id: MODULE:kit_signaling title: Kit signaling pathway module description: Stem cell factor (KIT ligand) binds and dimerizes the class III receptor tyrosine kinase KIT, whose autophosphorylated intracellular tyrosines recruit SH2-domain effectors (GRB2, PI3K p85, SHP2, Src-family kinases) that drive Ras-MAPK, PI3K-AKT, and STAT5 outputs controlling survival, proliferation, and migration of hematopoietic progenitors, mast cells, melanocytes, germ cells, and interstitial cells of Cajal. status: DRAFT evidence: - source_id: file:genes/DANRE/kita/kita-ai-review.yaml title: Zebrafish kita gene review (teleost KIT co-ortholog) statement: >- Alternate-species exemplar. Zebrafish kita (UniProtKB:Q8JFR5, the sparse mutant) is a teleost-duplication co-ortholog of mammalian KIT with core stem cell factor receptor and transmembrane RTK activity; its melanophore and hematopoietic phenotypes, and its divergence from the paralog kitb, document the teleost variation of the pathway. - source_id: file:genes/DANRE/kitlga/kitlga-ai-review.yaml title: Zebrafish kitlga gene review (teleost KIT ligand co-ortholog) statement: >- Alternate-species exemplar. Zebrafish kitlga (UniProtKB:Q56JH6) is the Kita ligand, a teleost-duplication co-ortholog of KITLG that retains the ancestral pigmentation role, whereas the paralog kitlgb does not fully substitute (PMID:17257055). - source_id: file:modules/kit_signaling-deep-research-falcon.md title: Kit signaling pathway Falcon module review statement: >- Falcon/Edison module review generated 2026-09-25 is linked as supporting evidence for module boundaries, core mechanism, variation, constraints, and failure modes. It confirms the ligand-dimerization-autophosphorylation order and the effector docking map (Src-family kinases and SHP2 at the juxtamembrane tyrosines, GRB2 at Y703/Y936, PI3K p85 at Y721), treats STAT5 as a conditional rather than universal output, and places CBL/SHP1 attenuation, GAB2 scaffolding, and PLC-gamma outside the compact core modeled here. Open questions in that report require manual review before promotion to curated knowledge gaps. - source_id: GO:0038109 title: Kit signaling pathway statement: The module is grounded in the GO biological process term for Kit signaling pathway, defined as the series of molecular signals initiated by stem cell factor binding to the tyrosine kinase receptor KIT, followed by receptor dimerization, autophosphorylation, and phosphorylation of substrates that activate distinct downstream cascades. - source_id: PMID:23073628 title: "Stem cell factor receptor/c-Kit: from basic science to clinical implications." statement: >- Physiological Reviews summary (Lennartsson and Ronnstrand 2012): SCF is a dimeric ligand that activates c-Kit; activation leads to autophosphorylation, and signaling proteins are recruited through SH2 and PTB interaction domains that bind phosphorylated tyrosines in the intracellular region of c-Kit. c-Kit signaling mediates cell survival, migration, and proliferation and is crucial for hematopoiesis, pigmentation, fertility, and gut movement. Abstract verified against PubMed; used to set the module boundary and the three-step decomposition. - source_id: PMID:15526160 title: Signal transduction via the stem cell factor receptor/c-Kit. statement: >- Review (Ronnstrand 2004): ligand stimulation leads to receptor dimerization, activation of intrinsic tyrosine kinase activity, and phosphorylation of key receptor tyrosines that serve as docking sites for SH2-containing signal transduction molecules, which are recruited to the receptor and often activated by receptor-mediated phosphorylation. Abstract verified against PubMed; supports the phosphotyrosine effector-recruitment step. - source_id: PMID:17662946 title: Structural basis for activation of the receptor tyrosine kinase KIT by stem cell factor. statement: >- Crystal structures of the KIT ectodomain before and after SCF binding show that KIT dimerization is driven by SCF binding, followed by lateral D4-D4 and D5-D5 contacts; this is the GOA IDA reference for GO:0038109 on human KIT (UniProtKB:P10721). Abstract verified against PubMed. - source_id: PMID:21135090 title: Mechanisms of STAT protein activation by oncogenic KIT mutants in neoplastic mast cells. statement: >- STAT1, STAT3, and STAT5 are activated downstream of KIT and KIT can directly phosphorylate STATs on activation-specific tyrosines in vitro; this is the GOA IMP reference for GO:0046427 (positive regulation of receptor signaling pathway via JAK-STAT) on human KIT. Abstract verified against PubMed; supports the STAT5 output annoton. - source_id: PMID:21640708 title: Mechanism of activation of human c-KIT kinase by internal tandem duplications of the juxtamembrane domain and point mutations at aspartic acid 816. statement: GOA reference on human KIT for GO:0004714 (transmembrane receptor protein tyrosine kinase activity, IDA) and GO:0046777 (protein autophosphorylation, IDA), and for GO:0043410 (positive regulation of MAPK cascade, IMP). Title verified against PubMed. - source_id: PANTHER:PTN001230349 title: PAINT node PTN001230349 for KIT statement: Local PAINT IBD node in PTHR24416 with propagated terms C:GO:0005886, F:GO:0004714, P:GO:0007169; PAINT date 20260828. - source_id: PANTHER:PTN002814378 title: PAINT node PTN002814378 for KIT statement: Local PAINT IBD node in PTHR24416 (taxon Euteleostomi) with propagated terms P:GO:0038109, P:GO:0046427; PAINT dates 20200930 and 20201025. Human KIT is the sole experimental seed. - source_id: PANTHER:PTN008404985 title: PAINT node PTN008404985 for KIT statement: Local PAINT IBD node in PTHR24416 with propagated term P:GO:0016477; PAINT date 20250904. - source_id: PANTHER:PTN005273574 title: PAINT node PTN005273574 for GRB2 statement: Local PAINT IBD node in PTHR46037 with propagated terms C:GO:0005737, C:GO:0005886, C:GO:0008180, F:GO:0001784, F:GO:0005154, P:GO:0007165; PAINT date 20260530. - source_id: PANTHER:PTN008302071 title: PAINT node PTN008302071 for PIK3R1 statement: Local PAINT IBD node in PTHR10155 with propagated terms C:GO:0005943; PAINT date 20240516. - source_id: PANTHER:PTN002926797 title: PAINT node PTN002926797 for PTPN11 statement: Local PAINT IBD node in PTHR46559 with propagated terms C:GO:0005737, F:GO:0004726, F:GO:0050839, P:GO:0038127, P:GO:0070374; PAINT date 20251220. - source_id: PANTHER:PTN002521457 title: PAINT node PTN002521457 for LYN statement: Local PAINT IBD node in PTHR24418 with propagated terms C:GO:0005886, F:GO:0004713; PAINT date 20260828. - source_id: PANTHER:PTN002521528 title: PAINT node PTN002521528 for LYN statement: Local PAINT IBD node in PTHR24418 with propagated terms F:GO:0004715, F:GO:0005102, P:GO:0007169, P:GO:0030154; PAINT date 20260529. - source_id: PANTHER:PTN000560991 title: PAINT node PTN000560991 for SOS1 statement: Local PAINT IBD node in PTHR23113 with propagated terms F:GO:0005085, P:GO:0007265; PAINT date 20250903. - source_id: PANTHER:PTN000005674 title: PAINT node PTN000005674 for PIK3CA statement: Local PAINT IBD node in PTHR10048 with propagated terms F:GO:0016303, P:GO:0016477, P:GO:0043491; PAINT date 20260828. - source_id: PANTHER:PTN000799659 title: PAINT node PTN000799659 for PIK3CA statement: Local PAINT IBD node in PTHR10048 with propagated terms C:GO:0005943, F:GO:0046934; PAINT date 20260828. - source_id: PANTHER:PTN000210448 title: PAINT node PTN000210448 for STAT5A statement: Local PAINT IBD node in PTHR11801 with propagated terms C:GO:0005634, C:GO:0005737; PAINT date 20260528. - source_id: PANTHER:PTN000210451 title: PAINT node PTN000210451 for STAT5A statement: Local PAINT IBD node in PTHR11801 with propagated term P:GO:0019221; PAINT date 20260828. - source_id: PANTHER:PTN000927860 title: PAINT node PTN000927860 for STAT5A statement: Local PAINT IBD node in PTHR11801 with propagated term P:GO:0042127; PAINT date 20250902. - source_id: PANTHER:PTN002611905 title: PAINT node PTN002611905 for KITLG statement: Local PAINT IBD node in PTHR11574 (Euteleostomi root) with propagated terms C:GO:0005886, P:GO:0008284; PAINT date 20260528. - source_id: file:interpro/panther/PTHR11574/PTHR11574-review.yaml title: PANTHER PTHR11574 (KIT LIGAND) family review statement: Documents family-wide coherence of PTHR11574 for GO:0005125 (cytokine activity) and GO:0038109 (Kit signaling pathway) across Euteleostomi root node PTN002611905. - source_id: file:genes/human/KITLG/KITLG-ai-review.yaml title: Human KITLG gene review statement: Curates human KITLG with GO:0005125 (cytokine activity) and proposes NEW GO:0038109 (Kit signaling pathway), replacing receptor-specific binding GO:0005173. - source_id: PMID:17257055 title: Gene Duplication of the zebrafish kit ligand and partitioning of melanocyte development functions to kit ligand a. statement: Establishes zebrafish kitlga and kitlgb as teleost whole-genome duplication co-orthologs of mammalian KITLG and demonstrates that kitlga acts through the kita receptor to drive embryonic melanocyte migration and survival. notes: >- Curated compact signaling-pathway module built to the same three-step template as the sibling receptor tyrosine kinase modules (pdgfr_signaling, egfr_signaling, fgfr_signaling): ligand engagement, phosphotyrosine effector recruitment, and downstream output. KIT is a class III receptor tyrosine kinase in the same PANTHER family (PTHR24416) as PDGFRA/PDGFRB, CSF1R, and FLT3; the module is kept separate from pdgfr_signaling because GO models Kit signaling as its own pathway term (GO:0038109) with its own PAINT node (PTN002814378) and its own ligand family (KITLG, family PTHR11574, rooted at Euteleostomi node PTN002611905, which carries PAINT IBDs for C:GO:0005886 and P:GO:0008284; the ligand participant uses GO:0005125 cytokine activity, a child of receptor ligand activity, rather than the receptor-specific binding term GO:0005173). Effector choice follows the reviews cited in evidence: GRB2 and PI3K p85 are the canonical SH2 adaptors recruited to phosphorylated KIT, SHP2 (PTPN11) is the KIT-associated phosphatase that couples to the Ras-ERK branch, and LYN is the Src-family kinase representative for the juxtamembrane phosphotyrosine docking site. Downstream outputs are limited to the three branches with GOA support on human KIT: positive regulation of MAPK cascade (IMP) and STAT activation (IMP, PMID:21135090) are experimentally grounded, while the PI3K-AKT branch (GO:0051897) is supported only by TAS (PMID:16129412); PLCG1 and other Ras-branch components are deliberately left to broader modules. PTN anchors are included only when the exemplar accession appears in an IBD seed row in interpro/panther; roles without local PAINT seeds remain grounded by verified UniProt exemplar accessions. UniProt protein names were taken verbatim from the UniProt REST API; PANTHER family labels from interpro/panther/panther.obo; PMIDs and titles were checked against PubMed. All nine human members (KIT, KITLG, GRB2, PIK3R1, PTPN11, LYN, SOS1, PIK3CA, STAT5A) now have curated gene reviews in genes/human, and gocams/index.tsv contains no KIT activity, so this module is not yet cross-checked against a production GO-CAM. Taxonomic scope: the class III RTK family (PTHR24416) is metazoan-deep, but the discrete Kit signaling pathway (GO:0038109) and the KIT-KITLG ligand-receptor pair are a bony-vertebrate feature (the IBD node carrying GO:0038109/GO:0046427, PTN002814378, is placed at NCBITaxon:117571 Euteleostomi); downstream effectors are ancient and shared across RTK pathways. As an alternate-species exemplar documenting teleost variation, the zebrafish co-orthologs kita (Q8JFR5, the sparse mutant) and kitlga (Q56JH6) were reviewed (genes/DANRE/kita, genes/DANRE/kitlga): they arose from the teleost whole-genome duplication and retain the ancestral pigmentation/hematopoiesis roles, while the paralogs kitb and kitlgb diverged and do not fully compensate, so zebrafish is not a one-to-one substitute for mammalian KIT/KITLG. Falcon integration (2026-09-25): Falcon findings are linked as evidence; the report's characterization of STAT5 as a conditional, lineage-dependent output is reflected in the output-step description and in the recorded knowledge gap. Automatically extracted open-question headings were not retained as knowledge_gap entries because they were not manually curated, and machine-generated Falcon citations remain curation support rather than adjudicated references. module: id: kit_signaling label: Kit signaling pathway module_type: SIGNALING_PATHWAY concepts: - preferred_term: Kit signaling pathway term: id: GO:0038109 label: Kit signaling pathway description: Stem cell factor binds and dimerizes KIT, activating its intrinsic tyrosine kinase; autophosphorylated receptor tyrosines recruit SH2 effectors that activate Ras-MAPK, PI3K-AKT, and STAT cascades. context: taxa: - preferred_term: bony vertebrates term: id: NCBITaxon:117571 label: Euteleostomi cellular_components: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane - preferred_term: cytosol term: id: GO:0005829 label: cytosol - preferred_term: nucleus term: id: GO:0005634 label: nucleus parts: - order: 1 role: scf ligand-receptor engagement node: id: scf_engages_kit label: SCF engages KIT module_type: REGULATORY_STEP description: Dimeric stem cell factor binds the KIT ectodomain, driving receptor dimerization, lateral D4-D4/D5-D5 contacts, kinase activation, and autophosphorylation. annotons: - id: kitlg_scf_ligand label: SCF ligand participant: selector_type: FAMILY family: preferred_term: Kit ligand (stem cell factor) family term: id: PANTHER:PTHR11574 label: KIT LIGAND representative_members: - preferred_term: KITLG term: id: UniProtKB:P21583 label: "Kit ligand (Mast cell growth factor) (MGF) (Stem cell factor) (SCF) (c-Kit ligand) [Cleaved into: Soluble KIT ligand (sKITLG)]" - preferred_term: kitlga term: id: UniProtKB:Q56JH6 label: Kit ligand (Mast cell growth factor) (Stem cell factor) (c-Kit ligand) ancestral_nodes: - preferred_term: PAINT node PTN002611905 for KITLG term: id: PANTHER:PTN002611905 label: PTN002611905 description: Local PAINT IBD node in PTHR11574 (Euteleostomi root) with propagated terms C:GO:0005886, P:GO:0008284; PAINT date 20260528. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN002611905 in PTHR11574. role_description: Stem cell factor (Kit ligand) cytokine family that binds the KIT ectodomain to drive receptor homodimerization and kinase activation. Membrane-bound and soluble SCF isoforms both bind KIT. function: preferred_term: cytokine activity term: id: GO:0005125 label: cytokine activity processes: - preferred_term: Kit signaling pathway term: id: GO:0038109 label: Kit signaling pathway locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane evidence: - source_id: PMID:17662946 statement: SCF binding drives KIT dimerization; the ligand's sole structural role is to bring two KIT molecules together. - source_id: PMID:17257055 statement: Zebrafish kitlga is the functional ligand for the kita receptor, promoting embryonic melanocyte migration and survival. - source_id: PANTHER:PTN002611905 statement: Local PAINT IBD node in PTHR11574 with propagated terms C:GO:0005886, P:GO:0008284; PAINT date 20260528. - id: kit_kit_receptor label: KIT receptor participant: selector_type: FAMILY family: preferred_term: KIT receptor family/ortholog group term: id: PANTHER:PTHR24416 label: TYROSINE-PROTEIN KINASE RECEPTOR representative_members: - preferred_term: KIT term: id: UniProtKB:P10721 label: Mast/stem cell growth factor receptor Kit (SCFR) (EC 2.7.10.1) (Piebald trait protein) (PBT) (Proto-oncogene c-Kit) (Tyrosine-protein kinase Kit) (p145 c-kit) (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) (CD antigen CD117) ancestral_nodes: - preferred_term: PAINT node PTN001230349 for KIT term: id: PANTHER:PTN001230349 label: PTN001230349 description: Local PAINT IBD node in PTHR24416 with propagated terms C:GO:0005886, F:GO:0004714, P:GO:0007169; PAINT date 20260828. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN001230349 in PTHR24416. - preferred_term: PAINT node PTN002814378 for KIT term: id: PANTHER:PTN002814378 label: PTN002814378 description: Local PAINT IBD node in PTHR24416 (taxon Euteleostomi) with propagated terms P:GO:0038109, P:GO:0046427; PAINT dates 20200930 and 20201025. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN002814378 in PTHR24416. - preferred_term: PAINT node PTN008404985 for KIT term: id: PANTHER:PTN008404985 label: PTN008404985 description: Local PAINT IBD node in PTHR24416 with propagated term P:GO:0016477; PAINT date 20250904. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN008404985 in PTHR24416. evidence: - source_id: file:interpro/panther/PTHR24416/PTHR24416-deep-research-falcon.md title: PTHR24416 Falcon family review statement: >- Falcon family-level GO review: ACCEPT current state (no GO terms mapped) - The absence of InterPro2GO mappings is well-justified for this highly heterogeneous family-level entry. Use this PANTHER family as context with representative members/PTN anchors, not as blanket pathway propagation. role_description: Curated exemplar for the KIT receptor role in Kit signaling pathway. function: preferred_term: stem cell factor receptor activity term: id: GO:0005020 label: stem cell factor receptor activity evidence: - source_id: PMID:21640708 statement: GOA IDA reference on human KIT for transmembrane receptor protein tyrosine kinase activity and protein autophosphorylation. - order: 2 role: phosphotyrosine effector recruitment node: id: kit_effector_recruitment label: KIT phosphotyrosine effector recruitment module_type: REGULATORY_STEP description: Autophosphorylated KIT juxtamembrane, kinase-insert, and C-terminal tyrosines dock SH2-domain adaptors, the PI3K regulatory subunit, the SHP2 phosphatase, and Src-family kinases. annotons: - id: grb2_grb2_adaptor label: GRB2 adaptor participant: selector_type: FAMILY family: preferred_term: GRB2 adaptor family/ortholog group term: id: PANTHER:PTHR46037 label: PROTEIN ENHANCER OF SEVENLESS 2B representative_members: - preferred_term: GRB2 term: id: UniProtKB:P62993 label: Growth factor receptor-bound protein 2 (Adapter protein GRB2) (Protein Ash) (SH2/SH3 adapter GRB2) ancestral_nodes: - preferred_term: PAINT node PTN005273574 for GRB2 term: id: PANTHER:PTN005273574 label: PTN005273574 description: Local PAINT IBD node in PTHR46037 with propagated terms C:GO:0005737, C:GO:0005886, C:GO:0008180, F:GO:0001784, F:GO:0005154, P:GO:0007165; PAINT date 20260530. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN005273574 in PTHR46037. evidence: - source_id: file:interpro/panther/PTHR46037/PTHR46037-deep-research-falcon.md title: PTHR46037 Falcon family review statement: >- Falcon family-level GO review: The current status of PTHR46037 is that no InterPro2GO terms are mapped. This is a reasonable conservative position given the family's functional heterogeneity, but it may represent an under-annotation of a well-characterized protein family. Use this PANTHER family as context with representative members/PTN anchors, not as blanket pathway propagation. role_description: Curated exemplar for the GRB2 adaptor role in Kit signaling pathway; GRB2 SH2 binds phosphorylated KIT and its SH3 domains bring SOS to the membrane. function: preferred_term: phosphotyrosine residue binding term: id: GO:0001784 label: phosphotyrosine residue binding - id: pik3r1_pi3k_p85_adaptor label: PI3K p85 adaptor participant: selector_type: FAMILY family: preferred_term: PI3K p85 adaptor family/ortholog group term: id: PANTHER:PTHR10155 label: PHOSPHATIDYLINOSITOL 3-KINASE REGULATORY SUBUNIT representative_members: - preferred_term: PIK3R1 term: id: UniProtKB:P27986 label: Phosphatidylinositol 3-kinase regulatory subunit alpha (PI3-kinase regulatory subunit alpha) (PI3K regulatory subunit alpha) (PtdIns-3-kinase regulatory subunit alpha) (Phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha) (PI3-kinase subunit p85-alpha) (PtdIns-3-kinase regulatory subunit p85-alpha) ancestral_nodes: - preferred_term: PAINT node PTN008302071 for PIK3R1 term: id: PANTHER:PTN008302071 label: PTN008302071 description: Local PAINT IBD node in PTHR10155 with propagated terms C:GO:0005943; PAINT date 20240516. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN008302071 in PTHR10155. evidence: - source_id: file:interpro/panther/PTHR10155/PTHR10155-deep-research-falcon.md title: PTHR10155 Falcon family review statement: >- Falcon family-level GO review: Current status: no InterPro2GO terms are mapped to PTHR10155, and the available evidence indicates that this absence is appropriate rather than missing annotation. Use this PANTHER family as context with representative members/PTN anchors, not as blanket pathway propagation. role_description: Curated exemplar for the PI3K p85 regulatory-subunit role in Kit signaling pathway; p85 SH2 domains dock on the phosphorylated KIT kinase insert and recruit the p110 catalytic subunit to the membrane. function: preferred_term: 1-phosphatidylinositol-3-kinase regulator activity term: id: GO:0046935 label: 1-phosphatidylinositol-3-kinase regulator activity - id: ptpn11_shp2_phosphatase label: SHP2 phosphatase participant: selector_type: FAMILY family: preferred_term: SHP2 (PTPN11) phosphatase family/ortholog group term: id: PANTHER:PTHR46559 label: TYROSINE-PROTEIN PHOSPHATASE NON-RECEPTOR TYPE 11 representative_members: - preferred_term: PTPN11 term: id: UniProtKB:Q06124 label: Tyrosine-protein phosphatase non-receptor type 11 (EC 3.1.3.48) (Protein-tyrosine phosphatase 1D) (PTP-1D) (Protein-tyrosine phosphatase 2C) (PTP-2C) (SH-PTP2) (SHP-2) (Shp2) (SH-PTP3) ancestral_nodes: - preferred_term: PAINT node PTN002926797 for PTPN11 term: id: PANTHER:PTN002926797 label: PTN002926797 description: Local PAINT IBD node in PTHR46559 with propagated terms C:GO:0005737, F:GO:0004726, F:GO:0050839, P:GO:0038127, P:GO:0070374; PAINT date 20251220. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN002926797 in PTHR46559. role_description: Curated exemplar for the SHP2 phosphatase role in Kit signaling pathway; SHP2 is recruited by its SH2 domains to phosphorylated KIT and promotes Ras-ERK signaling downstream of the receptor. function: preferred_term: non-membrane spanning protein tyrosine phosphatase activity term: id: GO:0004726 label: non-membrane spanning protein tyrosine phosphatase activity - id: lyn_src_family_kinase label: Src-family kinase participant: selector_type: FAMILY family: preferred_term: Src-family tyrosine kinase family/ortholog group term: id: PANTHER:PTHR24418 label: TYROSINE-PROTEIN KINASE representative_members: - preferred_term: LYN term: id: UniProtKB:P07948 label: Tyrosine-protein kinase Lyn (EC 2.7.10.2) (Lck/Yes-related novel protein tyrosine kinase) (V-yes-1 Yamaguchi sarcoma viral related oncogene homolog) (p53Lyn) (p56Lyn) ancestral_nodes: - preferred_term: PAINT node PTN002521457 for LYN term: id: PANTHER:PTN002521457 label: PTN002521457 description: Local PAINT IBD node in PTHR24418 with propagated terms C:GO:0005886, F:GO:0004713; PAINT date 20260828. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN002521457 in PTHR24418. - preferred_term: PAINT node PTN002521528 for LYN term: id: PANTHER:PTN002521528 label: PTN002521528 description: Local PAINT IBD node in PTHR24418 with propagated terms F:GO:0004715, F:GO:0005102, P:GO:0007169, P:GO:0030154; PAINT date 20260529. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN002521528 in PTHR24418. role_description: Curated exemplar for the Src-family kinase role in Kit signaling pathway; Src-family kinases dock on the phosphorylated KIT juxtamembrane region and phosphorylate receptor-proximal substrates. LYN is the representative for hematopoietic and mast cell contexts; other Src-family members fill the role in other cell types. function: preferred_term: non-membrane spanning protein tyrosine kinase activity term: id: GO:0004715 label: non-membrane spanning protein tyrosine kinase activity - order: 3 role: ras-mapk, pi3k-akt, and stat output node: id: kit_ras_pi3k_stat_output label: Ras-MAPK, PI3K-AKT, and STAT5 output module_type: REGULATORY_STEP description: Recruited effectors activate three canonical branches, Ras-MAPK through GRB2-bound SOS, PI3K-AKT through the p85-p110 lipid kinase, and STAT5 transcriptional output, which together drive survival, proliferation, and migration. The Ras-MAPK and PI3K-AKT branches are robust and partly redundant; STAT5 activation is a conditional, lineage-dependent output. annotons: - id: sos1_ras_gef label: SOS Ras GEF participant: selector_type: FAMILY family: preferred_term: SOS Ras guanine nucleotide exchange factor family/ortholog group term: id: PANTHER:PTHR23113 label: GUANINE NUCLEOTIDE EXCHANGE FACTOR representative_members: - preferred_term: SOS1 term: id: UniProtKB:Q07889 label: Son of sevenless homolog 1 (SOS-1) ancestral_nodes: - preferred_term: PAINT node PTN000560991 for SOS1 term: id: PANTHER:PTN000560991 label: PTN000560991 description: Local PAINT IBD node in PTHR23113 with propagated terms F:GO:0005085, P:GO:0007265; PAINT date 20250903. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN000560991 in PTHR23113. role_description: Curated exemplar for the Ras GEF role in Kit signaling pathway; SOS is carried to the membrane by GRB2 and loads GTP onto Ras to initiate the MAPK cascade (GOA IMP on human KIT for positive regulation of MAPK cascade). function: preferred_term: guanyl-nucleotide exchange factor activity term: id: GO:0005085 label: guanyl-nucleotide exchange factor activity - id: pik3ca_pi3k_catalytic_subunit label: PI3K catalytic subunit participant: selector_type: FAMILY family: preferred_term: PI3K catalytic subunit family/ortholog group term: id: PANTHER:PTHR10048 label: PHOSPHATIDYLINOSITOL KINASE representative_members: - preferred_term: PIK3CA term: id: UniProtKB:P42336 label: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PI3-kinase subunit alpha) (PI3K-alpha) (PI3Kalpha) (PtdIns-3-kinase subunit alpha) (EC 2.7.1.137) (EC 2.7.1.153) (Phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit alpha) (PtdIns-3-kinase subunit p110-alpha) (p110alpha) (Phosphoinositide 3-kinase alpha) (Phosphoinositide-3-kinase catalytic alpha polypeptide) (Serine/threonine protein kinase PIK3CA) (EC 2.7.11.1) ancestral_nodes: - preferred_term: PAINT node PTN000005674 for PIK3CA term: id: PANTHER:PTN000005674 label: PTN000005674 description: Local PAINT IBD node in PTHR10048 with propagated terms F:GO:0016303, P:GO:0016477, P:GO:0043491; PAINT date 20260828. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN000005674 in PTHR10048. - preferred_term: PAINT node PTN000799659 for PIK3CA term: id: PANTHER:PTN000799659 label: PTN000799659 description: Local PAINT IBD node in PTHR10048 with propagated terms C:GO:0005943, F:GO:0046934; PAINT date 20260828. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN000799659 in PTHR10048. evidence: - source_id: file:interpro/panther/PTHR10048/PTHR10048-deep-research-falcon.md title: PTHR10048 Falcon family review statement: >- Falcon family-level GO review: The absence of InterPro2GO mappings for PTHR10048 is correct and sound given the family's biochemical and biological diversity (burke2018structuralbasisfor pages 5-6, eliasvillalobos2019newinsightsinto pages 12-17, tafur2020structuralinsightsinto pages 15-18) Use this PANTHER family as context with representative members/PTN anchors, not as blanket pathway propagation. role_description: Curated exemplar for the class IA PI3K catalytic-subunit role in Kit signaling pathway; p110 bound to p85 generates PtdIns(3,4,5)P3 at the membrane, activating AKT-dependent survival and migration signaling. function: preferred_term: 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity term: id: GO:0046934 label: 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity - id: stat5a_stat5_transcription_factor label: STAT5 transcription factor participant: selector_type: FAMILY family: preferred_term: STAT transcription factor family/ortholog group term: id: PANTHER:PTHR11801 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION representative_members: - preferred_term: STAT5A term: id: UniProtKB:P42229 label: Signal transducer and activator of transcription 5A ancestral_nodes: - preferred_term: PAINT node PTN000210448 for STAT5A term: id: PANTHER:PTN000210448 label: PTN000210448 description: Local PAINT IBD node in PTHR11801 with propagated terms C:GO:0005634, C:GO:0005737; PAINT date 20260528. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN000210448 in PTHR11801. - preferred_term: PAINT node PTN000210451 for STAT5A term: id: PANTHER:PTN000210451 label: PTN000210451 description: Local PAINT IBD node in PTHR11801 with propagated term P:GO:0019221; PAINT date 20260828. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN000210451 in PTHR11801. - preferred_term: PAINT node PTN000927860 for STAT5A term: id: PANTHER:PTN000927860 label: PTN000927860 description: Local PAINT IBD node in PTHR11801 with propagated term P:GO:0042127; PAINT date 20250902. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN000927860 in PTHR11801. role_description: Curated exemplar for the STAT5 transcriptional-output role in Kit signaling pathway; STAT5 is tyrosine-phosphorylated downstream of activated KIT, dimerizes, and moves to the nucleus to regulate proliferation and survival genes (GOA IMP on human KIT for positive regulation of receptor signaling pathway via JAK-STAT). function: preferred_term: DNA-binding transcription factor activity, RNA polymerase II-specific term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific evidence: - source_id: PMID:21135090 statement: STAT1, STAT3, and STAT5 are activated downstream of KIT, localize to the nucleus, and can be directly phosphorylated by KIT on activation-specific tyrosines in vitro. connections: - source: scf_engages_kit target: kit_effector_recruitment connection_type: CAUSES description: Ligand-driven dimerization and autophosphorylation create the phosphotyrosine docking sites that recruit SH2 effectors. - source: kit_effector_recruitment target: kit_ras_pi3k_stat_output connection_type: CAUSES description: Receptor-bound GRB2, p85, SHP2, and Src-family kinases activate the Ras-MAPK, PI3K-AKT, and STAT5 branches. knowledge_gaps: - gap_statement: >- Whether STAT activation downstream of ligand-stimulated wild-type KIT proceeds mainly by direct receptor phosphorylation, by Src-family kinases, or by JAK2 is not settled; the GO_REF/IMP evidence for GO:0046427 on human KIT comes from oncogenic D816 mutants in neoplastic mast cells. boundary: >- STAT1, STAT3, and STAT5 are activated downstream of KIT, and KIT can phosphorylate STAT activation-loop tyrosines in vitro; the module therefore models STAT5 as a direct output without asserting a JAK intermediate. gap_kind: - BIOLOGY - CURATION status: OPEN resolution: >- Compare STAT5 tyrosine phosphorylation after SCF stimulation of wild-type KIT in cells with and without JAK2 or Src-family kinase inhibition, and annotate the mediating kinase in a GO-CAM for the pathway.