamily-scoped term is assigned to SF43 as a unit. representative_members: - id: UniProtKB:Q24151 label: Signal transducer and transcription activator gene_symbol: Stat92E organism: Drosophila melanogaster - id: UniProtKB:Q9NAD6 label: Signal transducer and activator of transcription 1 gene_symbol: sta-1 organism: Caenorhabditis elegans gene_review: genes/worm/sta-1/sta-1-ai-review.yaml - id: UniProtKB:Q86I20 label: Signal transducer and activator of transcription gene_symbol: dstD organism: Dictyostelium discoideum - id: UniProtKB:B5X561 label: SH2 domain-containing protein A gene_symbol: SHA organism: Arabidopsis thaliana - id: UniProtKB:Q56XZ1 label: SH2 domain-containing protein B gene_symbol: SHB organism: Arabidopsis thaliana diverged_from_family: false - subfamily_id: PANTHER:PTHR11801:SF67 clade_node_id: PANTHER:PTN008527028 label: SUBFAMILY NOT NAMED description: >- A small unikont clade (PTN008527028), sister to the main STAT node PTN000927860 below the duplication PTN008527027, containing two leech (Helobdella) proteins and the uncharacterised Dictyostelium protein DDB_G0270046. UniProt records for these members carry no STAT domain cross-references, and none has been studied. It inherits only the root-level IBDs. representative_members: - id: UniProtKB:Q55CI5 label: Uncharacterized protein gene_symbol: DDB_G0270046 organism: Dictyostelium discoideum - subfamily_id: PANTHER:PTHR11801:SF41 clade_node_id: PANTHER:PTN002623821 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 2 description: >- Euteleostome STAT2. Activated by type I and type III interferons through TYK2/JAK1; with STAT1 and IRF9 it forms ISGF3, which binds ISRE elements and drives the antiviral interferon-stimulated gene programme. representative_members: - id: UniProtKB:P52630 label: Signal transducer and activator of transcription 2 gene_symbol: STAT2 organism: Homo sapiens gene_review: genes/human/STAT2/STAT2-ai-review.yaml - id: UniProtKB:Q9WVL2 label: Signal transducer and activator of transcription 2 gene_symbol: Stat2 organism: Mus musculus diverged_from_family: false - subfamily_id: PANTHER:PTHR11801:SF18 clade_node_id: PANTHER:PTN002623830 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 1-ALPHA_BETA description: >- Euteleostome STAT1, the interferon STAT. Homodimers mediate IFN-gamma (GAS) responses and STAT1 is a subunit of ISGF3 for type I interferon; it is also activated by IL-6-family and other cytokines. representative_members: - id: UniProtKB:P42224 label: Signal transducer and activator of transcription 1-alpha/beta gene_symbol: STAT1 organism: Homo sapiens gene_review: genes/human/STAT1/STAT1-ai-review.yaml - id: UniProtKB:P42225 label: Signal transducer and activator of transcription 1 gene_symbol: Stat1 organism: Mus musculus gene_review: genes/mouse/Stat1/Stat1-ai-review.yaml diverged_from_family: false - subfamily_id: PANTHER:PTHR11801:SF2 clade_node_id: PANTHER:PTN002623841 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 description: >- Euteleostome STAT3 (with the Xenopus stat3.1/stat3.2 duplicates). Transducer for IL-6-family cytokines, IL-10, leptin, growth hormone and growth-factor receptors. representative_members: - id: UniProtKB:P40763 label: Signal transducer and activator of transcription 3 gene_symbol: STAT3 organism: Homo sapiens gene_review: genes/human/STAT3/STAT3-ai-review.yaml - id: UniProtKB:P42227 label: Signal transducer and activator of transcription 3 gene_symbol: Stat3 organism: Mus musculus diverged_from_family: false - subfamily_id: PANTHER:PTHR11801:SF19 clade_node_id: PANTHER:PTN002623838 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 4 description: >- Euteleostome STAT4, the IL-12/IL-23 transducer that drives Th1 differentiation and IFN-gamma production. representative_members: - id: UniProtKB:Q14765 label: Signal transducer and activator of transcription 4 gene_symbol: STAT4 organism: Homo sapiens gene_review: genes/human/STAT4/STAT4-ai-review.yaml - id: UniProtKB:P42228 label: Signal transducer and activator of transcription 4 gene_symbol: Stat4 organism: Mus musculus diverged_from_family: false - subfamily_id: PANTHER:PTHR11801:SF39 clade_node_id: PANTHER:PTN002623856 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 5B description: >- Assigned at the euteleostome node above the STAT5/STAT6 duplication, so in practice it holds eutherian STAT5B, the single STAT5 of non-eutherian tetrapods and the teleost stat5.1/stat5.2 genes; tetrapod STAT6 (SF48), eutherian STAT5A (SF47) and teleost stat6 (SF66) are split off below it. STAT5 is the transducer for IL-2, IL-3, IL-5, IL-7, IL-9, IL-15, GM-CSF, thrombopoietin, erythropoietin, growth hormone and prolactin. representative_members: - id: UniProtKB:P51692 label: Signal transducer and activator of transcription 5B gene_symbol: STAT5B organism: Homo sapiens gene_review: genes/human/STAT5B/STAT5B-ai-review.yaml - id: UniProtKB:P42232 label: Signal transducer and activator of transcription 5B gene_symbol: Stat5b organism: Mus musculus diverged_from_family: false - subfamily_id: PANTHER:PTHR11801:SF47 clade_node_id: PANTHER:PTN000210582 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 5A description: >- Eutherian STAT5A, from the eutherian STAT5A/STAT5B duplication. Shares most cytokine inputs with STAT5B and is the predominant STAT5 in prolactin signalling in the mammary gland. representative_members: - id: UniProtKB:P42229 label: Signal transducer and activator of transcription 5A gene_symbol: STAT5A organism: Homo sapiens gene_review: genes/human/STAT5A/STAT5A-ai-review.yaml - id: UniProtKB:P42230 label: Signal transducer and activator of transcription 5A gene_symbol: Stat5a organism: Mus musculus diverged_from_family: false - subfamily_id: PANTHER:PTHR11801:SF48 clade_node_id: PANTHER:PTN008527039 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 6 description: >- Tetrapod STAT6, the IL-4/IL-13 transducer for Th2 differentiation and alternative macrophage activation. representative_members: - id: UniProtKB:P42226 label: Signal transducer and activator of transcription 6 gene_symbol: STAT6 organism: Homo sapiens - id: UniProtKB:P52633 label: Signal transducer and transcription activator 6 gene_symbol: Stat6 organism: Mus musculus diverged_from_family: false - subfamily_id: PANTHER:PTHR11801:SF66 clade_node_id: PANTHER:PTN007538597 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION description: >- A teleost clade (PTN007538597) containing zebrafish stat6 (ZFIN:ZDB-GENE-030131-9359, a PAINT seed for defense response) and its medaka ortholog. The PANTHER tree places it inside the euteleostome STAT5 node as sister to the teleost stat5 genes, not with tetrapod STAT6 (SF48). representative_members: - id: UniProtKB:B3DGV1 label: Signal transducer and activator of transcription gene_symbol: stat6 organism: Danio rerio diverged_from_family: false - subfamily_id: PANTHER:PTHR11801:SF49 clade_node_id: PANTHER:PTN002273440 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION B description: >- Nematode STA-2 orthologs (C. elegans and C. briggsae sta-2, P. pacificus), one product of the nematode STAT duplication PTN000210629. STA-2 is an epidermal transcription factor for antifungal and wound-induced antimicrobial-peptide genes, held at hemidesmosomes and regulated through the SLC6 transporter SNF-12 and a p38 MAPK cascade. representative_members: - id: UniProtKB:Q20977 label: Signal transducer and activator of transcription b gene_symbol: sta-2 organism: Caenorhabditis elegans gene_review: genes/worm/sta-2/sta-2-ai-review.yaml diverged_from_family: true divergence_description: >- Diverged in regulation, and possibly in how it engages DNA. STA-2 keeps the STAT DNA-binding-domain fold (IPR008967, IPR012345) and the SH2 region and acts as a transcriptional regulator, but it lacks the STAT DNA-binding-domain signatures that STA-1 carries (PF02864, IPR013801, cd14801), conserves none of the base-contacting residues of DNA-bound STAT1, and has no demonstrated sequence-specific DNA binding. It also lacks the coiled-coil domain and the C-terminal tyrosine phosphorylation motif that JAKs target, and C. elegans has no JAK. Receptor-JAK-STAT terms (GO:0007259 and the vertebrate cytokine pathways) must not be inherited here. - subfamily_id: PANTHER:PTHR11801:SF68 clade_node_id: PANTHER:PTN008527046 label: PROTEIN KINASE DOMAIN-CONTAINING PROTEIN description: >- A Caenorhabditis-specific duplicate of sta-1 (C. elegans T12G3.2, C. briggsae CBG06214) within the nematode sta-1 clade; uncharacterised. representative_members: - id: UniProtKB:D3YT30 label: Protein kinase domain-containing protein gene_symbol: T12G3.2 organism: Caenorhabditis elegans - subfamily_id: PANTHER:PTHR11801:SF65 clade_node_id: PANTHER:PTN000858339 label: C2H2-TYPE DOMAIN-CONTAINING PROTEIN-RELATED description: >- Dictyostelium STATa (dstA) and STATb (dstB) with three uncharacterised D. discoideum paralogs. PANTHER's subfamily name is not informative. STATa is tyrosine phosphorylated and enters the nucleus in response to extracellular cAMP acting through the serpentine receptor cAR1, and represses stalk genes in the prestalk tip; STATb has a highly aberrant SH2 domain, is constitutively nuclear and has a subtle role in growth. representative_members: - id: UniProtKB:O00910 label: Signal transducer and activator of transcription A gene_symbol: dstA organism: Dictyostelium discoideum gene_review: genes/DICDI/statA/statA-ai-review.yaml - id: UniProtKB:Q70GP4 label: Signal transducer and activator of transcription B gene_symbol: dstB organism: Dictyostelium discoideum diverged_from_family: true divergence_description: >- Diverged in upstream regulation and domain architecture, not in core activity. Dictyostelium STATs keep the coiled-coil, DNA-binding and SH2 domains and act as signal-dependent transcription factors, but lack the N-terminal and transactivation domains of metazoan STATs, and Dictyostelium has no JAK: STATs are activated through serpentine receptors and TKL kinases. The JAK-STAT term GO:0007259 does not apply; GO:0097696 (cell surface receptor signaling pathway via STAT) is the correct process term. - subfamily_id: PANTHER:PTHR11801:SF50 clade_node_id: PANTHER:PTN001719630 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION C description: >- Dictyostelium STATc (dstC) and its D. purpureum ortholog. STATc is tyrosine phosphorylated on Tyr922 in response to DIF-1 and to hyperosmotic and other stresses, by the TKL kinase Pyk2 (and Pyk3), counterbalanced by PTP3. representative_members: - id: UniProtKB:Q54BD4 label: Signal transducer and activator of transcription C gene_symbol: dstC organism: Dictyostelium discoideum gene_review: genes/DICDI/statC/statC-ai-review.yaml diverged_from_family: true divergence_description: >- As for SF65: a JAK-less, TKL-activated STAT. Its core transcription-factor activity is conserved, but receptor-JAK-STAT terms do not apply. node_assessments: - node_id: PANTHER:PTN000210448 asserted_term: id: GO:0005634 label: nucleus evidence: IBD node_taxon: id: NCBITaxon:2759 label: Eukaryota paint_snapshot: '20260528' seeds: - id: FB:FBgn0016917 label: Stat92E organism: Drosophila melanogaster - id: MGI:MGI:103034 label: Stat6 organism: Mus musculus - id: MGI:MGI:103035 label: Stat5b organism: Mus musculus - id: MGI:MGI:103036 label: Stat5a organism: Mus musculus - id: MGI:MGI:103038 label: Stat3 organism: Mus musculus - id: MGI:MGI:103039 label: Stat2 organism: Mus musculus - id: MGI:MGI:103062 label: Stat4 organism: Mus musculus - id: MGI:MGI:103063 label: Stat1 organism: Mus musculus - id: RGD:3772 label: Stat3 organism: Rattus norvegicus - id: UniProtKB:P40763 label: STAT3 organism: Homo sapiens - id: UniProtKB:P42224 label: STAT1 organism: Homo sapiens - id: UniProtKB:P42226 label: STAT6 organism: Homo sapiens - id: UniProtKB:P42229 label: STAT5A organism: Homo sapiens - id: UniProtKB:P51692 label: STAT5B organism: Homo sapiens - id: UniProtKB:P52630 label: STAT2 organism: Homo sapiens - id: UniProtKB:Q14765 label: STAT4 organism: Homo sapiens - id: UniProtKB:Q764M5 label: STAT1 organism: Sus scrofa - id: WB:WBGene00010251 label: sta-2 organism: Caenorhabditis elegans - id: WB:WBGene00013111 label: sta-1 organism: Caenorhabditis elegans - id: dictyBase:DDB_G0268638 label: dstB (STATb) organism: Dictyostelium discoideum - id: dictyBase:DDB_G0281381 label: dstA (STATa) organism: Dictyostelium discoideum - id: dictyBase:DDB_G0293532 label: dstC (STATc) organism: Dictyostelium discoideum assessment: SOUND assessment_reason: >- In the PANTHER 19 tree PTN000210448 is the family root (Eukaryota speciation), above both the unikont STATs and the Viridiplantae STAT-type linker-SH2 (STATL) clade. The seeds include Dictyostelium STATa/STATc (and STATb for nucleus), both C. elegans STATs, fly Stat92E and the vertebrate STATs, so the lowest node covering them is the unikont node and the root placement adds only the plant clade, which has no seed. Latent cytoplasmic STATs that move to the nucleus on activation are shown for every unikont lineage (Dictyostelium STATa nuclear translocation on cAR1 signalling, C. elegans STA-1, the vertebrate STATs). For the plant SHA/SHB proteins localisation has not been tested; a nuclear/cytoplasmic assertion is not contradicted by anything known, so no pruning is proposed. supported_by: - reference_id: PMID:9670017 supporting_text: "During mound formation, the time at which cell-type specific gene expression initiates, Dd-STAT becomes tyrosine phosphorylated and translocates into the nuclei of all cells." - reference_id: PMID:14701681 supporting_text: "it is constitutively enriched in the nucleus" - node_id: PANTHER:PTN000210448 asserted_term: id: GO:0005737 label: cytoplasm evidence: IBD node_taxon: id: NCBITaxon:2759 label: Eukaryota paint_snapshot: '20260528' seeds: - id: FB:FBgn0016917 label: Stat92E organism: Drosophila melanogaster - id: MGI:MGI:103034 label: Stat6 organism: Mus musculus - id: MGI:MGI:103035 label: Stat5b organism: Mus musculus - id: MGI:MGI:103036 label: Stat5a organism: Mus musculus - id: MGI:MGI:103038 label: Stat3 organism: Mus musculus - id: MGI:MGI:103039 label: Stat2 organism: Mus musculus - id: MGI:MGI:103062 label: Stat4 organism: Mus musculus - id: MGI:MGI:103063 label: Stat1 organism: Mus musculus - id: RGD:3772 label: Stat3 organism: Rattus norvegicus - id: UniProtKB:P40763 label: STAT3 organism: Homo sapiens - id: UniProtKB:P42224 label: STAT1 organism: Homo sapiens - id: UniProtKB:P42226 label: STAT6 organism: Homo sapiens - id: UniProtKB:P42229 label: STAT5A organism: Homo sapiens - id: UniProtKB:P51692 label: STAT5B organism: Homo sapiens - id: UniProtKB:P52630 label: STAT2 organism: Homo sapiens - id: UniProtKB:Q764M5 label: STAT1 organism: Sus scrofa - id: WB:WBGene00010251 label: sta-2 organism: Caenorhabditis elegans - id: WB:WBGene00013111 label: sta-1 organism: Caenorhabditis elegans - id: dictyBase:DDB_G0281381 label: dstA (STATa) organism: Dictyostelium discoideum - id: dictyBase:DDB_G0293532 label: dstC (STATc) organism: Dictyostelium discoideum assessment: SOUND assessment_reason: >- In the PANTHER 19 tree PTN000210448 is the family root (Eukaryota speciation), above both the unikont STATs and the Viridiplantae STAT-type linker-SH2 (STATL) clade. The seeds include Dictyostelium STATa/STATc (and STATb for nucleus), both C. elegans STATs, fly Stat92E and the vertebrate STATs, so the lowest node covering them is the unikont node and the root placement adds only the plant clade, which has no seed. Latent cytoplasmic STATs that move to the nucleus on activation are shown for every unikont lineage (Dictyostelium STATa nuclear translocation on cAR1 signalling, C. elegans STA-1, the vertebrate STATs). For the plant SHA/SHB proteins localisation has not been tested; a nuclear/cytoplasmic assertion is not contradicted by anything known, so no pruning is proposed. - node_id: PANTHER:PTN000210448 asserted_term: id: GO:0000978 label: RNA polymerase II cis-regulatory region sequence-specific DNA binding evidence: IBD node_taxon: id: NCBITaxon:2759 label: Eukaryota paint_snapshot: '20251218' seeds: - id: FB:FBgn0016917 label: Stat92E organism: Drosophila melanogaster - id: MGI:MGI:103034 label: Stat6 organism: Mus musculus - id: MGI:MGI:103035 label: Stat5b organism: Mus musculus - id: MGI:MGI:103036 label: Stat5a organism: Mus musculus - id: MGI:MGI:103038 label: Stat3 organism: Mus musculus - id: MGI:MGI:103062 label: Stat4 organism: Mus musculus - id: UniProtKB:P40763 label: STAT3 organism: Homo sapiens - id: UniProtKB:P42224 label: STAT1 organism: Homo sapiens assessment: NEEDS_PRUNING assessment_reason: >- PTN000210448 is the family root (Eukaryota). All seeds are bilaterian (fly Stat92E and mammalian STATs); extension to Dictyostelium is nevertheless well founded, because the four Dictyostelium STATs keep the STAT DNA-binding domain and STATa binds TTGA-containing promoter elements. The problem is the plant branch. The root also covers the Viridiplantae clade PTN004306971 (Arabidopsis SHA/STATLA and SHB/STATLB and their orthologs), which PANTHER files in SF43 together with Stat92E. These plant proteins carry the STAT-type linker-SH2 module but no STAT DNA-binding domain (no IPR008967, IPR013801, IPR012345 or IPR037059 cross-reference, in contrast to every unikont member checked), and no plant member has been shown to bind DNA or regulate transcription. GOA confirms that Arabidopsis SHA and SHB receive this IBA. An IRD on PTN004306971 (or moving the IBD to the unikont duplication node PTN008527027) is recommended. No subfamily is named as affected because SF43 also holds valid members (Stat92E, sta-1, dstD); SHA and SHB are recorded as member exceptions on the term assessment instead. supported_by: - reference_id: PMID:15073273 supporting_text: "Two novel genes carrying the linker-SH2 domain of STAT were discovered and subsequently cloned from Arabidopsis." - reference_id: PMID:24058787 supporting_text: "By the time of divergence of the amoebozoa, a family of proteins can be identified that resemble metazoan STATs, with coiled-coil, DNA-binding and SH2 domains" - reference_id: file:interpro/panther/PTHR11801/PTHR11801-bioinformatics/RESULTS.md supporting_text: "Arabidopsis SHA (B5X561) and SHB (Q56XZ1) carry no STAT DNA-binding-domain InterPro entry" - node_id: PANTHER:PTN000210448 asserted_term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific evidence: IBD node_taxon: id: NCBITaxon:2759 label: Eukaryota paint_snapshot: '20240729' seeds: - id: FB:FBgn0016917 label: Stat92E organism: Drosophila melanogaster - id: MGI:MGI:103035 label: Stat5b organism: Mus musculus - id: MGI:MGI:103036 label: Stat5a organism: Mus musculus - id: MGI:MGI:103038 label: Stat3 organism: Mus musculus - id: MGI:MGI:103062 label: Stat4 organism: Mus musculus - id: MGI:MGI:103063 label: Stat1 organism: Mus musculus - id: UniProtKB:P40763 label: STAT3 organism: Homo sapiens - id: UniProtKB:P42224 label: STAT1 organism: Homo sapiens - id: UniProtKB:P42226 label: STAT6 organism: Homo sapiens - id: UniProtKB:P51692 label: STAT5B organism: Homo sapiens - id: UniProtKB:P52630 label: STAT2 organism: Homo sapiens assessment: NEEDS_PRUNING assessment_reason: >- PTN000210448 is the family root (Eukaryota). All seeds are bilaterian (fly Stat92E and mammalian STATs); extension to Dictyostelium is nevertheless well founded, because the four Dictyostelium STATs keep the STAT DNA-binding domain and STATa binds TTGA-containing promoter elements. The problem is the plant branch. The root also covers the Viridiplantae clade PTN004306971 (Arabidopsis SHA/STATLA and SHB/STATLB and their orthologs), which PANTHER files in SF43 together with Stat92E. These plant proteins carry the STAT-type linker-SH2 module but no STAT DNA-binding domain (no IPR008967, IPR013801, IPR012345 or IPR037059 cross-reference, in contrast to every unikont member checked), and no plant member has been shown to bind DNA or regulate transcription. GOA confirms that Arabidopsis SHA and SHB receive this IBA. An IRD on PTN004306971 (or moving the IBD to the unikont duplication node PTN008527027) is recommended. No subfamily is named as affected because SF43 also holds valid members (Stat92E, sta-1, dstD); SHA and SHB are recorded as member exceptions on the term assessment instead. supported_by: - reference_id: PMID:15073273 supporting_text: "Two novel genes carrying the linker-SH2 domain of STAT were discovered and subsequently cloned from Arabidopsis." - reference_id: PMID:24058787 supporting_text: "By the time of divergence of the amoebozoa, a family of proteins can be identified that resemble metazoan STATs, with coiled-coil, DNA-binding and SH2 domains" - reference_id: file:interpro/panther/PTHR11801/PTHR11801-bioinformatics/RESULTS.md supporting_text: "Arabidopsis SHA (B5X561) and SHB (Q56XZ1) carry no STAT DNA-binding-domain InterPro entry" - node_id: PANTHER:PTN000210448 asserted_term: id: GO:0006357 label: regulation of transcription by RNA polymerase II evidence: IBD node_taxon: id: NCBITaxon:2759 label: Eukaryota paint_snapshot: '20260828' seeds: - id: MGI:MGI:103034 label: Stat6 organism: Mus musculus - id: MGI:MGI:103035 label: Stat5b organism: Mus musculus - id: MGI:MGI:103036 label: Stat5a organism: Mus musculus - id: MGI:MGI:103038 label: Stat3 organism: Mus musculus - id: MGI:MGI:103062 label: Stat4 organism: Mus musculus - id: RGD:1309063 label: Stat6 organism: Rattus norvegicus - id: RGD:3772 label: Stat3 organism: Rattus norvegicus - id: UniProtKB:P40763 label: STAT3 organism: Homo sapiens - id: UniProtKB:P42224 label: STAT1 organism: Homo sapiens - id: UniProtKB:P42226 label: STAT6 organism: Homo sapiens - id: UniProtKB:P52630 label: STAT2 organism: Homo sapiens - id: WB:WBGene00013111 label: sta-1 organism: Caenorhabditis elegans - id: ZFIN:ZDB-GENE-030820-2 label: stat5.1 (stat5a) organism: Danio rerio assessment: NEEDS_PRUNING assessment_reason: >- PTN000210448 is the family root (Eukaryota). All seeds are bilaterian (fly Stat92E and mammalian STATs, zebrafish stat5.1 and C. elegans STA-1); extension to Dictyostelium is nevertheless well founded, because the four Dictyostelium STATs keep the STAT DNA-binding domain and STATa binds TTGA-containing promoter elements. The problem is the plant branch. The root also covers the Viridiplantae clade PTN004306971 (Arabidopsis SHA/STATLA and SHB/STATLB and their orthologs), which PANTHER files in SF43 together with Stat92E. These plant proteins carry the STAT-type linker-SH2 module but no STAT DNA-binding domain (no IPR008967, IPR013801, IPR012345 or IPR037059 cross-reference, in contrast to every unikont member checked), and no plant member has been shown to bind DNA or regulate transcription. GOA confirms that Arabidopsis SHA and SHB receive this IBA. An IRD on PTN004306971 (or moving the IBD to the unikont duplication node PTN008527027) is recommended. No subfamily is named as affected because SF43 also holds valid members (Stat92E, sta-1, dstD); SHA and SHB are recorded as member exceptions on the term assessment instead. supported_by: - reference_id: PMID:15073273 supporting_text: "Two novel genes carrying the linker-SH2 domain of STAT were discovered and subsequently cloned from Arabidopsis." - reference_id: PMID:24058787 supporting_text: "By the time of divergence of the amoebozoa, a family of proteins can be identified that resemble metazoan STATs, with coiled-coil, DNA-binding and SH2 domains" - reference_id: file:interpro/panther/PTHR11801/PTHR11801-bioinformatics/RESULTS.md supporting_text: "Arabidopsis SHA (B5X561) and SHB (Q56XZ1) carry no STAT DNA-binding-domain InterPro entry" - node_id: PANTHER:PTN000210451 asserted_term: id: GO:0019221 label: cytokine-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:7711 label: Chordata paint_snapshot: '20260828' seeds: - id: MGI:MGI:103034 label: Stat6 organism: Mus musculus - id: MGI:MGI:103035 label: Stat5b organism: Mus musculus - id: MGI:MGI:103036 label: Stat5a organism: Mus musculus - id: MGI:MGI:103038 label: Stat3 organism: Mus musculus - id: MGI:MGI:103039 label: Stat2 organism: Mus musculus - id: MGI:MGI:103062 label: Stat4 organism: Mus musculus - id: MGI:MGI:103063 label: Stat1 organism: Mus musculus - id: RGD:1309063 label: Stat6 organism: Rattus norvegicus - id: UniProtKB:P40763 label: STAT3 organism: Homo sapiens - id: UniProtKB:P42224 label: STAT1 organism: Homo sapiens - id: UniProtKB:P42226 label: STAT6 organism: Homo sapiens - id: UniProtKB:P42229 label: STAT5A organism: Homo sapiens - id: UniProtKB:P51692 label: STAT5B organism: Homo sapiens - id: UniProtKB:P52630 label: STAT2 organism: Homo sapiens - id: UniProtKB:Q14765 label: STAT4 organism: Homo sapiens assessment: SOUND assessment_reason: >- PTN000210451 is the Chordata speciation node, one above the vertebrate STAT radiation (duplication PTN000210452), so Ciona and amphioxus STATs (SF43) also inherit the term. All seeds are vertebrate. The extension is reasonable: the canonical receptor-JAK-STAT module was assembled before the protostome-deuterostome split and urochordates retain a single JAK, which PANTHER's JAK family (PTHR45807) also places in Ciona and Branchiostoma. Cytokine-mediated signalling is the shared upstream context of every vertebrate STAT paralog. supported_by: - reference_id: PMID:24058793 supporting_text: "Cytokine signals are essential for generating a robust and specialized immune response. These signals are typically transmitted via canonical STAT homodimers." - reference_id: PMID:24058787 supporting_text: "with existing urochordates such as sea squirt (Ciona intestinalis) retaining a single JAK" - node_id: PANTHER:PTN000210451 asserted_term: id: GO:0043434 label: response to peptide hormone evidence: IBD node_taxon: id: NCBITaxon:7711 label: Chordata paint_snapshot: '20190221' seeds: - id: MGI:MGI:103035 label: Stat5b organism: Mus musculus - id: MGI:MGI:103036 label: Stat5a organism: Mus musculus - id: MGI:MGI:103038 label: Stat3 organism: Mus musculus - id: RGD:3771 label: Stat1 organism: Rattus norvegicus - id: RGD:3772 label: Stat3 organism: Rattus norvegicus - id: RGD:3774 label: Stat5b organism: Rattus norvegicus - id: UniProtKB:P40763 label: STAT3 organism: Homo sapiens - id: UniProtKB:P51692 label: STAT5B organism: Homo sapiens assessment: NEEDS_PRUNING assessment_reason: >- Chordata node; seeds are STAT3, STAT5A/STAT5B and rat Stat1, whose hormone inputs (leptin, growth hormone, prolactin) are peptide hormones. STAT2 (SF41) is a dedicated type I/III interferon transducer (ISGF3 component) with no peptide-hormone input; interferons are cytokines, not peptide hormones, and the STAT2 gene review removes this IBA on that basis. STAT4 (SF19) and STAT6 (SF48) also inherit without any seed or known hormone input, but nothing excludes one, so they are left outside the confirmed scope rather than named for pruning. An IRD on the STAT2 node PTN002623821 is recommended. affected_subfamilies: - id: PANTHER:PTHR11801:SF41 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 2 supported_by: - reference_id: PMID:17344214 supporting_text: "leptin induced Stat3-phosphorylation-dependent proliferation of MCF7 cells" - reference_id: PMID:12552091 supporting_text: "GH stimulated the reporter activities by four- to sixfold." - node_id: PANTHER:PTN000210452 asserted_term: id: GO:0090575 label: RNA polymerase II transcription regulator complex evidence: IBD paint_snapshot: '20231129' seeds: - id: UniProtKB:P40763 label: STAT3 organism: Homo sapiens - id: UniProtKB:P42224 label: STAT1 organism: Homo sapiens - id: UniProtKB:P42226 label: STAT6 organism: Homo sapiens - id: UniProtKB:P52630 label: STAT2 organism: Homo sapiens - id: UniProtKB:Q14765 label: STAT4 organism: Homo sapiens assessment: SOUND assessment_reason: >- PTN000210452 is the duplication node at the base of the vertebrate STAT radiation (all of SF2, SF18, SF19, SF39, SF41, SF47, SF48, SF66). Seeds are STAT1, STAT2, STAT3, STAT4 and STAT6, i.e. paralogs on several branches of the duplication, so this is the lowest node covering them. Activated vertebrate STATs act as homo- and heterodimers (and STAT1/STAT2 with IRF9 as ISGF3) bound to RNA polymerase II promoters, so a transcription regulator complex is a correct family-wide component for this clade. supported_by: - reference_id: PMID:24058793 supporting_text: "Heterodimerization of STAT proteins is one potential mechanism for signals to be modified downstream of the receptor" - node_id: PANTHER:PTN000210582 asserted_term: id: GO:0035723 label: interleukin-15-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:9347 label: Eutheria paint_snapshot: '20260728' seeds: - id: UniProtKB:P42229 label: STAT5A organism: Homo sapiens assessment: SOUND assessment_reason: >- PTN000210582 is the eutherian STAT5A node (SF47), below the eutherian STAT5A/STAT5B duplication. The single seed is human STAT5A, so the assertion stays within the seed's own orthology group and the placement is sound. IL-15, like IL-2, activates STAT5 in human T cells. The same cytokines also signal through STAT5B, which is outside this node; that is an incompleteness of propagation, not an error. - node_id: PANTHER:PTN000210582 asserted_term: id: GO:0035771 label: interleukin-4-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:9347 label: Eutheria paint_snapshot: '20260728' seeds: - id: UniProtKB:P42229 label: STAT5A organism: Homo sapiens assessment: SOUND assessment_reason: >- PTN000210582 is the eutherian STAT5A node (SF47), below the eutherian STAT5A/STAT5B duplication. The single seed is human STAT5A, so the assertion stays within the seed's own orthology group and the placement is sound. Caveat: in human T cells IL-4 activated STAT3 but not STAT5 (PMID:7568001), so this assertion rests on the curator's cell-type-specific evidence; the STAT5A gene review keeps it as non-core. The same cytokines also signal through STAT5B, which is outside this node; that is an incompleteness of propagation, not an error. supported_by: - reference_id: PMID:7568001 supporting_text: "IL-2 and IL-15 rapidly induced the tyrosine phosphorylation of STAT3 and STAT5" - node_id: PANTHER:PTN000210582 asserted_term: id: GO:0038043 label: interleukin-5-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:9347 label: Eutheria paint_snapshot: '20260728' seeds: - id: UniProtKB:P42229 label: STAT5A organism: Homo sapiens assessment: SOUND assessment_reason: >- PTN000210582 is the eutherian STAT5A node (SF47), below the eutherian STAT5A/STAT5B duplication. The single seed is human STAT5A, so the assertion stays within the seed's own orthology group and the placement is sound. IL-5 signals through the common beta chain and STAT5. The same cytokines also signal through STAT5B, which is outside this node; that is an incompleteness of propagation, not an error. - node_id: PANTHER:PTN000210582 asserted_term: id: GO:0038110 label: interleukin-2-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:9347 label: Eutheria paint_snapshot: '20260728' seeds: - id: UniProtKB:P42229 label: STAT5A organism: Homo sapiens assessment: SOUND assessment_reason: >- PTN000210582 is the eutherian STAT5A node (SF47), below the eutherian STAT5A/STAT5B duplication. The single seed is human STAT5A, so the assertion stays within the seed's own orthology group and the placement is sound. IL-2 activates both STAT5A and STAT5B in lymphocytes. The same cytokines also signal through STAT5B, which is outside this node; that is an incompleteness of propagation, not an error. supported_by: - reference_id: PMID:8631883 supporting_text: "both Stat5A and Stat5B are activated by interleukin-2 (IL-2) in peripheral blood lymphocytes" - reference_id: PMID:7568001 supporting_text: "IL-2 and IL-15 rapidly induced the tyrosine phosphorylation of STAT3 and STAT5" - node_id: PANTHER:PTN000210582 asserted_term: id: GO:0038111 label: interleukin-7-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:9347 label: Eutheria paint_snapshot: '20260728' seeds: - id: UniProtKB:P42229 label: STAT5A organism: Homo sapiens assessment: SOUND assessment_reason: >- PTN000210582 is the eutherian STAT5A node (SF47), below the eutherian STAT5A/STAT5B duplication. The single seed is human STAT5A, so the assertion stays within the seed's own orthology group and the placement is sound. IL-7 signalling in T cells is principally mediated by STAT5. The same cytokines also signal through STAT5B, which is outside this node; that is an incompleteness of propagation, not an error. - node_id: PANTHER:PTN000210582 asserted_term: id: GO:0038113 label: interleukin-9-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:9347 label: Eutheria paint_snapshot: '20260728' seeds: - id: UniProtKB:P42229 label: STAT5A organism: Homo sapiens assessment: SOUND assessment_reason: >- PTN000210582 is the eutherian STAT5A node (SF47), below the eutherian STAT5A/STAT5B duplication. The single seed is human STAT5A, so the assertion stays within the seed's own orthology group and the placement is sound. The IL-9 receptor activates STAT5 homodimers via JAK1/JAK3. The same cytokines also signal through STAT5B, which is outside this node; that is an incompleteness of propagation, not an error. - node_id: PANTHER:PTN000210582 asserted_term: id: GO:0038156 label: interleukin-3-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:9347 label: Eutheria paint_snapshot: '20260728' seeds: - id: UniProtKB:P42229 label: STAT5A organism: Homo sapiens assessment: SOUND assessment_reason: >- PTN000210582 is the eutherian STAT5A node (SF47), below the eutherian STAT5A/STAT5B duplication. The single seed is human STAT5A, so the assertion stays within the seed's own orthology group and the placement is sound. IL-3 signals through the common beta chain and STAT5. The same cytokines also signal through STAT5B, which is outside this node; that is an incompleteness of propagation, not an error. - node_id: PANTHER:PTN000210582 asserted_term: id: GO:0038163 label: thrombopoietin-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:9347 label: Eutheria paint_snapshot: '20260728' seeds: - id: UniProtKB:P42229 label: STAT5A organism: Homo sapiens assessment: SOUND assessment_reason: >- PTN000210582 is the eutherian STAT5A node (SF47), below the eutherian STAT5A/STAT5B duplication. The single seed is human STAT5A, so the assertion stays within the seed's own orthology group and the placement is sound. Thrombopoietin receptor (Mpl) signalling activates STAT5. The same cytokines also signal through STAT5B, which is outside this node; that is an incompleteness of propagation, not an error. - node_id: PANTHER:PTN000927860 asserted_term: id: GO:0006952 label: defense response evidence: IBD paint_snapshot: '20260828' seeds: - id: FB:FBgn0016917 label: Stat92E organism: Drosophila melanogaster - id: MGI:MGI:103038 label: Stat3 organism: Mus musculus - id: MGI:MGI:103039 label: Stat2 organism: Mus musculus - id: MGI:MGI:103063 label: Stat1 organism: Mus musculus - id: RGD:3772 label: Stat3 organism: Rattus norvegicus - id: RGD:3774 label: Stat5b organism: Rattus norvegicus - id: UniProtKB:P42224 label: STAT1 organism: Homo sapiens - id: UniProtKB:P52630 label: STAT2 organism: Homo sapiens - id: WB:WBGene00010251 label: sta-2 organism: Caenorhabditis elegans - id: ZFIN:ZDB-GENE-030131-9359 label: stat6 organism: Danio rerio assessment: UNRESOLVED assessment_reason: >- PTN000927860 is the Unikonts node (see the GO:0007259 assessment). Every seed is bilaterian, including C. elegans sta-2, whose epidermal antifungal and wound-induced antimicrobial-peptide role shows that STAT participation in defence does not depend on JAK. Within the nematode branch the sign is not uniform: C. elegans STA-1 represses Orsay-virus-induced genes, so for it the inherited positive term is a regulatory sign inversion (the sta-1 review modifies it to GO:0050687 negative regulation of defense response to virus); this is a member-level divergence below the node, not a reason to move it. The lowest node covering the seeds is Bilateria (PTN000210449), so the extension to the Dictyostelium STATs rests on the curator's judgement alone. No Dictyostelium STAT has been tested for a role in defence (STATc mediates osmotic and other stress responses, which are not defence responses), and nothing shows it lacks one. The Dictyostelium gene reviews keep the IBA as non-core. Left unresolved: neither a pruning nor a confirmation is warranted on present evidence. supported_by: - reference_id: PMID:21575913 supporting_text: "the two proteins function together to regulate AMP gene expression in the epidermis" - reference_id: PMID:26716073 supporting_text: "Both the STAT family protein STA-2 and the GATA transcription factor ELT-3 are required for the transcription of nlps" - reference_id: PMID:28874466 supporting_text: "sta-1 mutants were 100-fold less permissive to infection than wild-type animals" - node_id: PANTHER:PTN000927860 asserted_term: id: GO:0007259 label: cell surface receptor signaling pathway via JAK-STAT evidence: IBD paint_snapshot: '20241120' seeds: - id: FB:FBgn0016917 label: Stat92E organism: Drosophila melanogaster - id: MGI:MGI:103035 label: Stat5b organism: Mus musculus - id: MGI:MGI:103036 label: Stat5a organism: Mus musculus - id: MGI:MGI:103063 label: Stat1 organism: Mus musculus - id: RGD:3771 label: Stat1 organism: Rattus norvegicus - id: RGD:3773 label: Stat5a organism: Rattus norvegicus - id: RGD:3774 label: Stat5b organism: Rattus norvegicus - id: UniProtKB:P40763 label: STAT3 organism: Homo sapiens - id: UniProtKB:P42224 label: STAT1 organism: Homo sapiens - id: UniProtKB:P42226 label: STAT6 organism: Homo sapiens - id: UniProtKB:P52630 label: STAT2 organism: Homo sapiens - id: ZFIN:ZDB-GENE-030820-2 label: stat5.1 (stat5a) organism: Danio rerio - id: ZFIN:ZDB-GENE-980526-68 label: stat3 organism: Danio rerio assessment: TOO_DEEP assessment_reason: >- PAINT records no taxon; the PANTHER 19 tree places PTN000927860 at the Unikonts speciation, the common ancestor of the Eumetazoa clade (PTN000927862) and the Dictyostelium STAT clade (PTN001370513). All seeds are bilaterian (fly Stat92E, mammalian, rat and zebrafish STATs), so the lowest node they support is Bilateria (PTN000210449); the placement is one ancestral speciation deeper than the seeds and reaches organisms without JAK. Dictyostelium has no orthologs of the animal tyrosine kinases; its STATs are activated by TKL kinases (Pyk2 for STATc) or via the cAMP receptor cAR1 (STATa). C. elegans has no JAK homolog and its STATs act JAK-independently. PANTHER's own JAK family (PTHR45807) has no member in C. elegans, C. briggsae, P. pacificus, Dictyostelium or Nematostella. The canonical pathway was assembled in Bilateria. GOA confirms the term reaches Dictyostelium dstD and C. elegans sta-1 and sta-2. Recommended fix: move the IBD to PTN000210449 (Bilateria) and place an IRD on the nematode STAT duplication node PTN000210629, which covers SF49, SF68 and the sta-1 clade. Affected subfamilies are the Dictyostelium SF65 and SF50 and the nematode SF49 and SF68; the root catch-all SF43 also holds affected members (Dictyostelium dstD, C. elegans sta-1, P. pacificus, Nematostella and Trichoplax STATs) but cannot be named as a unit because it also holds the valid Stat92E seed. For the Dictyostelium proteins GO:0097696 (cell surface receptor signaling pathway via STAT), the JAK-agnostic parent, is the correct process term. The evolutionary reviews agree with this placement: STAT-like proteins with coiled-coil, DNA-binding and SH2 domains were present by the divergence of the amoebozoa, and the four Dictyostelium STATs form a distinct clade, but the canonical receptor-JAK-STAT pathway was assembled only in Bilateria, before the protostome-deuterostome split (PMID:24058787, PMID:24058748; quotes on the GO:0007259 term assessment). affected_subfamilies: - id: PANTHER:PTHR11801:SF65 label: C2H2-TYPE DOMAIN-CONTAINING PROTEIN-RELATED - id: PANTHER:PTHR11801:SF50 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION C - id: PANTHER:PTHR11801:SF49 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION B - id: PANTHER:PTHR11801:SF68 label: PROTEIN KINASE DOMAIN-CONTAINING PROTEIN supported_by: - reference_id: PMID:24058748 supporting_text: "However, they lack the N-terminal and transactivation domains characteristic of STAT proteins from higher organisms" - reference_id: PMID:24058748 supporting_text: "the slime mold STATs form a distinct clade" - reference_id: PMID:24058787 supporting_text: "By the time of divergence of the amoebozoa, a family of proteins can be identified that resemble metazoan STATs, with coiled-coil, DNA-binding and SH2 domains" - node_id: PANTHER:PTN000927860 asserted_term: id: GO:0042127 label: regulation of cell population proliferation evidence: IBD paint_snapshot: '20250902' seeds: - id: FB:FBgn0016917 label: Stat92E organism: Drosophila melanogaster - id: MGI:MGI:103034 label: Stat6 organism: Mus musculus - id: MGI:MGI:103035 label: Stat5b organism: Mus musculus - id: MGI:MGI:103036 label: Stat5a organism: Mus musculus - id: MGI:MGI:103038 label: Stat3 organism: Mus musculus - id: RGD:3771 label: Stat1 organism: Rattus norvegicus - id: RGD:3772 label: Stat3 organism: Rattus norvegicus - id: RGD:3774 label: Stat5b organism: Rattus norvegicus - id: UniProtKB:P42224 label: STAT1 organism: Homo sapiens - id: UniProtKB:P42229 label: STAT5A organism: Homo sapiens - id: ZFIN:ZDB-GENE-980526-68 label: stat3 organism: Danio rerio - id: dictyBase:DDB_G0268638 label: dstB (STATb) organism: Dictyostelium discoideum assessment: SOUND assessment_reason: >- PTN000927860 is the Unikonts node. Unlike its two sibling IBDs, this one has an amoebozoan seed (Dictyostelium STATb: STATb-null cells are gradually lost from mixed cultures with parental cells) as well as fly, mouse, rat, human and zebrafish seeds, so the Unikonts node is the lowest node covering them. Regulation of cell proliferation does not presuppose JAK. It is a broad, non-core term for most members, and the plant clade (outside this node) correctly does not inherit it. - node_id: PANTHER:PTN002623821 asserted_term: id: GO:0070721 label: ISGF3 complex evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20231129' seeds: - id: UniProtKB:P52630 label: STAT2 organism: Homo sapiens assessment: SOUND assessment_reason: >- PTN002623821 is the euteleostome STAT2 node (SF41). STAT2 is the defining STAT subunit of ISGF3 with STAT1 and IRF9; the seed is human STAT2. Teleosts have type I interferons, STAT2 and IRF9, so the euteleostome placement is reasonable. supported_by: - reference_id: PMID:24065129 supporting_text: "the transcription factor ISGF3 (IRF9 and tyrosine-phosphorylated STATs 1 and 2) drives the first rapid response phase" - node_id: PANTHER:PTN002623821 asserted_term: id: GO:0060337 label: type I interferon-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20190221' seeds: - id: MGI:MGI:103039 label: Stat2 organism: Mus musculus - id: UniProtKB:P52630 label: STAT2 organism: Homo sapiens assessment: SOUND assessment_reason: >- Euteleostome STAT2 node (SF41); seeds are human STAT2 and mouse Stat2. Type I interferon signalling through ISGF3 is the core function of STAT2. supported_by: - reference_id: PMID:24065129 supporting_text: "the transcription factor ISGF3 (IRF9 and tyrosine-phosphorylated STATs 1 and 2) drives the first rapid response phase" - node_id: PANTHER:PTN002623830 asserted_term: id: GO:0070721 label: ISGF3 complex evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20231129' seeds: - id: UniProtKB:P42224 label: STAT1 organism: Homo sapiens assessment: SOUND assessment_reason: >- PTN002623830 is the euteleostome STAT1 node (SF18); seed human STAT1. STAT1 is the other STAT subunit of ISGF3. supported_by: - reference_id: PMID:24065129 supporting_text: "the transcription factor ISGF3 (IRF9 and tyrosine-phosphorylated STATs 1 and 2) drives the first rapid response phase" - node_id: PANTHER:PTN002623830 asserted_term: id: GO:0031663 label: lipopolysaccharide-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20260728' seeds: - id: MGI:MGI:103063 label: Stat1 organism: Mus musculus assessment: UNRESOLVED assessment_reason: >- Euteleostome STAT1 node (SF18). The single seed is mouse Stat1, whose involvement in LPS responses is downstream of TRIF-dependent type I interferon production, i.e. STAT1 transduces the autocrine interferon signal rather than the LPS receptor signal itself. The extension from one mouse seed to all euteleostomes, including teleosts, was not verified here. Kept as non-core in the STAT1 gene reviews. - node_id: PANTHER:PTN002623830 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:P42224 label: STAT1 organism: Homo sapiens assessment: SOUND assessment_reason: >- Euteleostome STAT1 node (SF18); seed human STAT1. IL-7 activates STAT1 as well as STAT5 in T cells under lymphopenic conditions. Non-core for STAT1; the gene review keeps it as non-core. - node_id: PANTHER:PTN002623830 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:P42224 label: STAT1 organism: Homo sapiens assessment: SOUND assessment_reason: >- Euteleostome STAT1 node (SF18); seed human STAT1. The IL-9 receptor activates STAT1 homodimers and STAT1-STAT3 heterodimers. Non-core for STAT1. - node_id: PANTHER:PTN002623830 asserted_term: id: GO:0060337 label: type I interferon-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20190221' seeds: - id: MGI:MGI:103063 label: Stat1 organism: Mus musculus - id: UniProtKB:P42224 label: STAT1 organism: Homo sapiens assessment: SOUND assessment_reason: >- Euteleostome STAT1 node (SF18); seeds human STAT1 and mouse Stat1. Core STAT1 function. supported_by: - reference_id: PMID:24065129 supporting_text: "the transcription factor ISGF3 (IRF9 and tyrosine-phosphorylated STATs 1 and 2) drives the first rapid response phase" - node_id: PANTHER:PTN002623841 asserted_term: id: GO:0033210 label: leptin-mediated signaling pathway evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20190221' seeds: - id: MGI:MGI:103038 label: Stat3 organism: Mus musculus - id: UniProtKB:P40763 label: STAT3 organism: Homo sapiens assessment: SOUND assessment_reason: >- PTN002623841 is the euteleostome STAT3 node (SF2); seeds human STAT3 and mouse Stat3. Leptin receptor signalling through STAT3 is the best-characterised STAT input for this hormone. supported_by: - reference_id: PMID:17344214 supporting_text: "leptin induced Stat3-phosphorylation-dependent proliferation of MCF7 cells" - node_id: PANTHER:PTN002623841 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:P40763 label: STAT3 organism: Homo sapiens assessment: SOUND assessment_reason: >- Euteleostome STAT3 node (SF2); seed human STAT3. IL-2 and IL-15 activate STAT3 as well as STAT5 in human T cells. supported_by: - reference_id: PMID:8631883 supporting_text: "both Stat5A and Stat5B are activated by interleukin-2 (IL-2) in peripheral blood lymphocytes" - reference_id: PMID:7568001 supporting_text: "IL-2 and IL-15 rapidly induced the tyrosine phosphorylation of STAT3 and STAT5" - node_id: PANTHER:PTN002623841 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:P40763 label: STAT3 organism: Homo sapiens assessment: SOUND assessment_reason: >- Euteleostome STAT3 node (SF2); seed human STAT3. The IL-9 receptor activates STAT1-STAT3 heterodimers. - node_id: PANTHER:PTN002623841 asserted_term: id: GO:0060397 label: growth hormone receptor signaling pathway via JAK-STAT evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20190221' seeds: - id: MGI:MGI:103038 label: Stat3 organism: Mus musculus - id: UniProtKB:P40763 label: STAT3 organism: Homo sapiens assessment: SOUND assessment_reason: >- Euteleostome STAT3 node (SF2); seeds human STAT3 and mouse Stat3. Growth hormone activates STAT3- and STAT5-dependent reporters via JAK2. supported_by: - reference_id: PMID:12552091 supporting_text: "luciferase reporters with binding elements for STAT3 and STAT5 or the beta-casein promoter. GH stimulated the reporter activities by four- to sixfold." - node_id: PANTHER:PTN002623856 asserted_term: id: GO:0060397 label: growth hormone receptor signaling pathway via JAK-STAT evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20190221' seeds: - id: MGI:MGI:103035 label: Stat5b organism: Mus musculus - id: MGI:MGI:103036 label: Stat5a organism: Mus musculus - id: UniProtKB:P51692 label: STAT5B organism: Homo sapiens assessment: TOO_DEEP assessment_reason: >- PTN002623856 is the euteleostome node above the STAT5/STAT6 duplication: it carries SF39 and its descendants include the tetrapod STAT6 clade (SF48, node PTN008527039), the eutherian STAT5A clade (SF47) and the teleost clade SF66, which contains zebrafish stat6 (ZFIN:ZDB-GENE-030131-9359). The seeds are all STAT5 (mouse Stat5a/Stat5b, human STAT5B). Growth hormone receptor signalling is a STAT5 (and STAT3) function; no evidence links STAT6 to growth hormone. The IBD should sit on the STAT5 branches (the tetrapod STAT5 node PTN008527041 and the teleost stat5 node PTN000210618) rather than above the STAT5/STAT6 split. affected_subfamilies: - id: PANTHER:PTHR11801:SF48 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 6 - id: PANTHER:PTHR11801:SF66 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION supported_by: - reference_id: PMID:12552091 supporting_text: "luciferase reporters with binding elements for STAT3 and STAT5 or the beta-casein promoter. GH stimulated the reporter activities by four- to sixfold." term_assessments: - assessed_term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific scope: FAMILY_WIDE scope_reason: >- Sequence-specific, signal-dependent DNA-binding transcription factor activity is the defining STAT activity and is shown for vertebrate, Drosophila, C. elegans (STA-1) and Dictyostelium STATs, all of which keep the STAT DNA-binding domain. The exceptions are the plant STAT-type linker-SH2 proteins, which lack that domain. C. elegans STA-2 (SF49) is an unresolved case rather than an exception: it regulates antimicrobial-peptide transcription but keeps only the DNA-binding-domain fold, and sequence-specific binding is undemonstrated, so its gene review marks GO:0000978 over-annotated and generalises this term to GO:0140110 transcription regulator activity, without asserting that either is wrong. member_exceptions: - member: id: UniProtKB:B5X561 label: SH2 domain-containing protein A gene_symbol: SHA organism: Arabidopsis thaliana exception_reason: >- Arabidopsis SHA belongs to the Viridiplantae STAT-type linker-SH2 (STATL) clade PTN004306971, which PANTHER places in SF43 with Stat92E. It carries the STAT linker-SH2 module and a ConA-like/laminin-G-type N-terminal region but no STAT DNA-binding domain, and no plant member has been shown to bind DNA or regulate transcription. It receives this term only by descent from the family root PTN000210448, whose seeds are all bilaterian. An IRD on PTN004306971 is recommended. pruned_node_id: PANTHER:PTN000210448 lost_in_clade_node_id: PANTHER:PTN004306971 supported_by: - reference_id: PMID:15073273 supporting_text: Two novel genes carrying the linker-SH2 domain of STAT were discovered and subsequently cloned from Arabidopsis. - reference_id: PMID:24058787 supporting_text: By the time of divergence of the amoebozoa, a family of proteins can be identified that resemble metazoan STATs, with coiled-coil, DNA-binding and SH2 domains - reference_id: file:interpro/panther/PTHR11801/PTHR11801-bioinformatics/RESULTS.md supporting_text: Arabidopsis SHA (B5X561) and SHB (Q56XZ1) carry no STAT DNA-binding-domain InterPro entry - member: id: UniProtKB:Q56XZ1 label: SH2 domain-containing protein B gene_symbol: SHB organism: Arabidopsis thaliana exception_reason: >- Arabidopsis SHB belongs to the Viridiplantae STAT-type linker-SH2 (STATL) clade PTN004306971, which PANTHER places in SF43 with Stat92E. It carries the STAT linker-SH2 module and a ConA-like/laminin-G-type N-terminal region but no STAT DNA-binding domain, and no plant member has been shown to bind DNA or regulate transcription. It receives this term only by descent from the family root PTN000210448, whose seeds are all bilaterian. An IRD on PTN004306971 is recommended. pruned_node_id: PANTHER:PTN000210448 lost_in_clade_node_id: PANTHER:PTN004306971 supported_by: - reference_id: PMID:15073273 supporting_text: Two novel genes carrying the linker-SH2 domain of STAT were discovered and subsequently cloned from Arabidopsis. - reference_id: PMID:24058787 supporting_text: By the time of divergence of the amoebozoa, a family of proteins can be identified that resemble metazoan STATs, with coiled-coil, DNA-binding and SH2 domains - reference_id: file:interpro/panther/PTHR11801/PTHR11801-bioinformatics/RESULTS.md supporting_text: Arabidopsis SHA (B5X561) and SHB (Q56XZ1) carry no STAT DNA-binding-domain InterPro entry supported_by: - &id001 reference_id: PMID:9630226 supporting_text: STAT-1 utilizes a DNA-binding domain with an immunoglobulin fold, similar to that of NFkappaB and the p53 tumor suppressor protein. - &id002 reference_id: PMID:8608596 supporting_text: The phosphorylated protein binds specifically to the consensus sequence TTCCCGGAA. - &id003 reference_id: PMID:16873887 supporting_text: STA-1, is structurally and functionally related to other vertebrate and invertebrate STAT proteins, recognizing a cis DNA element conserved through phylogeny. - reference_id: PMID:24058748 supporting_text: However, they lack the N-terminal and transactivation domains characteristic of STAT proteins from higher organisms - assessed_term: id: GO:0000978 label: RNA polymerase II cis-regulatory region sequence-specific DNA binding scope: FAMILY_WIDE scope_reason: >- Same basis as GO:0000981: GAS/ISRE-type and TTGA-type promoter elements are bound by vertebrate, insect, nematode (STA-1) and Dictyostelium STATs; plant STATL proteins lack the DNA-binding domain. C. elegans STA-2 stays in scope as an unresolved case (see GO:0000981); its gene review marks this term over-annotated, which the family/gene cross-check reports for adjudication. member_exceptions: - member: id: UniProtKB:B5X561 label: SH2 domain-containing protein A gene_symbol: SHA organism: Arabidopsis thaliana exception_reason: >- Arabidopsis SHA belongs to the Viridiplantae STAT-type linker-SH2 (STATL) clade PTN004306971, which PANTHER places in SF43 with Stat92E. It carries the STAT linker-SH2 module and a ConA-like/laminin-G-type N-terminal region but no STAT DNA-binding domain, and no plant member has been shown to bind DNA or regulate transcription. It receives this term only by descent from the family root PTN000210448, whose seeds are all bilaterian. An IRD on PTN004306971 is recommended. pruned_node_id: PANTHER:PTN000210448 lost_in_clade_node_id: PANTHER:PTN004306971 supported_by: - reference_id: PMID:15073273 supporting_text: Two novel genes carrying the linker-SH2 domain of STAT were discovered and subsequently cloned from Arabidopsis. - reference_id: PMID:24058787 supporting_text: By the time of divergence of the amoebozoa, a family of proteins can be identified that resemble metazoan STATs, with coiled-coil, DNA-binding and SH2 domains - reference_id: file:interpro/panther/PTHR11801/PTHR11801-bioinformatics/RESULTS.md supporting_text: Arabidopsis SHA (B5X561) and SHB (Q56XZ1) carry no STAT DNA-binding-domain InterPro entry - member: id: UniProtKB:Q56XZ1 label: SH2 domain-containing protein B gene_symbol: SHB organism: Arabidopsis thaliana exception_reason: >- Arabidopsis SHB belongs to the Viridiplantae STAT-type linker-SH2 (STATL) clade PTN004306971, which PANTHER places in SF43 with Stat92E. It carries the STAT linker-SH2 module and a ConA-like/laminin-G-type N-terminal region but no STAT DNA-binding domain, and no plant member has been shown to bind DNA or regulate transcription. It receives this term only by descent from the family root PTN000210448, whose seeds are all bilaterian. An IRD on PTN004306971 is recommended. pruned_node_id: PANTHER:PTN000210448 lost_in_clade_node_id: PANTHER:PTN004306971 supported_by: - reference_id: PMID:15073273 supporting_text: Two novel genes carrying the linker-SH2 domain of STAT were discovered and subsequently cloned from Arabidopsis. - reference_id: PMID:24058787 supporting_text: By the time of divergence of the amoebozoa, a family of proteins can be identified that resemble metazoan STATs, with coiled-coil, DNA-binding and SH2 domains - reference_id: file:interpro/panther/PTHR11801/PTHR11801-bioinformatics/RESULTS.md supporting_text: Arabidopsis SHA (B5X561) and SHB (Q56XZ1) carry no STAT DNA-binding-domain InterPro entry supported_by: - *id001 - *id002 - *id003 - assessed_term: id: GO:0006357 label: regulation of transcription by RNA polymerase II scope: FAMILY_WIDE scope_reason: >- Participation follows directly from the DNA-binding transcription factor activity, which is exercised at RNA polymerase II promoters in every lineage with a STAT DNA-binding domain. STATs act as activators in some contexts and repressors in others (Dictyostelium STATa represses stalk genes; C. elegans STA-1 represses antiviral genes), which this regulation term covers. member_exceptions: - member: id: UniProtKB:B5X561 label: SH2 domain-containing protein A gene_symbol: SHA organism: Arabidopsis thaliana exception_reason: >- Arabidopsis SHA belongs to the Viridiplantae STAT-type linker-SH2 (STATL) clade PTN004306971, which PANTHER places in SF43 with Stat92E. It carries the STAT linker-SH2 module and a ConA-like/laminin-G-type N-terminal region but no STAT DNA-binding domain, and no plant member has been shown to bind DNA or regulate transcription. It receives this term only by descent from the family root PTN000210448, whose seeds are all bilaterian. An IRD on PTN004306971 is recommended. pruned_node_id: PANTHER:PTN000210448 lost_in_clade_node_id: PANTHER:PTN004306971 supported_by: - reference_id: PMID:15073273 supporting_text: Two novel genes carrying the linker-SH2 domain of STAT were discovered and subsequently cloned from Arabidopsis. - reference_id: PMID:24058787 supporting_text: By the time of divergence of the amoebozoa, a family of proteins can be identified that resemble metazoan STATs, with coiled-coil, DNA-binding and SH2 domains - reference_id: file:interpro/panther/PTHR11801/PTHR11801-bioinformatics/RESULTS.md supporting_text: Arabidopsis SHA (B5X561) and SHB (Q56XZ1) carry no STAT DNA-binding-domain InterPro entry - member: id: UniProtKB:Q56XZ1 label: SH2 domain-containing protein B gene_symbol: SHB organism: Arabidopsis thaliana exception_reason: >- Arabidopsis SHB belongs to the Viridiplantae STAT-type linker-SH2 (STATL) clade PTN004306971, which PANTHER places in SF43 with Stat92E. It carries the STAT linker-SH2 module and a ConA-like/laminin-G-type N-terminal region but no STAT DNA-binding domain, and no plant member has been shown to bind DNA or regulate transcription. It receives this term only by descent from the family root PTN000210448, whose seeds are all bilaterian. An IRD on PTN004306971 is recommended. pruned_node_id: PANTHER:PTN000210448 lost_in_clade_node_id: PANTHER:PTN004306971 supported_by: - reference_id: PMID:15073273 supporting_text: Two novel genes carrying the linker-SH2 domain of STAT were discovered and subsequently cloned from Arabidopsis. - reference_id: PMID:24058787 supporting_text: By the time of divergence of the amoebozoa, a family of proteins can be identified that resemble metazoan STATs, with coiled-coil, DNA-binding and SH2 domains - reference_id: file:interpro/panther/PTHR11801/PTHR11801-bioinformatics/RESULTS.md supporting_text: Arabidopsis SHA (B5X561) and SHB (Q56XZ1) carry no STAT DNA-binding-domain InterPro entry supported_by: - reference_id: PMID:9670017 supporting_text: The tyrosine phosphorylation and nuclear localization of Dd-STAT are induced very rapidly by extracellular cAMP through the serpentine cAMP receptor cAR1 - reference_id: PMID:16873887 supporting_text: recognizing a cis DNA element conserved through phylogeny - assessed_term: id: GO:0005634 label: nucleus scope: FAMILY_WIDE scope_reason: >- Signal-dependent nuclear accumulation of a latent cytoplasmic protein is shared by all characterised STATs; Dictyostelium STATb is constitutively nuclear. Plant STATL localisation is untested and not contradicted. supported_by: - reference_id: PMID:9670017 supporting_text: During mound formation, the time at which cell-type specific gene expression initiates, Dd-STAT becomes tyrosine phosphorylated and translocates into the nuclei of all cells. - reference_id: PMID:14701681 supporting_text: it is constitutively enriched in the nucleus - assessed_term: id: GO:0007259 label: cell surface receptor signaling pathway via JAK-STAT scope: SUBFAMILY_ONLY applicable_subfamilies: - id: PANTHER:PTHR11801:SF2 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 - id: PANTHER:PTHR11801:SF18 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 1-ALPHA_BETA - id: PANTHER:PTHR11801:SF19 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 4 - id: PANTHER:PTHR11801:SF39 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 5B - id: PANTHER:PTHR11801:SF41 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 2 - id: PANTHER:PTHR11801:SF47 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 5A - id: PANTHER:PTHR11801:SF48 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 6 - id: PANTHER:PTHR11801:SF66 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION scope_reason: >- Receptor-JAK-STAT signalling requires JAK, which arose with the canonical pathway in Bilateria and is absent from Dictyostelium and from C. elegans (and from all three nematodes in PANTHER's JAK family). The term is safe for the vertebrate STAT subfamilies listed. It also holds for the JAK-bearing invertebrate members of SF43 (Drosophila Stat92E, activated by the JAK Hopscotch; arthropods; the invertebrate deuterostomes), but SF43 is PANTHER's root catch-all and also holds C. elegans STA-1, Dictyostelium dstD, cnidarian and placozoan STATs and the plant STATL proteins, so it is not listed and SF43 members need individual judgement. It does not apply to the Dictyostelium subfamilies SF65 and SF50 or to the nematode subfamilies SF49 and SF68, whose members are activated JAK-independently. The Dictyostelium gene reviews replace it with GO:0097696; the sta-2 gene review removes it. supported_by: - reference_id: PMID:24058787 supporting_text: the interaction of these proteins to form an active pathway, which occurred in bilateria - 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 STAT family has more ancient roots, with a range of STAT-like proteins present in extant eukaryotes. - reference_id: PMID:24058748 supporting_text: the slime mold STATs form a distinct clade - reference_id: PMID:8608596 supporting_text: This protein becomes phosphorylated on Tyr-704 when coexpressed in Schneider cells with a Drosophila janus kinase (JAK), Hopscotch (HOP). - reference_id: PMID:28874466 supporting_text: There is no conserved homolog of the JAK kinases in C. elegans - reference_id: PMID:22699506 supporting_text: There are no orthologs of the animal tyrosine kinases, but there are very many tyrosine kinase-like kinases (TKLs) - reference_id: PMID:21575913 supporting_text: These findings reveal an unorthodox mode of regulation for a STAT factor - assessed_term: id: GO:0097696 label: cell surface receptor signaling pathway via STAT scope: SUBFAMILY_ONLY applicable_subfamilies: - id: PANTHER:PTHR11801:SF2 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 - id: PANTHER:PTHR11801:SF18 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 1-ALPHA_BETA - id: PANTHER:PTHR11801:SF19 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 4 - id: PANTHER:PTHR11801:SF39 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 5B - id: PANTHER:PTHR11801:SF41 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 2 - id: PANTHER:PTHR11801:SF47 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 5A - id: PANTHER:PTHR11801:SF48 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 6 - id: PANTHER:PTHR11801:SF66 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION - id: PANTHER:PTHR11801:SF65 label: C2H2-TYPE DOMAIN-CONTAINING PROTEIN-RELATED - id: PANTHER:PTHR11801:SF50 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION C scope_reason: >- The JAK-agnostic parent of GO:0007259, which GO itself notes is for STAT signalling without JAK, as in Dictyostelium. It is correct for the Dictyostelium STATs (STATa downstream of the serpentine cAMP receptor cAR1; STATc downstream of DIF-1 via TKL kinases, although its receptor is not identified) and, through GO:0007259, for the vertebrate subfamilies. It is not asserted for the nematode STATs: STA-2 is regulated through a transporter and hemidesmosome release and STA-1 through the kinase SID-3, and neither has an identified cell-surface receptor input. No PAINT node asserts this term; it is the replacement the Dictyostelium gene reviews propose for the TOO_DEEP GO:0007259 IBD. supported_by: - reference_id: PMID:9670017 supporting_text: The tyrosine phosphorylation and nuclear localization of Dd-STAT are induced very rapidly by extracellular cAMP through the serpentine cAMP receptor cAR1 - reference_id: PMID:22699506 supporting_text: Pyk2 phosphorylates STATc on Tyr922 in vitro and complexes with STATc both in vitro and in vivo. - reference_id: PMID:21534947 supporting_text: The cellular slime mould, Dictyostelium discoideum, is the simplest multicellular organism using molecules homologous to STATs, Dd-STATa-d. - reference_id: PMID:24058748 supporting_text: the Dictyostelium genome encodes four STATs, dstA, dstB, dstC and dstD - assessed_term: id: GO:0006952 label: defense response scope: SUBFAMILY_ONLY applicable_subfamilies: - id: PANTHER:PTHR11801:SF2 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 - id: PANTHER:PTHR11801:SF18 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 1-ALPHA_BETA - id: PANTHER:PTHR11801:SF19 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 4 - id: PANTHER:PTHR11801:SF39 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 5B - id: PANTHER:PTHR11801:SF41 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 2 - id: PANTHER:PTHR11801:SF47 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 5A - id: PANTHER:PTHR11801:SF48 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 6 - id: PANTHER:PTHR11801:SF66 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION - id: PANTHER:PTHR11801:SF49 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION B scope_reason: >- Defence roles are shown for vertebrate STATs (interferon and cytokine-driven immunity), Drosophila Stat92E and C. elegans STA-2 (epidermal antifungal and wound responses), so the function is at least bilaterian and does not depend on JAK. C. elegans STA-1 (SF43) is the cautionary case: it acts in antiviral immunity but as a constitutive repressor of virus-induced genes (sta-1 mutants are less permissive to Orsay virus), so its gene review modifies the inherited term to negative regulation of defense response to virus rather than keeping it. SF43 is not listed as a unit (see GO:0007259). The Dictyostelium subfamilies are left out because no Dictyostelium STAT has been tested; their gene reviews keep the IBA as non-core, which this review neither supports nor contradicts (node assessment UNRESOLVED). supported_by: - reference_id: PMID:21575913 supporting_text: the two proteins function together to regulate AMP gene expression in the epidermis - reference_id: PMID:26716073 supporting_text: Both the STAT family protein STA-2 and the GATA transcription factor ELT-3 are required for the transcription of nlps - reference_id: PMID:28874466 supporting_text: sta-1 mutants were 100-fold less permissive to infection than wild-type animals - assessed_term: id: GO:0019221 label: cytokine-mediated signaling pathway scope: SUBFAMILY_ONLY applicable_subfamilies: - id: PANTHER:PTHR11801:SF2 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 - id: PANTHER:PTHR11801:SF18 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 1-ALPHA_BETA - id: PANTHER:PTHR11801:SF19 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 4 - id: PANTHER:PTHR11801:SF39 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 5B - id: PANTHER:PTHR11801:SF41 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 2 - id: PANTHER:PTHR11801:SF47 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 5A - id: PANTHER:PTHR11801:SF48 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 6 - id: PANTHER:PTHR11801:SF66 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION scope_reason: >- Every vertebrate STAT paralog is a cytokine-receptor transducer. The IBD sits at Chordata, so the invertebrate chordate STATs in SF43 also inherit it; Ciona retains a single JAK, which makes that extension plausible but untested. supported_by: - reference_id: PMID:24058793 supporting_text: Cytokine signals are essential for generating a robust and specialized immune response. These signals are typically transmitted via canonical STAT homodimers. - reference_id: PMID:24058787 supporting_text: with existing urochordates such as sea squirt (Ciona intestinalis) retaining a single JAK - assessed_term: id: GO:0090575 label: RNA polymerase II transcription regulator complex scope: SUBFAMILY_ONLY applicable_subfamilies: - id: PANTHER:PTHR11801:SF2 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 - id: PANTHER:PTHR11801:SF18 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 1-ALPHA_BETA - id: PANTHER:PTHR11801:SF19 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 4 - id: PANTHER:PTHR11801:SF39 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 5B - id: PANTHER:PTHR11801:SF41 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 2 - id: PANTHER:PTHR11801:SF47 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 5A - id: PANTHER:PTHR11801:SF48 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 6 - id: PANTHER:PTHR11801:SF66 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION scope_reason: >- Asserted at the vertebrate STAT duplication node. Activated vertebrate STATs bind promoters as homo- and heterodimers and, for STAT1/STAT2, as ISGF3. supported_by: - reference_id: PMID:24058793 supporting_text: Heterodimerization of STAT proteins is one potential mechanism for signals to be modified downstream of the receptor - assessed_term: id: GO:0070721 label: ISGF3 complex scope: SUBFAMILY_ONLY applicable_subfamilies: - id: PANTHER:PTHR11801:SF18 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 1-ALPHA_BETA - id: PANTHER:PTHR11801:SF41 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 2 scope_reason: >- ISGF3 contains STAT1, STAT2 and IRF9, so only the STAT1 and STAT2 subfamilies qualify. supported_by: - reference_id: PMID:24065129 supporting_text: the transcription factor ISGF3 (IRF9 and tyrosine-phosphorylated STATs 1 and 2) drives the first rapid response phase - assessed_term: id: GO:0060337 label: type I interferon-mediated signaling pathway scope: SUBFAMILY_ONLY applicable_subfamilies: - id: PANTHER:PTHR11801:SF18 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 1-ALPHA_BETA - id: PANTHER:PTHR11801:SF41 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 2 scope_reason: >- Type I interferon signalling runs through ISGF3 (STAT1, STAT2, IRF9). Other STATs can be activated by type I interferon in some cells but are not asserted by PAINT and are not core. supported_by: - reference_id: PMID:24065129 supporting_text: the transcription factor ISGF3 (IRF9 and tyrosine-phosphorylated STATs 1 and 2) drives the first rapid response phase - assessed_term: id: GO:0060397 label: growth hormone receptor signaling pathway via JAK-STAT scope: SUBFAMILY_ONLY applicable_subfamilies: - id: PANTHER:PTHR11801:SF2 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 - id: PANTHER:PTHR11801:SF39 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 5B - id: PANTHER:PTHR11801:SF47 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 5A scope_reason: >- Growth hormone signals through JAK2 to STAT5 and STAT3. The euteleostome IBD on PTN002623856 is placed above the STAT5/STAT6 split and so also reaches STAT6 (SF48) and teleost stat6 (SF66), which are excluded here (node assessment TOO_DEEP). supported_by: - reference_id: PMID:12552091 supporting_text: luciferase reporters with binding elements for STAT3 and STAT5 or the beta-casein promoter. GH stimulated the reporter activities by four- to sixfold. - assessed_term: id: GO:0043434 label: response to peptide hormone scope: SUBFAMILY_ONLY applicable_subfamilies: - id: PANTHER:PTHR11801:SF2 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 - id: PANTHER:PTHR11801:SF18 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 1-ALPHA_BETA - id: PANTHER:PTHR11801:SF39 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 5B - id: PANTHER:PTHR11801:SF47 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 5A scope_reason: >- Supported by seeds in the STAT3, STAT1 and STAT5 subfamilies (leptin, growth hormone and prolactin inputs). STAT2 is excluded (interferons are cytokines, not peptide hormones; node assessment NEEDS_PRUNING). STAT4 and STAT6 inherit it without evidence and are left outside the confirmed scope. supported_by: - reference_id: PMID:17344214 supporting_text: leptin induced Stat3-phosphorylation-dependent proliferation of MCF7 cells - reference_id: PMID:12552091 supporting_text: GH stimulated the reporter activities by four- to sixfold. - assessed_term: id: GO:0033210 label: leptin-mediated signaling pathway scope: SUBFAMILY_ONLY applicable_subfamilies: - id: PANTHER:PTHR11801:SF2 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 scope_reason: >- Leptin receptor signalling through STAT3 is the asserted and best documented case. supported_by: - reference_id: PMID:17344214 supporting_text: leptin induced Stat3-phosphorylation-dependent proliferation of MCF7 cells - assessed_term: id: GO:0038110 label: interleukin-2-mediated signaling pathway scope: SUBFAMILY_ONLY applicable_subfamilies: - id: PANTHER:PTHR11801:SF2 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 - id: PANTHER:PTHR11801:SF39 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 5B - id: PANTHER:PTHR11801:SF47 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 5A scope_reason: >- IL-2 activates STAT5A, STAT5B and STAT3 in lymphocytes. PAINT asserts it on the STAT5A (PTN000210582) and STAT3 (PTN002623841) nodes only; STAT5B (SF39) is equally supported but not reached by either IBD. supported_by: - reference_id: PMID:8631883 supporting_text: both Stat5A and Stat5B are activated by interleukin-2 (IL-2) in peripheral blood lymphocytes - reference_id: PMID:7568001 supporting_text: IL-2 and IL-15 rapidly induced the tyrosine phosphorylation of STAT3 and STAT5 references: - id: PMID:24058787 title: Evolution of the JAK-STAT pathway. - id: PMID:24058748 title: Comparative evolutionary genomics of the STAT family of transcription factors. - id: PMID:21534947 title: STAT signaling in Dictyostelium development. - id: PMID:26716073 title: Mechanisms of innate immunity in C. elegans epidermis. - id: PMID:28874466 title: An Alternative STAT Signaling Pathway Acts in Viral Immunity in Caenorhabditis elegans. - 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:9670017 title: Developmentally and spatially regulated activation of a Dictyostelium STAT protein by a serpentine receptor. - id: PMID:14701681 title: Dd-STATb, a Dictyostelium STAT protein with a highly aberrant SH2 domain, functions as a regulator of gene expression during growth and early development. - id: PMID:21575913 title: Unusual regulation of a STAT protein by an SLC6 family transporter in C. elegans epidermal innate immunity. - id: PMID:16873887 title: 'C. elegans STAT: evolution of a regulatory switch.' - id: PMID:8608596 title: Identification of a Stat gene that functions in Drosophila development. - id: PMID:15073273 title: Identification of the linker-SH2 domain of STAT as the origin of the SH2 domain using two-dimensional structural alignment. - id: PMID:9630226 title: Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA. - id: PMID:24058793 title: 'STAT heterodimers in immunity: A mixed message or a unique signal?' - id: PMID:24065129 title: IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage. - id: PMID:12552091 title: Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2. - id: PMID:17344214 title: leptin-induced growth stimulation of breast cancer cells involves recruitment of histone acetyltransferases and mediator complex to CYCLIN D1 promoter via activation of Stat3. - id: PMID:8631883 title: Cloning of human Stat5B. Reconstitution of interleukin-2-induced Stat5A and Stat5B DNA binding activity in COS-7 cells. - id: PMID:7568001 title: Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15. - id: file:interpro/panther/PTHR11801/PTHR11801-bioinformatics/RESULTS.md title: PTHR11801 tree placement, JAK-family taxon and domain checks - 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; the script and its output are in PTHR11801-bioinformatics/. PAINT records no taxon for PTN000927860 (the tree calls it Unikonts) or PTN000210452 (a duplication). Seed identifiers were resolved by UniProt cross-reference queries (MGI:103034 Stat6, 103035 Stat5b, 103036 Stat5a, 103038 Stat3, 103039 Stat2, 103062 Stat4, 103063 Stat1; RGD:3771 Stat1, 3772 Stat3, 3773 Stat5a, 3774 Stat5b, 1309063 Stat6; ZFIN:ZDB-GENE-030820-2 stat5.1, ZDB-GENE-980526-68 stat3, ZDB-GENE-030131-9359 stat6). None of the in-repo STAT gene reviews has a PANTHER subfamily cross-reference in its cached UniProt record (only the family line is present), so the family/gene cross-check cannot place them in subfamilies: SUBFAMILY_ONLY assessments are reported as unresolved for them, and a member exception on a SUBFAMILY_ONLY term would be reported as outside scope. That is why C. elegans STA-1 is not carved out by a member exception on GO:0007259; it would not need one in any case, because its subfamily SF43 is not in that term's scope. Disagreements with gene reviews, none of them blocking: the Dictyostelium statA and statC reviews keep GO:0006952 as non-core, which matches this review's UNRESOLVED node call; they MODIFY GO:0007259 to GO:0097696, consistent with the TOO_DEEP call. The sta-1 and sta-2 reviews both REMOVE GO:0007259 (agreeing with the TOO_DEEP call and the proposed nematode IRD); sta-1 also MODIFYs GO:0006952 to negative regulation of defense response to virus and marks GO:0042127 as over-annotated. The STAT4 review keeps GO:0043434 as non-core, which this review leaves outside the confirmed scope without pruning. The Falcon deep-research report wrongly states that C. elegans has a single STAT gene (it has sta-1 and sta-2, plus the uncharacterised T12G3.2 in SF68) and does not discuss the plant STATL proteins; its main conclusion, that JAK-STAT and cytokine terms must not be mapped family-wide, agrees with this review. InterPro2GO maps GO:0003700 to IPR001217 (STAT), which reaches the plant STATL proteins as IEA; that mapping has the same plant problem as the root-level PAINT transcription factor IBDs. Evolutionary reviews used for the taxon arguments: Liongue and Ward 2013 (PMID:24058787) for the eukaryote-wide roots of STAT-like proteins and the bilaterian assembly of the canonical pathway; Wang and Levy 2012 (PMID:24058748) for STAT gene duplications in over 20 eukaryotic genomes, the separate Dictyostelium STAT clade and the vertebrate STAT1-6 expansion by whole-genome duplication; Kawata 2011 (PMID:21534947, abstract only) for the four Dictyostelium STATs. Caveat from Wang and Levy: they describe C. elegans F58E6.1, which is sta-2 (SF49), as so diverged that it "can no longer be considered a bona fide member" of the STAT family, and report that it showed no STAT-motif DNA binding when co-expressed with a tyrosine kinase. Later work establishes STA-2 as the epidermal transcriptional regulator of antimicrobial-peptide genes, so this review keeps it in family scope, but direct DNA binding by STA-2 remains undemonstrated. 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.