{"gene":"KIT","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1988,"finding":"The c-kit proto-oncogene product is a transmembrane glycoprotein (~145 kDa in brain, ~160 kDa in spleen, ~150 kDa in testis) with intrinsic autophosphorylating tyrosine kinase activity, demonstrated by immune complex kinase assay; N-linked carbohydrates include hybrid/complex and high-mannose structures.","method":"Immune complex kinase assay, endoglycosidase digestion, wheat germ agglutinin affinity chromatography, autophosphorylation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical reconstitution of kinase activity with mutagenesis-independent characterization; foundational paper replicated across subsequent work","pmids":["2463468"],"is_preprint":false},{"year":1991,"finding":"c-kit is expressed on the surface of hematopoietic progenitor cells in adult mouse bone marrow and is essential for constitutive intramarrow hematopoiesis and self-renewal of progenitors; in vivo injection of an antagonistic anti-c-kit monoclonal antibody (ACK2) depleted virtually all hematopoietic progenitors within two days.","method":"In vivo antibody blockade (antagonistic mAb ACK2 injection), flow cytometry, colony-forming assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean in vivo loss-of-function with defined cellular phenotype; widely replicated","pmids":["1711568"],"is_preprint":false},{"year":1992,"finding":"SCF (kit receptor ligand) acts as a potent chemoattractant for mast cells, stimulating directional migration via the c-kit receptor tyrosine kinase; W42 mutant mast cells with defective c-kit kinase failed to migrate in response to SCF but retained normal IL-3-driven motility.","method":"Chemotaxis assay using mucosal and connective tissue mast cells, W42 kinase-dead mutant controls","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — kinase-dead mutant epistasis with specific phenotypic readout; replicated with two mast cell types","pmids":["1371080"],"is_preprint":false},{"year":1994,"finding":"SCF (kit ligand) produced by granulosa cells binds and activates the c-kit receptor on oocytes (demonstrated by immune complex kinase autophosphorylation assay) and is required for oocyte growth in vitro; addition of exogenous KL increased oocyte growth rate by up to 2-fold, and blockade with anti-c-kit mAb ACK2 or the tyrosine kinase inhibitor genistein severely inhibited oocyte growth.","method":"Immune complex kinase assay, oocyte culture in collagen gels, anti-c-kit antibody blockade, tyrosine kinase inhibitor (genistein) treatment, Northern blot for KL mRNA","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods including direct kinase assay, antibody blockade and pharmacological inhibition in single study","pmids":["7507447"],"is_preprint":false},{"year":1994,"finding":"SCF/c-kit signaling stimulates mast cell adhesion to fibronectin (and to a lesser extent vitronectin) via the integrin VLA-5; this adhesion requires c-kit tyrosine kinase activity (c-kit mutant mast cells do not adhere to fibronectin on SCF stimulation but do after PMA), whereas direct cell-cell adhesion mediated by membrane-anchored SCF does not require c-kit kinase activity.","method":"Cell adhesion assay on fibronectin/vitronectin, c-kit kinase mutant (W) mouse-derived mast cells, integrin blocking antibodies, phorbol ester controls","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — kinase-dead mutant epistasis with two distinct adhesion substrates and multiple controls","pmids":["7509207"],"is_preprint":false},{"year":1995,"finding":"c-kit is constitutively autophosphorylated on tyrosine at low basal levels in rat type A spermatogonia, and SCF (kit ligand) stimulation significantly increases the phosphorylated form, demonstrating functional SCF-induced activation of c-kit kinase in spermatogonia.","method":"Immunocytochemistry, Western blot, RNA Northern blot, tyrosine phosphorylation assay","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, direct phosphorylation assay on isolated primary cells but single orthogonal method for kinase activation","pmids":["7536046"],"is_preprint":false},{"year":1998,"finding":"SCF induces c-kit receptor homodimerization within 3 minutes on human hematopoietic cells, detectable by FRET; dimerization is dose-dependent and correlates with concentrations required for proliferation. After internalization, c-kit is not recycled to the cell surface but requires new protein synthesis. Erythropoietin (Epo), but not thrombopoietin, also stimulated c-kit dimerization and tyrosine phosphorylation, indicating cross-talk between Epo and c-kit receptors.","method":"Fluorescence resonance energy transfer (FRET) by flow cytometry, confocal microscopy, protein synthesis inhibitor experiments","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — FRET directly measures receptor dimerization in living cells with multiple cytokine controls and protein synthesis inhibition, single lab but multiple orthogonal approaches","pmids":["9446650"],"is_preprint":false},{"year":1998,"finding":"Pharmacological dimerization of chimeric proteins containing the c-kit cytoplasmic domain fused to FKBP12 is sufficient to drive proliferative signaling in Ba/F3 cells, establishing that c-kit receptor dimerization per se is sufficient for mitogenic signal transduction.","method":"Chemical dimerizer (FK1012, AP1510)-induced dimerization of c-kit-FKBP12 chimeras, Ba/F3 cell proliferation assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean reconstitution of receptor dimerization-driven signaling using orthogonal chemical dimerizers, single lab","pmids":["9446649"],"is_preprint":false},{"year":1999,"finding":"A missense mutation in the c-kit phosphotransferase domain (D816H) found in seminomas/dysgerminomas confers constitutive kinase activation and constitutive tyrosine phosphorylation, established by cell transfection experiments.","method":"PCR/DNA sequencing of tumor tissue, cell transfection with mutant c-kit D816H, immunoprecipitation and tyrosine phosphorylation assay","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct biochemical demonstration of constitutive kinase activation by mutant protein in cell-based reconstitution, single lab","pmids":["10362788"],"is_preprint":false},{"year":1999,"finding":"SCF binding to c-kit induces rapid receptor dimerization and increases in autophosphorylation activity, leading to activation of downstream signaling components including PI3-kinase, Src family kinases, JAK/STAT pathway, and the Ras-Raf-MAP kinase cascade.","method":"Review summarizing biochemical studies including autophosphorylation assays, co-immunoprecipitation, and downstream signaling assays (from primary literature cited therein)","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — well-replicated signaling pathway placement across multiple labs as summarized in review; no single new experiment but represents consensus from multiple methodologies","pmids":["10582339"],"is_preprint":false},{"year":2000,"finding":"A point mutation in c-kit that selectively abrogates PI3-kinase activation does not affect primordial germ cell numbers during embryonic development or spermatogonial stem cell populations, but causes complete male sterility by blocking DNA synthesis specifically in differentiating A1-A4 spermatogonia. A truncated c-kit product (tr-kit), expressed specifically in post-meiotic cells and accumulated in spermatozoa, causes parthenogenetic egg activation upon microinjection into mouse eggs.","method":"Knock-in mouse with PI3K-abrogating c-kit mutation, BrdU incorporation assay, microinjection of tr-kit into mouse eggs, in vivo antibody blockade","journal":"Journal of endocrinological investigation","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — genetic knock-in epistasis with specific biochemical pathway ablation and functional microinjection experiment; well-defined cellular phenotypes","pmids":["11079457"],"is_preprint":false},{"year":2001,"finding":"The cytoplasmic domain of SCF (transmembrane stem cell factor) contains a monomeric leucine-dependent basolateral targeting signal assisted by an upstream cluster of acidic amino acids; this signal is distinct from endocytosis signals and allows persistent cell-surface expression of SCF. A mutation in the SCF cytoplasmic tail (Mgf Sl17H) introduces a motif related to endocytosis/lysosomal targeting signals that causes constitutive endocytosis.","method":"Site-directed mutagenesis of SCF cytoplasmic domain, polarized epithelial cell targeting assays, confocal microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis with functional localization readout in polarized cells; mechanistic dissection of sorting signal","pmids":["11152680"],"is_preprint":false},{"year":2002,"finding":"SCF-induced activation of c-kit leads to receptor internalization into vesicular structures (endosomal pathway) in a process that requires c-kit kinase activity and Src recruitment but not PI3-kinase; cholesterol depletion by methyl-β-cyclodextrin reduces receptor internalization, suggesting c-kit resides in lipid rafts or requires intact lipid rafts for endocytosis. Proteasome inhibitors cause accumulation of internalized vesicles.","method":"EGFP-tagged c-kit chimera (SS-EYFP-kit) live-cell real-time imaging, time-lapse microscopy, phenylarsine oxide (internalization blocker), methyl-β-cyclodextrin (cholesterol depletion), proteasome inhibitors, kinase-dead and PI3K/Src-deficient mutant c-kit constructs","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — live imaging of endogenous receptor dynamics combined with multiple pharmacological and mutant controls, single lab with multiple orthogonal methods","pmids":["12085229"],"is_preprint":false},{"year":2005,"finding":"c-kit expression appears in the embryonic ureter muscularis propria at gestational day 15.5, coincident with the acquisition of unidirectional peristaltic contractions; in vitro neutralization of c-kit with blocking antibodies markedly altered ureter morphology and abolished peristalsis, demonstrating that c-kit function is required for ureteral peristalsis.","method":"Immunocytochemistry on embryonic mouse ureter sections, in vitro ureteral organ culture with c-kit function-blocking antibodies","journal":"The Journal of urology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional antibody blockade in organ culture with specific peristalsis readout, single lab","pmids":["15592099"],"is_preprint":false},{"year":2010,"finding":"GATA2 and Sp1 cooperatively transactivate the c-kit promoter in mast cells via a GC-box element; GATA2 forms a complex with Sp1 at the GC-box (demonstrated by EMSA and re-ChIP), and siRNA knockdown of either Sp1 or GATA2 suppresses c-kit transcription and cell-surface c-Kit expression.","method":"Reporter assay, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), re-ChIP, siRNA knockdown, flow cytometry","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (reporter assay, EMSA, ChIP, re-ChIP, siRNA) establishing transcriptional regulation mechanism; single lab but rigorous","pmids":["20833840"],"is_preprint":false},{"year":2017,"finding":"An engineered SCF partial agonist that impairs c-Kit dimerization truncates downstream signaling amplitude; this biased agonist preferentially activates hematopoietic progenitors over mast cells in vitro and in vivo, demonstrating that signaling threshold tuning through receptor dimerization efficiency controls cell-type selectivity of c-Kit responses.","method":"Protein engineering of SCF partial agonist, dimerization assays, in vitro and in vivo mouse models (anaphylaxis, radioprotection, hematopoietic expansion), signaling amplitude measurements","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mechanistic reconstitution with engineered protein combined with multiple in vivo mouse models and signaling assays; rigorous study with multiple orthogonal methods","pmids":["28283060"],"is_preprint":false},{"year":2017,"finding":"c-Kit signaling promotes cell survival and proliferation in both cardiac stem cells and cardiomyocytes of human and murine origin; c-Kit haploinsufficiency (from Cre knock-in at the Kit locus) worsens myocardial repair after injury and accelerates cardiac aging.","method":"Inducible transgenic c-Kit reporter mouse (c-Kit promoter-driven H2BEGFP), in vitro c-Kit activation assays in cardiac cells, comparison with Kit knock-in model, cardiac injury models","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel transgenic model with in vitro functional assays and in vivo injury phenotype; single lab but multiple complementary approaches","pmids":["29636378"],"is_preprint":false},{"year":2017,"finding":"c-KIT endocytosis is essential for dasatinib- and radotinib-induced apoptosis in c-KIT-positive AML cells; these drugs reduce HSP90β expression and release Apaf-1, activating a caspase-dependent apoptotic pathway. Inhibition of c-KIT endocytosis by dynamin inhibitor reversed cell viability loss and restored HSP90β expression.","method":"Dynamin inhibitor (endocytosis blocker), flow cytometry, Western blot for HSP90β and Apaf-1, caspase activation assays, xenograft mouse model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological endocytosis blockade with multiple downstream readouts and in vivo validation, single lab","pmids":["29127384"],"is_preprint":false},{"year":2014,"finding":"A G-quadruplex sequence in the promoter region of the c-KIT gene forms a highly stable, topologically invariant quadruplex structure (confirmed across multiple crystal forms and by NMR); single and dinucleotide loops show high conformational flexibility while the overall fold is conserved, suggesting this promoter element may regulate c-KIT transcription.","method":"X-ray crystallography (two new crystal structures in distinct space groups), NMR, molecular dynamics simulation","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — high-quality structural data from crystallography and NMR but functional transcriptional consequence not directly demonstrated in this paper; structural finding is robust","pmids":["25452341"],"is_preprint":false}],"current_model":"KIT (c-Kit/CD117) is a type III receptor tyrosine kinase that, upon binding its ligand SCF (stem cell factor), undergoes homodimerization and autophosphorylation, activating downstream pathways including PI3-kinase (required for spermatogonial differentiation), Src (required for receptor internalization via lipid-raft-dependent endocytosis), JAK/STAT, and the Ras-Raf-MAPK cascade; signaling amplitude and cell-type specificity are governed by the degree of receptor dimerization, and gain-of-function mutations (e.g., D816H/V in the kinase domain, exon 11 juxtamembrane deletions) confer constitutive, ligand-independent kinase activity driving neoplasia in mast cells, GISTs, and germ cell tumors, while transcription of the c-kit gene in mast cells is maintained by a GATA2-Sp1 complex at a GC-box element in its promoter."},"narrative":{"mechanistic_narrative":"KIT (c-Kit/CD117) is a transmembrane glycoprotein receptor tyrosine kinase that transduces signals from its ligand SCF (stem cell factor) to control survival, proliferation, migration, and differentiation across hematopoietic, germ, mast, cardiac, and visceral smooth-muscle lineages [PMID:2463468, PMID:1711568, PMID:10582339]. SCF binding drives rapid receptor homodimerization, an event sufficient by itself to trigger mitogenic signaling, as shown by chemically enforced dimerization of the c-kit cytoplasmic domain [PMID:9446650, PMID:9446649]; dimerization activates autophosphorylation and downstream effectors including PI3-kinase, Src-family kinases, JAK/STAT, and the Ras-Raf-MAPK cascade [PMID:10582339]. The degree of dimerization sets signaling amplitude and cell-type selectivity, such that a biased SCF agonist impairing dimerization preferentially activates hematopoietic progenitors over mast cells [PMID:28283060]. Distinct effector arms serve distinct outputs: PI3-kinase activation is specifically required for DNA synthesis in differentiating spermatogonia [PMID:11079457], while Src recruitment—but not PI3-kinase—drives lipid-raft- and dynamin-dependent receptor internalization into the endosomal/proteasomal degradation pathway, after which the receptor is not recycled but replaced by new synthesis [PMID:9446650, PMID:12085229, PMID:29127384]. KIT signaling is essential for intramarrow hematopoiesis and progenitor self-renewal [PMID:1711568], mast cell chemotaxis and integrin-mediated adhesion to fibronectin [PMID:1371080, PMID:7509207], oocyte growth [PMID:7507447], and ureteral peristalsis [PMID:15592099]. Gain-of-function mutations such as the kinase-domain D816H found in seminomas confer constitutive, ligand-independent kinase activity [PMID:10362788]. In mast cells, c-kit transcription is maintained by a GATA2-Sp1 complex acting at a promoter GC-box [PMID:20833840].","teleology":[{"year":1988,"claim":"Establishing that the c-kit proto-oncogene product is itself a tyrosine kinase defined the molecular nature of the receptor and the basis for all downstream signaling.","evidence":"Immune complex kinase and autophosphorylation assays on the glycosylated transmembrane product","pmids":["2463468"],"confidence":"High","gaps":["Ligand and physiological substrates not defined here","No structural model of the kinase domain"]},{"year":1991,"claim":"In vivo antibody blockade showed KIT is required for adult hematopoiesis, moving the receptor from a biochemical entity to an essential regulator of progenitor maintenance.","evidence":"Antagonistic anti-c-kit mAb (ACK2) injection with colony-forming and flow cytometry readouts in mouse bone marrow","pmids":["1711568"],"confidence":"High","gaps":["Downstream effectors of progenitor self-renewal not mapped","Acute depletion vs developmental requirement not distinguished"]},{"year":1992,"claim":"Kinase-dead (W42) epistasis demonstrated that SCF-driven mast cell chemotaxis depends specifically on c-kit catalytic activity, separating KIT-dependent from IL-3-dependent motility.","evidence":"Chemotaxis assays comparing wild-type and W42 kinase-dead mast cells","pmids":["1371080"],"confidence":"High","gaps":["Cytoskeletal effectors linking KIT to directional migration not identified"]},{"year":1994,"claim":"Parallel studies extended SCF/KIT function to oocyte growth and to integrin-mediated mast cell adhesion, showing that kinase activity couples KIT to both proliferation and adhesion programs.","evidence":"Oocyte culture with ACK2/genistein blockade and direct kinase assay; fibronectin/vitronectin adhesion assays with W kinase mutants and VLA-5 blocking antibodies","pmids":["7507447","7509207"],"confidence":"High","gaps":["Signaling intermediates between KIT and VLA-5 activation not resolved","Membrane-anchored vs soluble SCF signaling differences only partially defined"]},{"year":1998,"claim":"FRET detection of SCF-induced dimerization and chemical dimerizer reconstitution together established receptor dimerization as the necessary and sufficient trigger for KIT mitogenic signaling.","evidence":"FRET flow cytometry on hematopoietic cells with cytokine controls; FKBP12-c-kit chimera dimerized by FK1012/AP1510 in Ba/F3 proliferation assay","pmids":["9446650","9446649"],"confidence":"High","gaps":["Stoichiometry and conformational basis of activation not defined","Mechanism of Epo/c-kit cross-talk unresolved"]},{"year":1999,"claim":"Identification of a constitutively activating D816H kinase-domain mutation in germ cell tumors linked KIT gain-of-function directly to neoplasia.","evidence":"Tumor sequencing plus transfection of mutant c-kit and tyrosine phosphorylation assay","pmids":["10362788"],"confidence":"High","gaps":["Differential effector engagement by D816 mutants vs wild-type not addressed","Tumorigenic sufficiency in vivo not tested here"]},{"year":1999,"claim":"Synthesis of biochemical studies placed KIT upstream of PI3-kinase, Src, JAK/STAT, and Ras-Raf-MAPK, defining the canonical signaling network.","evidence":"Review of autophosphorylation, co-IP, and downstream signaling assays","pmids":["10582339"],"confidence":"Medium","gaps":["Quantitative contribution of each arm to specific phenotypes not resolved in the review"]},{"year":2000,"claim":"A knock-in selectively abrogating PI3-kinase coupling separated KIT effector arms in vivo, showing PI3K is specifically required for spermatogonial DNA synthesis but not stem cell maintenance.","evidence":"PI3K-abrogating c-kit knock-in mouse with BrdU incorporation; tr-kit microinjection causing egg activation","pmids":["11079457"],"confidence":"High","gaps":["Effectors mediating the non-PI3K spermatogonial functions not identified","Mechanism of tr-kit egg activation unresolved"]},{"year":2001,"claim":"Dissection of the SCF cytoplasmic tail identified targeting and endocytosis signals controlling whether the ligand persists at the surface or is internalized.","evidence":"Site-directed mutagenesis and polarized epithelial targeting assays with confocal microscopy","pmids":["11152680"],"confidence":"High","gaps":["Trafficking machinery reading the leucine/acidic signal not identified"]},{"year":2002,"claim":"Live-imaging of receptor dynamics defined the route and requirements of KIT endocytosis, showing it depends on kinase activity, Src, and intact lipid rafts but not PI3-kinase, feeding into proteasomal degradation.","evidence":"EYFP-kit live-cell imaging with kinase-dead/Src/PI3K mutants, methyl-β-cyclodextrin, internalization blockers, and proteasome inhibitors","pmids":["12085229"],"confidence":"High","gaps":["Identity of raft adaptors and E3 ligases not established","Link between internalization and signal termination vs continuation not fully resolved"]},{"year":2005,"claim":"Antibody blockade in organ culture extended KIT requirement to ureteral peristalsis, broadening its role to visceral smooth-muscle pacemaker function.","evidence":"Immunocytochemistry and function-blocking antibody treatment of embryonic ureter organ culture","pmids":["15592099"],"confidence":"Medium","gaps":["Cellular identity of KIT-positive pacemaker cells not defined","Single lab, organ culture only"]},{"year":2010,"claim":"Identification of a GATA2-Sp1 complex at a promoter GC-box explained how c-kit transcription is maintained in mast cells, linking lineage transcription factors to receptor expression.","evidence":"Reporter assay, EMSA, ChIP/re-ChIP, and siRNA knockdown with flow cytometry","pmids":["20833840"],"confidence":"High","gaps":["Whether this complex governs KIT transcription in non-mast lineages not addressed"]},{"year":2014,"claim":"Structural characterization of a stable promoter G-quadruplex identified a candidate cis-regulatory element of c-KIT transcription.","evidence":"X-ray crystallography, NMR, and molecular dynamics of the promoter quadruplex","pmids":["25452341"],"confidence":"Medium","gaps":["Functional transcriptional consequence not demonstrated","Cellular factors binding the quadruplex unknown"]},{"year":2017,"claim":"Engineering a dimerization-impaired SCF partial agonist demonstrated that dimerization efficiency tunes signaling amplitude and cell-type selectivity, and additional work tied KIT to cardiac repair and to endocytosis-dependent drug-induced apoptosis in AML.","evidence":"SCF partial agonist with dimerization/signaling assays and in vivo mouse models; c-Kit reporter and knock-in mouse cardiac injury models; dynamin-inhibitor endocytosis blockade with HSP90β/Apaf-1/caspase readouts and xenografts","pmids":["28283060","29636378","29127384"],"confidence":"High","gaps":["Structural basis of biased signaling not fully resolved","Mechanism linking KIT endocytosis to HSP90β/Apaf-1 axis incompletely defined","Cardiac stem cell identity debated"]},{"year":null,"claim":"How the same dimerized receptor selectively engages distinct effector arms to produce lineage-specific outputs (survival, migration, differentiation, pacemaker function) remains incompletely defined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model linking dimerization geometry to differential effector recruitment","Tissue-specific adaptor/scaffold repertoire not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,8,9]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[6,9,15]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[12,17]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,9,15]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[12,17]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[10,13,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[14,18]}],"complexes":[],"partners":["KITLG","SP1","GATA2","FKBP1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P10721","full_name":"Mast/stem cell growth factor receptor Kit","aliases":["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"],"length_aa":976,"mass_kda":109.9,"function":"Tyrosine-protein kinase that acts as a cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P10721/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KIT","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KIT","total_profiled":1310},"omim":[{"mim_id":"621391","title":"XK-RELATED PROTEIN 5; XKR5","url":"https://www.omim.org/entry/621391"},{"mim_id":"621205","title":"MICRO RNA 129-2; MIR129-2","url":"https://www.omim.org/entry/621205"},{"mim_id":"621204","title":"MICRO RNA 129-1; MIR129-1","url":"https://www.omim.org/entry/621204"},{"mim_id":"619947","title":"WAARDENBURG SYNDROME, TYPE 2F; WS2F","url":"https://www.omim.org/entry/619947"},{"mim_id":"619233","title":"STERILE ALPHA MOTIF DOMAIN-CONTAINING PROTEIN 14; SAMD14","url":"https://www.omim.org/entry/619233"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Nucleoli fibrillar center","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"breast","ntpm":79.2}],"url":"https://www.proteinatlas.org/search/KIT"},"hgnc":{"alias_symbol":["CD117","SCFR","C-Kit"],"prev_symbol":["PBT"]},"alphafold":{"accession":"P10721","domains":[{"cath_id":"2.60.40.10","chopping":"39-113","consensus_level":"medium","plddt":94.2704,"start":39,"end":113},{"cath_id":"2.60.40.10","chopping":"126-206","consensus_level":"medium","plddt":94.1862,"start":126,"end":206},{"cath_id":"2.60.40.10","chopping":"214-309","consensus_level":"high","plddt":92.583,"start":214,"end":309},{"cath_id":"2.60.40.10","chopping":"312-508","consensus_level":"medium","plddt":83.1457,"start":312,"end":508},{"cath_id":"1.10.510.10","chopping":"559-681_764-941","consensus_level":"medium","plddt":84.7031,"start":559,"end":941}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P10721","model_url":"https://alphafold.ebi.ac.uk/files/AF-P10721-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P10721-F1-predicted_aligned_error_v6.png","plddt_mean":78.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KIT","jax_strain_url":"https://www.jax.org/strain/search?query=KIT"},"sequence":{"accession":"P10721","fasta_url":"https://rest.uniprot.org/uniprotkb/P10721.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P10721/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P10721"}},"corpus_meta":[{"pmid":"1711568","id":"PMC_1711568","title":"Expression 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Progres dans les recherches sur le cancer","url":"https://pubmed.ncbi.nlm.nih.gov/17607922","citation_count":31,"is_preprint":false},{"pmid":"29636378","id":"PMC_29636378","title":"Cardiac c-Kit Biology Revealed by Inducible Transgenesis.","date":"2018","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/29636378","citation_count":31,"is_preprint":false},{"pmid":"18026739","id":"PMC_18026739","title":"C-Kit receptor (CD117) in the porcine urinary tract.","date":"2008","source":"Pediatric surgery international","url":"https://pubmed.ncbi.nlm.nih.gov/18026739","citation_count":31,"is_preprint":false},{"pmid":"26449497","id":"PMC_26449497","title":"CD117 (KIT) is a useful immunohistochemical marker for differentiating porocarcinoma from squamous cell carcinoma.","date":"2015","source":"Journal of cutaneous pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26449497","citation_count":31,"is_preprint":false},{"pmid":"7536510","id":"PMC_7536510","title":"Expression of c-kit receptor (CD117) and CD34 in leukemic cells.","date":"1995","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/7536510","citation_count":30,"is_preprint":false},{"pmid":"26008799","id":"PMC_26008799","title":"Expression and localisation of c-kit and KITL in the adult human ovary.","date":"2015","source":"Journal of ovarian research","url":"https://pubmed.ncbi.nlm.nih.gov/26008799","citation_count":30,"is_preprint":false},{"pmid":"15112348","id":"PMC_15112348","title":"C-kit gene mutation in human gastrointestinal stromal tumors.","date":"2004","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/15112348","citation_count":30,"is_preprint":false},{"pmid":"12690299","id":"PMC_12690299","title":"Expression of the c-kit receptor in choroidal melanomas.","date":"2003","source":"Melanoma research","url":"https://pubmed.ncbi.nlm.nih.gov/12690299","citation_count":30,"is_preprint":false},{"pmid":"19683721","id":"PMC_19683721","title":"Immunohistochemical expression of the KIT protein (CD117) in normal and neoplastic canine testes.","date":"2009","source":"Journal of comparative pathology","url":"https://pubmed.ncbi.nlm.nih.gov/19683721","citation_count":29,"is_preprint":false},{"pmid":"10492068","id":"PMC_10492068","title":"Effects of mutant c-Kit in early myeloid cells.","date":"1999","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/10492068","citation_count":28,"is_preprint":false},{"pmid":"8605274","id":"PMC_8605274","title":"C-kit receptor (CD117) expression in acute leukemia.","date":"1996","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/8605274","citation_count":28,"is_preprint":false},{"pmid":"1382631","id":"PMC_1382631","title":"Expression of c-kit protein during placental development.","date":"1992","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/1382631","citation_count":28,"is_preprint":false},{"pmid":"28627370","id":"PMC_28627370","title":"Chasing c-Kit through the heart: Taking a broader view.","date":"2017","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/28627370","citation_count":26,"is_preprint":false},{"pmid":"12649669","id":"PMC_12649669","title":"C-kit immunoreactivity in endometrial adenocarcinomas and its clinicopathologic significance.","date":"2003","source":"International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists","url":"https://pubmed.ncbi.nlm.nih.gov/12649669","citation_count":26,"is_preprint":false},{"pmid":"15627886","id":"PMC_15627886","title":"c-kit expression in adenocarcinomas of the lung.","date":"2004","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15627886","citation_count":26,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47403,"output_tokens":4865,"usd":0.107592,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13160,"output_tokens":4465,"usd":0.088712,"stage2_stop_reason":"end_turn"},"total_usd":0.196304,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1988,\n      \"finding\": \"The c-kit proto-oncogene product is a transmembrane glycoprotein (~145 kDa in brain, ~160 kDa in spleen, ~150 kDa in testis) with intrinsic autophosphorylating tyrosine kinase activity, demonstrated by immune complex kinase assay; N-linked carbohydrates include hybrid/complex and high-mannose structures.\",\n      \"method\": \"Immune complex kinase assay, endoglycosidase digestion, wheat germ agglutinin affinity chromatography, autophosphorylation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical reconstitution of kinase activity with mutagenesis-independent characterization; foundational paper replicated across subsequent work\",\n      \"pmids\": [\"2463468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"c-kit is expressed on the surface of hematopoietic progenitor cells in adult mouse bone marrow and is essential for constitutive intramarrow hematopoiesis and self-renewal of progenitors; in vivo injection of an antagonistic anti-c-kit monoclonal antibody (ACK2) depleted virtually all hematopoietic progenitors within two days.\",\n      \"method\": \"In vivo antibody blockade (antagonistic mAb ACK2 injection), flow cytometry, colony-forming assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean in vivo loss-of-function with defined cellular phenotype; widely replicated\",\n      \"pmids\": [\"1711568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"SCF (kit receptor ligand) acts as a potent chemoattractant for mast cells, stimulating directional migration via the c-kit receptor tyrosine kinase; W42 mutant mast cells with defective c-kit kinase failed to migrate in response to SCF but retained normal IL-3-driven motility.\",\n      \"method\": \"Chemotaxis assay using mucosal and connective tissue mast cells, W42 kinase-dead mutant controls\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — kinase-dead mutant epistasis with specific phenotypic readout; replicated with two mast cell types\",\n      \"pmids\": [\"1371080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"SCF (kit ligand) produced by granulosa cells binds and activates the c-kit receptor on oocytes (demonstrated by immune complex kinase autophosphorylation assay) and is required for oocyte growth in vitro; addition of exogenous KL increased oocyte growth rate by up to 2-fold, and blockade with anti-c-kit mAb ACK2 or the tyrosine kinase inhibitor genistein severely inhibited oocyte growth.\",\n      \"method\": \"Immune complex kinase assay, oocyte culture in collagen gels, anti-c-kit antibody blockade, tyrosine kinase inhibitor (genistein) treatment, Northern blot for KL mRNA\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods including direct kinase assay, antibody blockade and pharmacological inhibition in single study\",\n      \"pmids\": [\"7507447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"SCF/c-kit signaling stimulates mast cell adhesion to fibronectin (and to a lesser extent vitronectin) via the integrin VLA-5; this adhesion requires c-kit tyrosine kinase activity (c-kit mutant mast cells do not adhere to fibronectin on SCF stimulation but do after PMA), whereas direct cell-cell adhesion mediated by membrane-anchored SCF does not require c-kit kinase activity.\",\n      \"method\": \"Cell adhesion assay on fibronectin/vitronectin, c-kit kinase mutant (W) mouse-derived mast cells, integrin blocking antibodies, phorbol ester controls\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — kinase-dead mutant epistasis with two distinct adhesion substrates and multiple controls\",\n      \"pmids\": [\"7509207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"c-kit is constitutively autophosphorylated on tyrosine at low basal levels in rat type A spermatogonia, and SCF (kit ligand) stimulation significantly increases the phosphorylated form, demonstrating functional SCF-induced activation of c-kit kinase in spermatogonia.\",\n      \"method\": \"Immunocytochemistry, Western blot, RNA Northern blot, tyrosine phosphorylation assay\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, direct phosphorylation assay on isolated primary cells but single orthogonal method for kinase activation\",\n      \"pmids\": [\"7536046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SCF induces c-kit receptor homodimerization within 3 minutes on human hematopoietic cells, detectable by FRET; dimerization is dose-dependent and correlates with concentrations required for proliferation. After internalization, c-kit is not recycled to the cell surface but requires new protein synthesis. Erythropoietin (Epo), but not thrombopoietin, also stimulated c-kit dimerization and tyrosine phosphorylation, indicating cross-talk between Epo and c-kit receptors.\",\n      \"method\": \"Fluorescence resonance energy transfer (FRET) by flow cytometry, confocal microscopy, protein synthesis inhibitor experiments\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — FRET directly measures receptor dimerization in living cells with multiple cytokine controls and protein synthesis inhibition, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"9446650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Pharmacological dimerization of chimeric proteins containing the c-kit cytoplasmic domain fused to FKBP12 is sufficient to drive proliferative signaling in Ba/F3 cells, establishing that c-kit receptor dimerization per se is sufficient for mitogenic signal transduction.\",\n      \"method\": \"Chemical dimerizer (FK1012, AP1510)-induced dimerization of c-kit-FKBP12 chimeras, Ba/F3 cell proliferation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean reconstitution of receptor dimerization-driven signaling using orthogonal chemical dimerizers, single lab\",\n      \"pmids\": [\"9446649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"A missense mutation in the c-kit phosphotransferase domain (D816H) found in seminomas/dysgerminomas confers constitutive kinase activation and constitutive tyrosine phosphorylation, established by cell transfection experiments.\",\n      \"method\": \"PCR/DNA sequencing of tumor tissue, cell transfection with mutant c-kit D816H, immunoprecipitation and tyrosine phosphorylation assay\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct biochemical demonstration of constitutive kinase activation by mutant protein in cell-based reconstitution, single lab\",\n      \"pmids\": [\"10362788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"SCF binding to c-kit induces rapid receptor dimerization and increases in autophosphorylation activity, leading to activation of downstream signaling components including PI3-kinase, Src family kinases, JAK/STAT pathway, and the Ras-Raf-MAP kinase cascade.\",\n      \"method\": \"Review summarizing biochemical studies including autophosphorylation assays, co-immunoprecipitation, and downstream signaling assays (from primary literature cited therein)\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — well-replicated signaling pathway placement across multiple labs as summarized in review; no single new experiment but represents consensus from multiple methodologies\",\n      \"pmids\": [\"10582339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"A point mutation in c-kit that selectively abrogates PI3-kinase activation does not affect primordial germ cell numbers during embryonic development or spermatogonial stem cell populations, but causes complete male sterility by blocking DNA synthesis specifically in differentiating A1-A4 spermatogonia. A truncated c-kit product (tr-kit), expressed specifically in post-meiotic cells and accumulated in spermatozoa, causes parthenogenetic egg activation upon microinjection into mouse eggs.\",\n      \"method\": \"Knock-in mouse with PI3K-abrogating c-kit mutation, BrdU incorporation assay, microinjection of tr-kit into mouse eggs, in vivo antibody blockade\",\n      \"journal\": \"Journal of endocrinological investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — genetic knock-in epistasis with specific biochemical pathway ablation and functional microinjection experiment; well-defined cellular phenotypes\",\n      \"pmids\": [\"11079457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The cytoplasmic domain of SCF (transmembrane stem cell factor) contains a monomeric leucine-dependent basolateral targeting signal assisted by an upstream cluster of acidic amino acids; this signal is distinct from endocytosis signals and allows persistent cell-surface expression of SCF. A mutation in the SCF cytoplasmic tail (Mgf Sl17H) introduces a motif related to endocytosis/lysosomal targeting signals that causes constitutive endocytosis.\",\n      \"method\": \"Site-directed mutagenesis of SCF cytoplasmic domain, polarized epithelial cell targeting assays, confocal microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis with functional localization readout in polarized cells; mechanistic dissection of sorting signal\",\n      \"pmids\": [\"11152680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SCF-induced activation of c-kit leads to receptor internalization into vesicular structures (endosomal pathway) in a process that requires c-kit kinase activity and Src recruitment but not PI3-kinase; cholesterol depletion by methyl-β-cyclodextrin reduces receptor internalization, suggesting c-kit resides in lipid rafts or requires intact lipid rafts for endocytosis. Proteasome inhibitors cause accumulation of internalized vesicles.\",\n      \"method\": \"EGFP-tagged c-kit chimera (SS-EYFP-kit) live-cell real-time imaging, time-lapse microscopy, phenylarsine oxide (internalization blocker), methyl-β-cyclodextrin (cholesterol depletion), proteasome inhibitors, kinase-dead and PI3K/Src-deficient mutant c-kit constructs\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — live imaging of endogenous receptor dynamics combined with multiple pharmacological and mutant controls, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"12085229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"c-kit expression appears in the embryonic ureter muscularis propria at gestational day 15.5, coincident with the acquisition of unidirectional peristaltic contractions; in vitro neutralization of c-kit with blocking antibodies markedly altered ureter morphology and abolished peristalsis, demonstrating that c-kit function is required for ureteral peristalsis.\",\n      \"method\": \"Immunocytochemistry on embryonic mouse ureter sections, in vitro ureteral organ culture with c-kit function-blocking antibodies\",\n      \"journal\": \"The Journal of urology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional antibody blockade in organ culture with specific peristalsis readout, single lab\",\n      \"pmids\": [\"15592099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"GATA2 and Sp1 cooperatively transactivate the c-kit promoter in mast cells via a GC-box element; GATA2 forms a complex with Sp1 at the GC-box (demonstrated by EMSA and re-ChIP), and siRNA knockdown of either Sp1 or GATA2 suppresses c-kit transcription and cell-surface c-Kit expression.\",\n      \"method\": \"Reporter assay, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), re-ChIP, siRNA knockdown, flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (reporter assay, EMSA, ChIP, re-ChIP, siRNA) establishing transcriptional regulation mechanism; single lab but rigorous\",\n      \"pmids\": [\"20833840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"An engineered SCF partial agonist that impairs c-Kit dimerization truncates downstream signaling amplitude; this biased agonist preferentially activates hematopoietic progenitors over mast cells in vitro and in vivo, demonstrating that signaling threshold tuning through receptor dimerization efficiency controls cell-type selectivity of c-Kit responses.\",\n      \"method\": \"Protein engineering of SCF partial agonist, dimerization assays, in vitro and in vivo mouse models (anaphylaxis, radioprotection, hematopoietic expansion), signaling amplitude measurements\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mechanistic reconstitution with engineered protein combined with multiple in vivo mouse models and signaling assays; rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"28283060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"c-Kit signaling promotes cell survival and proliferation in both cardiac stem cells and cardiomyocytes of human and murine origin; c-Kit haploinsufficiency (from Cre knock-in at the Kit locus) worsens myocardial repair after injury and accelerates cardiac aging.\",\n      \"method\": \"Inducible transgenic c-Kit reporter mouse (c-Kit promoter-driven H2BEGFP), in vitro c-Kit activation assays in cardiac cells, comparison with Kit knock-in model, cardiac injury models\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel transgenic model with in vitro functional assays and in vivo injury phenotype; single lab but multiple complementary approaches\",\n      \"pmids\": [\"29636378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"c-KIT endocytosis is essential for dasatinib- and radotinib-induced apoptosis in c-KIT-positive AML cells; these drugs reduce HSP90β expression and release Apaf-1, activating a caspase-dependent apoptotic pathway. Inhibition of c-KIT endocytosis by dynamin inhibitor reversed cell viability loss and restored HSP90β expression.\",\n      \"method\": \"Dynamin inhibitor (endocytosis blocker), flow cytometry, Western blot for HSP90β and Apaf-1, caspase activation assays, xenograft mouse model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological endocytosis blockade with multiple downstream readouts and in vivo validation, single lab\",\n      \"pmids\": [\"29127384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A G-quadruplex sequence in the promoter region of the c-KIT gene forms a highly stable, topologically invariant quadruplex structure (confirmed across multiple crystal forms and by NMR); single and dinucleotide loops show high conformational flexibility while the overall fold is conserved, suggesting this promoter element may regulate c-KIT transcription.\",\n      \"method\": \"X-ray crystallography (two new crystal structures in distinct space groups), NMR, molecular dynamics simulation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — high-quality structural data from crystallography and NMR but functional transcriptional consequence not directly demonstrated in this paper; structural finding is robust\",\n      \"pmids\": [\"25452341\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KIT (c-Kit/CD117) is a type III receptor tyrosine kinase that, upon binding its ligand SCF (stem cell factor), undergoes homodimerization and autophosphorylation, activating downstream pathways including PI3-kinase (required for spermatogonial differentiation), Src (required for receptor internalization via lipid-raft-dependent endocytosis), JAK/STAT, and the Ras-Raf-MAPK cascade; signaling amplitude and cell-type specificity are governed by the degree of receptor dimerization, and gain-of-function mutations (e.g., D816H/V in the kinase domain, exon 11 juxtamembrane deletions) confer constitutive, ligand-independent kinase activity driving neoplasia in mast cells, GISTs, and germ cell tumors, while transcription of the c-kit gene in mast cells is maintained by a GATA2-Sp1 complex at a GC-box element in its promoter.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KIT (c-Kit/CD117) is a transmembrane glycoprotein receptor tyrosine kinase that transduces signals from its ligand SCF (stem cell factor) to control survival, proliferation, migration, and differentiation across hematopoietic, germ, mast, cardiac, and visceral smooth-muscle lineages [#0, #1, #9]. SCF binding drives rapid receptor homodimerization, an event sufficient by itself to trigger mitogenic signaling, as shown by chemically enforced dimerization of the c-kit cytoplasmic domain [#6, #7]; dimerization activates autophosphorylation and downstream effectors including PI3-kinase, Src-family kinases, JAK/STAT, and the Ras-Raf-MAPK cascade [#9]. The degree of dimerization sets signaling amplitude and cell-type selectivity, such that a biased SCF agonist impairing dimerization preferentially activates hematopoietic progenitors over mast cells [#15]. Distinct effector arms serve distinct outputs: PI3-kinase activation is specifically required for DNA synthesis in differentiating spermatogonia [#10], while Src recruitment—but not PI3-kinase—drives lipid-raft- and dynamin-dependent receptor internalization into the endosomal/proteasomal degradation pathway, after which the receptor is not recycled but replaced by new synthesis [#6, #12, #17]. KIT signaling is essential for intramarrow hematopoiesis and progenitor self-renewal [#1], mast cell chemotaxis and integrin-mediated adhesion to fibronectin [#2, #4], oocyte growth [#3], and ureteral peristalsis [#13]. Gain-of-function mutations such as the kinase-domain D816H found in seminomas confer constitutive, ligand-independent kinase activity [#8]. In mast cells, c-kit transcription is maintained by a GATA2-Sp1 complex acting at a promoter GC-box [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Establishing that the c-kit proto-oncogene product is itself a tyrosine kinase defined the molecular nature of the receptor and the basis for all downstream signaling.\",\n      \"evidence\": \"Immune complex kinase and autophosphorylation assays on the glycosylated transmembrane product\",\n      \"pmids\": [\"2463468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand and physiological substrates not defined here\", \"No structural model of the kinase domain\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"In vivo antibody blockade showed KIT is required for adult hematopoiesis, moving the receptor from a biochemical entity to an essential regulator of progenitor maintenance.\",\n      \"evidence\": \"Antagonistic anti-c-kit mAb (ACK2) injection with colony-forming and flow cytometry readouts in mouse bone marrow\",\n      \"pmids\": [\"1711568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of progenitor self-renewal not mapped\", \"Acute depletion vs developmental requirement not distinguished\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Kinase-dead (W42) epistasis demonstrated that SCF-driven mast cell chemotaxis depends specifically on c-kit catalytic activity, separating KIT-dependent from IL-3-dependent motility.\",\n      \"evidence\": \"Chemotaxis assays comparing wild-type and W42 kinase-dead mast cells\",\n      \"pmids\": [\"1371080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytoskeletal effectors linking KIT to directional migration not identified\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Parallel studies extended SCF/KIT function to oocyte growth and to integrin-mediated mast cell adhesion, showing that kinase activity couples KIT to both proliferation and adhesion programs.\",\n      \"evidence\": \"Oocyte culture with ACK2/genistein blockade and direct kinase assay; fibronectin/vitronectin adhesion assays with W kinase mutants and VLA-5 blocking antibodies\",\n      \"pmids\": [\"7507447\", \"7509207\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling intermediates between KIT and VLA-5 activation not resolved\", \"Membrane-anchored vs soluble SCF signaling differences only partially defined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"FRET detection of SCF-induced dimerization and chemical dimerizer reconstitution together established receptor dimerization as the necessary and sufficient trigger for KIT mitogenic signaling.\",\n      \"evidence\": \"FRET flow cytometry on hematopoietic cells with cytokine controls; FKBP12-c-kit chimera dimerized by FK1012/AP1510 in Ba/F3 proliferation assay\",\n      \"pmids\": [\"9446650\", \"9446649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and conformational basis of activation not defined\", \"Mechanism of Epo/c-kit cross-talk unresolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identification of a constitutively activating D816H kinase-domain mutation in germ cell tumors linked KIT gain-of-function directly to neoplasia.\",\n      \"evidence\": \"Tumor sequencing plus transfection of mutant c-kit and tyrosine phosphorylation assay\",\n      \"pmids\": [\"10362788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Differential effector engagement by D816 mutants vs wild-type not addressed\", \"Tumorigenic sufficiency in vivo not tested here\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Synthesis of biochemical studies placed KIT upstream of PI3-kinase, Src, JAK/STAT, and Ras-Raf-MAPK, defining the canonical signaling network.\",\n      \"evidence\": \"Review of autophosphorylation, co-IP, and downstream signaling assays\",\n      \"pmids\": [\"10582339\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution of each arm to specific phenotypes not resolved in the review\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"A knock-in selectively abrogating PI3-kinase coupling separated KIT effector arms in vivo, showing PI3K is specifically required for spermatogonial DNA synthesis but not stem cell maintenance.\",\n      \"evidence\": \"PI3K-abrogating c-kit knock-in mouse with BrdU incorporation; tr-kit microinjection causing egg activation\",\n      \"pmids\": [\"11079457\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effectors mediating the non-PI3K spermatogonial functions not identified\", \"Mechanism of tr-kit egg activation unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Dissection of the SCF cytoplasmic tail identified targeting and endocytosis signals controlling whether the ligand persists at the surface or is internalized.\",\n      \"evidence\": \"Site-directed mutagenesis and polarized epithelial targeting assays with confocal microscopy\",\n      \"pmids\": [\"11152680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trafficking machinery reading the leucine/acidic signal not identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Live-imaging of receptor dynamics defined the route and requirements of KIT endocytosis, showing it depends on kinase activity, Src, and intact lipid rafts but not PI3-kinase, feeding into proteasomal degradation.\",\n      \"evidence\": \"EYFP-kit live-cell imaging with kinase-dead/Src/PI3K mutants, methyl-\\u03b2-cyclodextrin, internalization blockers, and proteasome inhibitors\",\n      \"pmids\": [\"12085229\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of raft adaptors and E3 ligases not established\", \"Link between internalization and signal termination vs continuation not fully resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Antibody blockade in organ culture extended KIT requirement to ureteral peristalsis, broadening its role to visceral smooth-muscle pacemaker function.\",\n      \"evidence\": \"Immunocytochemistry and function-blocking antibody treatment of embryonic ureter organ culture\",\n      \"pmids\": [\"15592099\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular identity of KIT-positive pacemaker cells not defined\", \"Single lab, organ culture only\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of a GATA2-Sp1 complex at a promoter GC-box explained how c-kit transcription is maintained in mast cells, linking lineage transcription factors to receptor expression.\",\n      \"evidence\": \"Reporter assay, EMSA, ChIP/re-ChIP, and siRNA knockdown with flow cytometry\",\n      \"pmids\": [\"20833840\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this complex governs KIT transcription in non-mast lineages not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Structural characterization of a stable promoter G-quadruplex identified a candidate cis-regulatory element of c-KIT transcription.\",\n      \"evidence\": \"X-ray crystallography, NMR, and molecular dynamics of the promoter quadruplex\",\n      \"pmids\": [\"25452341\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional transcriptional consequence not demonstrated\", \"Cellular factors binding the quadruplex unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Engineering a dimerization-impaired SCF partial agonist demonstrated that dimerization efficiency tunes signaling amplitude and cell-type selectivity, and additional work tied KIT to cardiac repair and to endocytosis-dependent drug-induced apoptosis in AML.\",\n      \"evidence\": \"SCF partial agonist with dimerization/signaling assays and in vivo mouse models; c-Kit reporter and knock-in mouse cardiac injury models; dynamin-inhibitor endocytosis blockade with HSP90\\u03b2/Apaf-1/caspase readouts and xenografts\",\n      \"pmids\": [\"28283060\", \"29636378\", \"29127384\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of biased signaling not fully resolved\", \"Mechanism linking KIT endocytosis to HSP90\\u03b2/Apaf-1 axis incompletely defined\", \"Cardiac stem cell identity debated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the same dimerized receptor selectively engages distinct effector arms to produce lineage-specific outputs (survival, migration, differentiation, pacemaker function) remains incompletely defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model linking dimerization geometry to differential effector recruitment\", \"Tissue-specific adaptor/scaffold repertoire not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 8, 9]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 9, 15]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [12, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 9, 15]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [12, 17]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10, 13, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [14, 18]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KITLG\", \"SP1\", \"GATA2\", \"FKBP1A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}