Affinage

KIT

Mast/stem cell growth factor receptor Kit · UniProt P10721

Round 2 corrected
Length
976 aa
Mass
109.9 kDa
Annotated
2026-04-28
130 papers in source corpus 38 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KIT is a type III receptor tyrosine kinase that, upon binding its ligand stem cell factor (SCF/MGF), undergoes rapid homodimerization, autophosphorylation, and activation of PI3K, MAPK/ERK, JAK/STAT3, and Src family kinase cascades to govern the development, proliferation, and survival of hematopoietic progenitors, melanocytes, germ cells, interstitial cells of Cajal, and mast cells (PMID:1698553, PMID:1690623, PMID:1283735, PMID:7507447). SCF-induced KIT dimerization efficiency controls signaling amplitude and cell-type-selective biological output, with engineered partial agonists demonstrating that reduced dimerization biases activation toward hematopoietic progenitors over mast cells (PMID:28283060, PMID:9446650). Downstream, MAPK phosphorylates the transcription factor Microphthalmia (MITF) to recruit p300/CBP and couple transactivation of melanocyte genes to ubiquitin-dependent proteasomal degradation of MITF, while Gαi1/3 proteins facilitate KIT endocytosis and Akt-mTOR/Erk signaling (PMID:9440696, PMID:10673502, PMID:37063428). Gain-of-function KIT mutations in the juxtamembrane domain cause gastrointestinal stromal tumors (GISTs) and are imatinib-sensitive, whereas activation-loop mutations (notably Asp816Val) constitutively activate STAT3-dependent transformation and confer imatinib resistance, and germline loss-of-function mutations cause piebaldism (PMID:9438854, PMID:11861291, PMID:1717985).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1987 High

    Identifying KIT as a transmembrane receptor tyrosine kinase with intrinsic autophosphorylation activity established the molecular framework for understanding how a proto-oncogene product could transduce extracellular signals.

    Evidence cDNA cloning and autophosphorylation assay in glioblastoma cells and transfected fibroblasts

    PMID:2448137

    Open questions at the time
    • Ligand identity unknown at this point
    • Downstream signaling targets uncharacterized
    • No structural information on the kinase domain
  2. 1990 High

    Genetic mapping of c-kit to the W locus and identification of SCF/MGF as its ligand resolved a decades-old question about what receptor-ligand system governs hematopoietic, melanocyte, and germ cell development.

    Evidence Genetic linkage of c-kit to W locus with kinase activity assays in W mutant mast cells; 125I-MGF cross-linking and immunoprecipitation confirming ligand identity

    PMID:1690623 PMID:1698553 PMID:1712701

    Open questions at the time
    • Mechanism of receptor activation upon ligand binding unknown
    • Downstream signaling cascades uncharacterized
    • Tissue-specific roles beyond hematopoiesis/melanocytes/germ cells not yet explored
  3. 1992 High

    Demonstrating that KIT signaling is required for interstitial cells of Cajal development and gut pacemaking revealed a non-hematopoietic physiological role and broadened the range of KIT-dependent cell lineages.

    Evidence Anti-c-kit antibody blockade in neonatal mice and W/Wv mutant gut motility analysis

    PMID:1283735

    Open questions at the time
    • Molecular mechanism by which KIT supports ICC differentiation unknown
    • Whether KIT signals differently in ICC vs. mast cells not addressed
  4. 1993 High

    Discovery of constitutively activating KIT point mutations (Val560Gly and Asp816Val) in mast cell leukemia established that somatic gain-of-function mutations in KIT drive neoplasia, creating the conceptual basis for targeted therapy.

    Evidence cDNA sequencing of HMC-1 cells, site-directed mutagenesis with reconstitution in 293T cells showing ligand-independent autophosphorylation

    PMID:7691885

    Open questions at the time
    • How juxtamembrane vs. activation-loop mutations differ mechanistically was unclear
    • Therapeutic targetability not yet tested
  5. 1994 High

    Delineation of the KIT→Syp/Grb2→Ras-Raf-MAPK signaling axis resolved how ligand-induced KIT dimerization couples to mitogenic signaling.

    Evidence GST-SH2 pulldown, co-immunoprecipitation, and Ras activation assay after SCF stimulation

    PMID:7523381

    Open questions at the time
    • PI3K and STAT pathways downstream of KIT not yet characterized
    • Signaling specificity between KIT isoforms unknown
  6. 1995 High

    Identification of KIT loss-of-function mutations in piebaldism families and Asp816Val in mastocytosis patients established a clinical mutation spectrum spanning both loss- and gain-of-function phenotypes.

    Evidence Genetic linkage and DNA sequencing in piebaldism kindred; RT-PCR sequencing of patient blood in mastocytosis

    PMID:1717985 PMID:7479840

    Open questions at the time
    • Genotype-phenotype correlation for different KIT domains incomplete
    • Mechanism by which loss-of-function selectively affects melanocytes unclear
  7. 1998 High

    Simultaneous discoveries that KIT→MAPK phosphorylates MITF to recruit p300/CBP for melanocyte gene transactivation, and that juxtamembrane KIT mutations drive GISTs, connected KIT signaling to both normal transcriptional programming and solid tumor oncogenesis.

    Evidence SCF stimulation with MAPK-dependent MITF phosphorylation and reporter assay; cDNA sequencing of GISTs with Ba/F3 transformation assay; germline KIT mutation in familial GIST

    PMID:9438854 PMID:9440696 PMID:9660747 PMID:9697690

    Open questions at the time
    • How MITF phosphorylation is coupled to its proteasomal degradation unknown
    • Structural basis for juxtamembrane autoinhibition not resolved
    • Whether GIST signaling differs from normal ICC signaling unclear
  8. 1999 High

    Functional dissection of KIT downstream pathways revealed that PI3K binding is specifically required for spermatogonial differentiation, Src kinases control KIT internalization, GNNK- isoform has enhanced signaling, and Asp816Val activates STAT3 for transformation — establishing pathway-selective and isoform-specific outputs.

    Evidence PI3K-binding knock-in mouse with male sterility; PP1 inhibition and Lyn-deficient cells blocking KIT internalization; GNNK± isoform comparison in NIH3T3; dominant-negative STAT3 blocking Asp816Val transformation

    PMID:10477727 PMID:10523834 PMID:11079457 PMID:11494148

    Open questions at the time
    • Integration of PI3K, STAT3, MAPK signals into a unified model lacking
    • How isoform expression is regulated in different tissues unknown
    • Whether STAT3 is required for all gain-of-function mutants unclear
  9. 2000 High

    Showing that MAPK and Rsk-1 dual phosphorylation of MITF couples transcriptional activation to ubiquitin-dependent degradation resolved how KIT produces short-lived bursts of melanocyte gene expression.

    Evidence Site-directed mutagenesis of MITF Ser73 and Ser409, reporter assay, p300 co-IP, and proteasomal degradation assay

    PMID:10673502

    Open questions at the time
    • E3 ligase responsible for phospho-MITF ubiquitination unidentified
    • Whether this coupling mechanism operates in non-melanocyte KIT-expressing cells unknown
  10. 2002 High

    Pharmacological classification of KIT mutations into imatinib-sensitive juxtamembrane and imatinib-resistant activation-loop categories, together with forced-dimerization experiments proving dimerization sufficiency, provided the mechanistic logic for mutation-specific targeted therapy.

    Evidence COS cell kinase inhibition assays comparing juxtamembrane vs. Asp816Val mutants with imatinib/SU9529; FKBP12-based chemical dimerization rescue of Ba/F3 cells

    PMID:11861291 PMID:12522257 PMID:9446649

    Open questions at the time
    • Structural basis for imatinib resistance at Asp816 not solved
    • Secondary resistance mechanisms not addressed
  11. 2003 High

    The crystal structure of the phosphorylated KIT kinase domain in a product complex provided the first atomic-resolution view of the active conformation, explaining transactivation geometry and informing inhibitor design.

    Evidence X-ray crystallography of phosphorylated c-KIT kinase domain

    PMID:12824176

    Open questions at the time
    • Structure of full-length KIT or KIT–SCF complex unavailable
    • How Asp816Val alters the activation loop conformation structurally unresolved at this time
  12. 2005 High

    Discovery of conserved G-quadruplex structures in the KIT promoter introduced a novel layer of transcriptional regulation potentially targetable by small molecules.

    Evidence NMR, circular dichroism, and UV melting analysis of two G-quadruplex-forming sequences in the c-kit promoter

    PMID:16045346 PMID:16784237

    Open questions at the time
    • Functional consequence of quadruplex formation on KIT transcription not demonstrated in cells
    • No quadruplex-binding compounds tested for transcriptional effect
  13. 2010 High

    Identifying GATA2/Sp1 cooperative transactivation of the c-kit promoter in mast cells, complementing the earlier SCL/TAL1 complex in hematopoietic progenitors, revealed cell-type-specific transcriptional control of KIT expression.

    Evidence ChIP, re-ChIP, EMSA, and siRNA knockdown in mast cells showing GATA2–Sp1 co-occupancy

    PMID:12239153 PMID:20833840

    Open questions at the time
    • How chromatin context and G-quadruplexes integrate with transcription factor binding unknown
    • Transcriptional regulation of KIT in melanocytes and ICC not comparably dissected
  14. 2017 High

    Engineered SCF partial agonists that reduce KIT dimerization efficiency demonstrated that signal amplitude, not just signal quality, determines cell-type-selective biological outcomes — separating hematopoietic expansion from mast cell activation.

    Evidence SCF engineering with in vitro dimerization assays, hematopoietic progenitor and mast cell activation assays, and mouse anaphylaxis/hematopoiesis models

    PMID:28283060

    Open questions at the time
    • Molecular basis for differential sensitivity thresholds in progenitors vs. mast cells unresolved
    • Clinical translatability of partial agonist approach not established
  15. 2023 High

    Discovery that Gαi1/3 proteins associate with activated KIT to promote its endocytosis and sustain Akt-mTOR/Erk signaling added a heterotrimeric G protein component to KIT signal transduction previously considered exclusively tyrosine-kinase-driven.

    Evidence Co-IP, Gαi1/3 siRNA/KO in HUVECs, dominant-negative mutants, and AAV-mediated endothelial knockdown in retinal angiogenesis model

    PMID:37063428

    Open questions at the time
    • Whether Gαi coupling operates in hematopoietic or mast cell contexts unknown
    • Structural basis for Gαi–KIT interaction uncharacterized
    • Role of Gαi in mutant KIT signaling not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length KIT–SCF complex structure at atomic resolution, the E3 ligase responsible for phospho-MITF degradation downstream of KIT, how G-quadruplex structures functionally regulate KIT transcription in vivo, and whether Gαi coupling modulates KIT signaling in the mast cell and hematopoietic contexts where KIT is most physiologically important.
  • No full-length KIT–SCF ectodomain complex structure
  • E3 ligase for MITF downstream of KIT unidentified
  • In vivo functional role of promoter G-quadruplexes not demonstrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016740 transferase activity 4 GO:0060089 molecular transducer activity 4
Localization
GO:0005886 plasma membrane 6
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-1643685 Disease 8 R-HSA-1266738 Developmental Biology 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-168256 Immune System 2
Partners
GNAI1GNAI3GRB2KITLGLYNMITFPTPN11STAT3

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1987 c-KIT encodes a 145 kDa transmembrane glycoprotein receptor tyrosine kinase structurally related to CSF-1 receptor and PDGF receptor, capable of self-phosphorylation on tyrosine residues; it was identified as a cell surface receptor for an unidentified ligand. cDNA cloning, peptide antibody identification, autophosphorylation assay in glioblastoma cells and transfected fibroblasts The EMBO journal High 2448137
1990 c-KIT (encoded at the W locus) functions as a transmembrane receptor tyrosine kinase essential for development of hematopoietic, melanocyte, and germ cell lineages; W mutations impair kinase activity in mast cells from W/Wv mice. Genetic linkage of c-kit to W locus, kinase activity assay in W mutant mast cells, expression studies Ciba Foundation symposium High 1690623
1990 MGF (mast cell growth factor) is a ligand for c-KIT; 125I-labeled MGF cross-links to c-kit-expressing cells and the complex is immunoprecipitated with anti-c-kit antiserum, establishing MGF as the c-KIT ligand. Ligand purification, [3H]thymidine proliferation assay, 125I cross-linking, immunoprecipitation Cell High 1698553
1990 c-KIT protein is expressed on the surface of oocytes (primordial through full-grown) and spermatogonia, and has autophosphorylation activity in the ovary; its expression correlates with oocyte growth and gonial proliferation in germ cells. RNA blot analysis, in situ hybridization, indirect immunofluorescence, immune complex kinase assay Development (Cambridge, England) High 1712701
1992 c-KIT signaling is required for the development of intestinal pacemaker cells (interstitial cells of Cajal); blockade with antagonistic anti-c-kit monoclonal antibody in neonatal mice and W/Wv mice results in defective autonomous gut pacing and lethal paralytic ileus. Anti-c-kit monoclonal antibody blockade in vivo, physiological analysis of gut motility in W/Wv mice Development (Cambridge, England) High 1283735
1992 c-KIT cooperates with erythropoietin in erythroid progenitor proliferation; anti-c-Kit antibody inhibits proliferation but not differentiation during the early phase of erythropoietin response, and erythropoietin downregulates c-kit gene expression. Anti-c-Kit antibody inhibition in culture, erythroid progenitor colony assay, gene expression analysis Development (Cambridge, England) Medium 1374312
1993 Two point mutations in c-KIT coding sequence (Val560Gly and Asp816Val) in mast cell leukemia line HMC-1 cause ligand-independent constitutive autophosphorylation and activation of c-KIT; Asp816Val alone is sufficient for constitutive activation as demonstrated by site-directed mutagenesis in 293T cells. cDNA sequencing, site-directed mutagenesis, immune complex kinase assay, tyrosine phosphorylation detection in transfected cells The Journal of clinical investigation High 7691885
1994 SCF binding to c-KIT induces receptor dimerization, kinase activation, and tyrosine phosphorylation of SH2-containing signaling molecules; downstream, Syp phosphatase associates with activated c-KIT via both its SH2 domains, becomes phosphorylated on tyrosine, and forms a complex with Grb2, linking c-KIT to Ras-Raf-MAP kinase activation. GST-SH2 domain pulldown, co-immunoprecipitation, in vitro binding assay, Ras activation assay The Journal of biological chemistry High 7523381
1994 SCF/c-KIT interaction regulates oocyte growth in vitro; immune complex kinase assay demonstrates ovarian c-KIT autophosphorylation activity; anti-c-kit antibody (ACK2) severely inhibits oocyte growth in coculture. Immune complex kinase assay, oocyte culture with exogenous KL, ACK2 antibody blockade, Northern analysis Developmental biology High 7507447
1995 A missense mutation in the KIT tyrosine kinase domain (Gly664Arg) causes piebaldism in humans, establishing that loss-of-function KIT mutations lead to melanocyte absence. Genetic linkage analysis, DNA sequencing of KIT gene in piebaldism family Proceedings of the National Academy of Sciences of the United States of America High 1717985
1995 A somatic Asp816Val point mutation in the catalytic domain of c-KIT causes ligand-independent autophosphorylation and is found in peripheral blood mononuclear cells of mastocytosis patients with associated hematologic disorders. RT-PCR, DNA sequencing of patient samples, correlation with ligand-independent autophosphorylation Proceedings of the National Academy of Sciences of the United States of America High 7479840
1996 Somatic activating c-KIT mutation (Asp816Val codon substitution) causes constitutive KIT receptor activation in mast cells of skin and spleen in urticaria pigmentosa/aggressive mastocytosis, establishing clonal and neoplastic nature of this disease. Tissue microdissection, DNA sequencing, demonstration of constitutive KIT activation Nature genetics High 8589724
1997 SCF stimulation of mast cells via c-KIT induces differential release of IL-6, producing >100-fold more IL-6 than unstimulated cells, at concentrations causing little histamine, TNF-alpha, or leukotriene C4 release, demonstrating a selective signaling output of c-KIT. ELISA measurement of cytokine/mediator release from bone marrow-derived mast cells after SCF stimulation Blood Medium 9108382
1997 HIV-1 Nef protein transactivates the c-kit promoter; overexpression of c-KIT in astrocytes induces apoptosis requiring the c-KIT tyrosine kinase domain, demonstrating a pro-apoptotic role for c-KIT in astrocytes. Promoter reporter assay, c-kit overexpression in astrocyte cell line, kinase domain mutagenesis, apoptosis assay Proceedings of the National Academy of Sciences of the United States of America Medium 9108086
1998 SCF stimulation of melanoma cells activates MAP kinase, which phosphorylates the transcription factor Microphthalmia (Mi) at a consensus serine, upregulating Mi-dependent transactivation of the tyrosinase gene promoter; this defines a KIT→MAPK→Mi signaling axis in melanocytes. SCF stimulation assay, MAP kinase activation, site-directed mutagenesis of Mi phosphorylation site, luciferase reporter assay Nature High 9440696
1998 c-KIT signaling via MAPK phosphorylation of Mi recruits the transcriptional coactivator p300/CBP specifically to phospho-Mi, enhancing Mi transcriptional activity; phosphorylation does not alter Mi nuclear localization, DNA binding, or dimerization. Co-immunoprecipitation, reporter assay, phosphorylation-specific interaction assay The Journal of biological chemistry High 9660747
1998 SCF induces dose-dependent c-KIT receptor dimerization detectable by FRET within 3 minutes, followed by receptor capping and internalization; c-KIT is not recycled to the cell surface after internalization. Erythropoietin, but not thrombopoietin, also induces c-KIT dimerization and tyrosine phosphorylation, indicating Epo-c-Kit cross-talk. FRET with fluorochrome-conjugated anti-c-Kit antibodies, flow cytometry, confocal microscopy Blood High 9446650
1998 Gastrointestinal stromal tumors harbor gain-of-function mutations in c-KIT in the juxtamembrane region; mutant KIT proteins are constitutively activated without SCF; transfection of mutant c-kit cDNA causes malignant transformation of Ba/F3 cells; GISTs may originate from interstitial cells of Cajal. cDNA sequencing, stable transfection/transformation assay in Ba/F3 cells, immunohistochemistry Science (New York, N.Y.) High 9438854
1998 Familial GISTs harbor germline mutations in the KIT gene, establishing that KIT germline mutations predispose to GIST development. Germline DNA sequencing in familial GIST kindred Nature genetics High 9697690
1999 c-KIT juxtamembrane mutations in canine mastocytomas cause constitutive (ligand-independent) tyrosine phosphorylation of KIT, providing in situ evidence that the juxtamembrane region normally inhibits receptor kinase activity. cDNA sequencing from tumor tissue, tyrosine phosphorylation assay in mast cell lines The Journal of investigative dermatology High 9989791
1999 The Asp816Val activating mutation in c-KIT causes germ cell tumors; this mutation results in constitutively activated, tyrosine-phosphorylated KIT kinase in transfected cells. DNA sequencing of tumor tissue, cell transfection, tyrosine phosphorylation assay The American journal of pathology High 10362788
1999 c-KIT phosphatidylinositol 3-kinase (PI3K) activation is specifically required for spermatogonial differentiation but not for primordial germ cell maintenance; a point mutation abolishing PI3K binding causes complete male sterility due to failure of DNA synthesis in differentiating spermatogonia. PI3K-binding point mutation knock-in mouse, spermatogonia proliferation assay, DNA synthesis measurement Journal of endocrinological investigation High 11079457
1999 A truncated c-kit product (tr-kit) expressed specifically in post-meiotic spermatids and mature sperm, when microinjected into mouse eggs, causes parthenogenetic activation, suggesting tr-kit plays a role in fertilization. Microinjection of tr-kit into mouse eggs, parthenogenetic activation assay Journal of endocrinological investigation Medium 11079457
1999 Src family kinase signaling is required for SCF-induced c-KIT internalization; PP1 (Src family kinase inhibitor) blocks capping and internalization of c-KIT; c-KIT can associate with clathrin independently of Src kinases; disruption of Lyn kinase expression also diminishes SCF-induced c-KIT internalization. PP1 inhibitor treatment, Lyn-deficient cell line, c-KIT trafficking assay, clathrin co-precipitation Blood High 10477727
1999 GNNK- isoform of c-KIT (lacking 4 amino acids in juxtamembrane extracellular region) shows more rapid and extensive tyrosine autophosphorylation, faster internalization, and stronger MAP kinase phosphorylation than GNNK+ isoform after ligand stimulation, resulting in superior transforming activity in NIH3T3 cells. Isoform expression in NIH3T3 cells, autophosphorylation assay, MAP kinase phosphorylation, colony formation, focus formation, nude mouse tumorigenicity Oncogene High 10523834
1999 Activating mutations of c-KIT at Asp816 cause constitutive STAT3 and STAT1 activation; dominant negative STAT3 (but not STAT1) inhibits mutant c-Kit-mediated anchorage-independent growth and tumor formation, and constitutively active STAT3 restores transforming ability. Transfection of dominant negative STAT3/STAT1, anchorage-independent growth assay, in vivo tumor formation Oncogene High 11494148
2000 c-KIT signaling triggers two phosphorylation events on Microphthalmia (Mi): MAPK/ERK targets Ser73 (upregulating transactivation and recruiting p300 coactivator) and p90 Rsk-1 targets Ser409; together these phosphorylations couple Mi transactivation to ubiquitin-dependent proteasomal degradation, creating short-lived Mi activation. Site-directed mutagenesis of Mi phosphorylation sites, reporter assay, co-immunoprecipitation with p300, ubiquitin-dependent degradation assay, protein stability measurement Genes & development High 10673502
2001 The cytoplasmic domain of stem cell factor (SCF) contains a monomeric leucine-dependent basolateral targeting signal assisted by a cluster of acidic amino acids; this signal allows persistent cell surface exposure of SCF for c-KIT signaling; a mutated SCF (Mgf Sl17H) instead induces constitutive endocytosis via a lysosomal targeting motif. Site-directed mutagenesis of SCF cytoplasmic domain, polarized epithelial cell expression, cell surface biotinylation, endocytosis assay The Journal of biological chemistry High 11152680
2002 The SCL/TAL1 transcription factor complex (containing SCL, LMO2, GATA-1/2, E2A, Ldb-1) directly activates the c-kit promoter in hematopoietic cells by tethering via Sp1 zinc finger interaction at a GC-box; chromatin immunoprecipitation demonstrates SCL, E2A, and Sp1 co-occupy the c-kit promoter in vivo. Transient transfection reporter assay, co-immunoprecipitation of endogenous proteins, transgenic mouse model, chromatin immunoprecipitation Blood High 12239153
2002 Pharmacological dimerization of membrane-targeted c-KIT-FKBP12 fusion proteins using FK1012 or AP1510 is sufficient to activate c-KIT signaling and rescue Ba/F3 cells from IL-3 dependence, demonstrating that receptor dimerization alone is sufficient for c-KIT proliferative signaling. Chemical dimerizer-induced receptor dimerization, cell proliferation assay, IL-3 independence rescue Blood High 9446649
2002 KIT and PDGFRA mutations are alternative and mutually exclusive oncogenic mechanisms in GISTs; ~35% of GISTs lacking KIT mutations have activating PDGFRA mutations; tumors with either KIT or PDGFRA oncoproteins activate the same downstream signaling intermediates. Mutation sequencing, Western blot for downstream signaling, cytogenetic analysis Science (New York, N.Y.) High 12522257
2002 The Asp816Val 'enzymatic site type' (EST) KIT mutation is resistant to imatinib (STI571) and SU9529 even at 10 µM, while juxtamembrane 'regulatory type' (RT) KIT mutations are sensitive; this classifies KIT mutations into two pharmacologically distinct categories. COS cell expression of wild-type and mutant KIT, kinase inhibition assay, HMC-1 subclone proliferation and apoptosis assay Blood High 11861291
2003 Crystal structure of c-KIT in a fully active phosphorylated product complex reveals ordered kinase activation and phosphate-binding loops, providing molecular basis for c-KIT kinase transactivation. X-ray crystallography of c-KIT phosphorylated product complex The Journal of biological chemistry High 12824176
2005 The c-kit promoter region contains a DNA sequence that forms a stable intramolecular G-quadruplex structure under physiological conditions, as characterized by NMR, circular dichroism, and melting temperature measurements; this quadruplex may regulate c-kit transcription. NMR, circular dichroism, UV melting temperature analysis Journal of the American Chemical Society High 16045346
2006 A second G-quadruplex-forming sequence (c-kit21) in the c-KIT promoter upstream of the transcription initiation site forms parallel quadruplexes under physiological conditions; mutational analysis reveals structural polymorphism; the sequence is highly conserved across human, mouse, rat, and chimpanzee. NMR, circular dichroism, UV spectroscopy, mutational analysis of quadruplex-forming sequence Biochemistry High 16784237
2008 Primary and secondary KIT mutation location determines sunitinib sensitivity; secondary KIT exon 13/14 mutations (ATP-binding pocket) confer sensitivity to sunitinib while exon 17/18 mutations (activation loop) confer resistance; biochemical profiling of specific mutants confirmed clinical findings. Tumor sequencing, biochemical profiling of KIT mutants in vitro, clinical outcome correlation in phase I/II trial Journal of clinical oncology High 18955458
2010 GATA2 and Sp1 co-occupy the c-kit promoter GC-box in mast cells and cooperatively transactivate c-kit; GATA2 is recruited to the c-kit promoter in a mast cell-specific manner by forming a complex with Sp1; siRNA knockdown of either factor reduces c-kit transcription and cell surface c-KIT expression. Reporter assay, EMSA, chromatin immunoprecipitation, re-ChIP, siRNA knockdown, flow cytometry Journal of immunology High 20833840
2017 Engineered SCF partial agonist that impairs c-KIT dimerization truncates downstream signaling amplitude, resulting in biased activation of hematopoietic progenitors over mast cells; this demonstrates that signal amplitude (tuned by c-KIT dimerization efficiency) determines cell-type-specific biological outputs. SCF engineering, receptor dimerization assay, in vitro and in vivo cell activation assays, mouse models of anaphylaxis and hematopoietic expansion Cell High 28283060
2023 Gαi1 and Gαi3 proteins associate with SCF-activated c-KIT, promote c-KIT endocytosis and adaptor protein binding, and are required for downstream Akt-mTOR and Erk activation; endothelial knockdown of Gαi1/3 suppresses SCF-induced retinal angiogenesis in vivo. Co-immunoprecipitation, Gαi1/3 siRNA/KO, dominant negative mutants, overexpression, HUVEC proliferation/migration/tube formation assay, in vivo AAV-mediated endothelial knockdown in retinal angiogenesis model International journal of biological sciences High 37063428

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science (New York, N.Y.) 3475 9438854
2003 PDGFRA activating mutations in gastrointestinal stromal tumors. Science (New York, N.Y.) 1874 12522257
1987 Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. The EMBO journal 1534 2448137
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1990 Identification of a ligand for the c-kit proto-oncogene. Cell 990 1698553
2005 The role of microRNA genes in papillary thyroid carcinoma. Proceedings of the National Academy of Sciences of the United States of America 980 16365291
1995 Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proceedings of the National Academy of Sciences of the United States of America 742 7479840
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
1993 Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. The Journal of clinical investigation 704 7691885
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 612 18955458
1992 Requirement of c-kit for development of intestinal pacemaker system. Development (Cambridge, England) 606 1283735
2005 Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 562 16076867
1998 MAP kinase links the transcription factor Microphthalmia to c-Kit signalling in melanocytes. Nature 529 9440696
2011 Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 514 21690468
2008 KIT gene mutations and copy number in melanoma subtypes. Clinical cancer research : an official journal of the American Association for Cancer Research 513 18980976
1996 Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. Nature genetics 509 8589724
2008 Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 471 18955451
2005 Putative DNA quadruplex formation within the human c-kit oncogene. Journal of the American Chemical Society 456 16045346
1999 Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. Proceedings of the National Academy of Sciences of the United States of America 456 9990072
2013 Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 453 23775962
2005 KIT (CD117): a review on expression in normal and neoplastic tissues, and mutations and their clinicopathologic correlation. Applied immunohistochemistry & molecular morphology : AIMM 447 16082245
1990 Gonadal expression of c-kit encoded at the W locus of the mouse. Development (Cambridge, England) 440 1712701
2000 Immunohistochemical spectrum of GISTs at different sites and their differential diagnosis with a reference to CD117 (KIT). Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 434 11048809
1998 Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. Nature genetics 433 9697690
2000 c-Kit triggers dual phosphorylations, which couple activation and degradation of the essential melanocyte factor Mi. Genes & development 420 10673502
2005 Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroenterology 413 15685537
2010 Genome-wide association study of hematological and biochemical traits in a Japanese population. Nature genetics 406 20139978
2006 KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood 400 16741248
2009 Large-scale structural analysis of the classical human protein tyrosine phosphatome. Cell 393 19167335
2002 The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations. Blood 371 11861291
1999 Activating c-kit gene mutations in human germ cell tumors. The American journal of pathology 356 10362788
2005 Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry. Journal of proteome research 350 16335952
2006 A conserved quadruplex motif located in a transcription activation site of the human c-kit oncogene. Biochemistry 332 16784237
2009 Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PloS one 325 19789626
2008 Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours. Histopathology 319 18312355
1991 Mutation of the KIT (mast/stem cell growth factor receptor) protooncogene in human piebaldism. Proceedings of the National Academy of Sciences of the United States of America 307 1717985
1999 Early signaling pathways activated by c-Kit in hematopoietic cells. The international journal of biochemistry & cell biology 305 10582339
2006 Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clinical cancer research : an official journal of the American Association for Cancer Research 304 16551858
2002 Immunohistochemical staining for KIT (CD117) in soft tissue sarcomas is very limited in distribution. American journal of clinical pathology 251 11865845
2006 Stem cell factor and its receptor c-Kit as targets for inflammatory diseases. European journal of pharmacology 208 16483568
2003 Structure of a c-kit product complex reveals the basis for kinase transactivation. The Journal of biological chemistry 207 12824176
1994 The ligand of the c-kit receptor promotes oocyte growth. Developmental biology 207 7507447
1999 Stem cell factor/c-kit system in spermatogenesis. Human reproduction update 171 10582791
1998 Lineage-specific signaling in melanocytes. C-kit stimulation recruits p300/CBP to microphthalmia. The Journal of biological chemistry 160 9660747
1992 Loss of c-kit expression in cultured melanoma cells. Oncogene 153 1371338
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