KIT (c-KIT / CD117)

KIT is a type-III receptor tyrosine kinase (RTK) and the canonical receptor for stem cell factor (SCF, encoded by kitlg). It gates survival, proliferation, and differentiation of several long-lived progenitor and pigment cell populations — including hematopoietic-stem-cells, melanocytes, melanocyte-stem-cells, mast cells, and interstitial cells of Cajal. In aging biology, KIT is relevant primarily as the receptor-side node of the keratinocyte → melanocyte paracrine axis that drives focal hyperpigmentation (skin-aging), and as a required surface marker for HSC maintenance and bone-marrow niche retention. Critically, in solar lentigo lesions the KIT receptor is not upregulated — the pathogenic signal is ligand-side (SCF/KITLG up 3.9-fold in keratinocytes), ruling out receptor sensitisation as the mechanism ¹.

Druggability note. Multiple FDA-approved KIT inhibitors exist (imatinib, sunitinib, avapritinib, ripretinib); all indications are oncological (GIST, mastocytosis, CML). No aging-indication-validated KIT modulator exists, so the aging-context tier per CLAUDE.md R26/R27 = 2 (high-quality clinical drug exists, not aging-validated). The max-druggability tier (for any indication) = 1.

Identity

Field	Value
UniProt	P10721 (KIT_HUMAN)
NCBI Gene	3815
HGNC symbol	KIT
Ensembl	ENSG00000157404
Chromosome	4q12
Mouse ortholog	Kit (W locus, “Dominant white spotting”)
Protein length	976 aa (precursor, including 25-aa signal peptide; mature chain 26–976)
Molecular weight	~145 kDa (mature glycoprotein; core ~110 kDa)
Protein class	Type-III RTK; CSF-1/PDGF receptor subfamily
Paralogs (human)	PDGFRA, PDGFRB, CSF1R, FLT3

Structure

KIT is a single-pass type-I transmembrane glycoprotein with the canonical RTK Class III domain architecture ²:

Extracellular region (residues 26–524): Five immunoglobulin-like C2-type domains (D1–D5): Ig-like 1 (27–112), Ig-like 2 (121–205), Ig-like 3 (212–308), Ig-like 4 (317–410), Ig-like 5 (413–507). D1–D3 constitute the primary SCF-binding interface; D4–D5 receptor homodimer contact mediates ligand-induced dimerisation.
Transmembrane helix (525–545): Single-pass anchor.
Juxtamembrane domain (JMD, 546–588): Auto-inhibitory in basal state; gain-of-function mutations here (exon 11, e.g., V559D, W557_K558del) are the most common GIST mutations ³.
Split kinase domain (589–937): Bipartite — TK1 (catalytic) / kinase insert domain (KID) / TK2 (substrate binding). The KID is a ~100 aa insertion absent from other RTK classes that recruits regulatory effectors.
C-terminal tail (938–976): Regulatory phosphorylation sites.

Key phosphorylation sites

Autophosphorylation on ligand binding ²:

Residue	Domain	Role
Tyr-568, Tyr-570	Juxtamembrane	Recruits SRC-family kinases (LYN, FYN); activates RAS/MAPK
Tyr-703	KID	Recruits GRB2 → SOS → RAS cascade
Tyr-721	KID	Recruits PI3K p85 regulatory subunit → AKT survival
Tyr-823	Activation loop, TK2	Catalytic activation (analogous to PDGFR Tyr-857)
Tyr-936	KID	Recruits GRB7; auxiliary signalling

Inhibitory phosphorylation by PKC at Ser-741, Ser-746, Ser-821, Ser-959 attenuates kinase activity (feedback regulation by PKC isoforms activated downstream of PLC-γ) ².

Signalling

SCF (membrane-bound or soluble) → KIT extracellular domain D1–D3 binding → D4-mediated receptor homodimerisation → trans-autophosphorylation → recruitment of SH2-domain effectors:

PI3K–AKT axis (Tyr-721 → p85 subunit): cell survival, anti-apoptotic; required for HSC maintenance and mast cell survival.
RAS–RAF–MAPK axis (Tyr-568/570 + Tyr-703 → SRC + GRB2/SOS → RAS): proliferation and differentiation; activates MITF in melanocytes driving melanogenesis ⁴.
JAK–STAT axis (Tyr-568/570 → JAK2 → STAT1/3/5): transcriptional activation; relevant in HSC and mast cell contexts.
PLC-γ axis (Tyr-721 also recruits PLC-γ1): DAG + IP3 → PKC activation + Ca²⁺ release; negative feedback via PKC-mediated Ser phosphorylation of KIT.
SHP-1/SHP-2 (PTPN6/PTPN11) phosphatase recruitment: negative regulation and signal duration control.

Membrane-bound SCF (31 kDa isoform, encoded by alternatively spliced KITLG exon 6) acts via juxtacrine contact — signalling only occurs when a SCF-expressing cell is directly apposed to a KIT-expressing cell. The soluble isoform (18 kDa) can signal in trans. The Hattori 2004 solar lentigo study established that in aged/UV-damaged skin the membrane-bound isoform predominates and the soluble isoform is undetectable in epidermal preparations ¹.

Expression and cell-type distribution

KIT expression is relatively restricted; canonical high-expression populations:

Haematopoietic stem cells (HSCs): KIT (CD117) is a core component of the LSK (Lin⁻Sca-1⁺c-Kit⁺) immunophenotype used to isolate mouse HSCs; human HSCs are CD34⁺CD117⁺. KIT signalling is required for HSC maintenance and bone marrow niche retention — see hematopoietic-stem-cells.
Mast cells: KIT signalling is the primary survival/differentiation signal for mast cell precursors and mature mast cells throughout life.
Melanocytes and melanocyte stem cells (McSCs): KIT is expressed on differentiated melanocytes and on the McSC pool in the hair follicle bulge. SCF–KIT signalling drives melanogenic activation (MITF target gene upregulation, tyrosinase expression) and McSC maintenance ⁴. See melanocyte-stem-cells.
Primordial germ cells: KIT is essential for PGC migration to the gonadal ridge during development; loss-of-function causes sterility in the Kit^W series.
Interstitial cells of Cajal (ICC): CD117 is the canonical ICC marker used diagnostically to distinguish ICC-derived GISTs from other mesenchymal tumours ³.

Aging context

Solar lentigo (focal skin hyperpigmentation)

The solar lentigo (age spot, lentigo senilis) lesion provides the best-characterised human context for KIT signalling in aged tissue. Hattori et al. 2004 (n=29 Japanese patients, paired biopsies) compared lesional and perilesional epidermis using microdissected epidermal sheets (dispase-separated, dermis-free) ¹:

Lesional SCF mRNA: 3.9-fold elevated in epidermis (p<0.01; RT-PCR, n=7 pairs)
Lesional membrane-bound 31 kDa SCF protein: 1.6-fold elevated (p<0.05; Western blot, n=6 pairs)
Soluble 18 kDa SCF: not detected in lesional or perilesional epidermal preparations
c-KIT mRNA: 1.16-fold, NS — the KIT receptor itself is not upregulated in lesional melanocytes

This null result for KIT is load-bearing: it rules out the alternative hypothesis that aged melanocytes become more sensitive (more KIT) to ambient SCF. The signal gain is entirely ligand-side. Secondary citations that describe “KIT upregulation” in solar lentigo are incorrect and should be treated with scepticism unless they cite independent data ¹. contradictory-evidence — the common “KIT upregulation in age spots” claim in reviews is not supported by Hattori 2004 primary data and no replicated direct measurement of lesional KIT protein levels in LS exists as of 2026.

Dimension	Status	Notes
Pathway conserved across human skin types?	partial	Hattori 2004 cohort: Japanese adults only (Fitzpatrick III–IV); LS occurs pan-ethnically but isoform proportions may differ by phototype needs-replication
Replicated independently?	partial	SCF/KIT axis is widely cited; per-isoform WB data and the KIT null result need independent cohort confirmation
Functional blocking tested?	no	No anti-KIT neutralisation or KIT-ECD decoy experiment in LS lesions; causality is mechanistically inferred no-mechanism

Hair follicle melanocyte stem cell aging

KIT–SCF signalling is required for McSC maintenance in the hair follicle niche. Hachiya et al. 2009 (human follicle explants + mouse models) demonstrated that blocking KIT with neutralising antibodies suppresses melanogenic marker expression and causes reversible hair depigmentation ⁴. needs-replication (small n; mouse/human mixed evidence base).

In the most current understanding, McSC depletion with age (hair greying) occurs via a senescence-coupled differentiation programme: DNA double-strand breaks in McSCs trigger “seno-differentiation” — KIT-expressing stem cells undergo p21-driven terminal differentiation rather than self-renewing, depleting the pool ⁵. This places KIT-expressing McSCs at the intersection of stem-cell-exhaustion and cellular-senescence hallmarks. Antagonistically, carcinogen-driven activation of arachidonic acid metabolism plus niche-derived SCF signals can prevent this differentiation and instead promote McSC self-renewal and expansion — increasing melanoma risk ⁵. needs-human-replication — the Mohri 2025 findings are primarily from mouse + in vitro genotoxic-stress models.

Hematopoietic stem cell pool regulation and aging

Gao et al. 2024 (Science, citation percentile 100th) revealed a novel KIT-dependent mechanism for HSC niche retention: a subset of HSCs acquires macrophage-associated surface markers via trogocytosis — direct membrane transfer from bone marrow macrophages to HSCs — and this process is regulated by the C-KIT receptor ⁶. Trogocytosis-acquired macrophage markers cause HSCs to be retained in the niche rather than mobilised. This establishes KIT not just as a proliferation/survival signal but as a niche-anchoring regulatory node.

In aged mice and humans, HSCs expand numerically but become functionally impaired and show myeloid lineage skewing (see hematopoietic-stem-cells). Whether age-related changes in KIT surface levels or KIT signalling fidelity contribute to these changes is not directly established; the field has focused more on epigenetic drift and intrinsic HSC changes than on KIT. needs-replication (KIT surface expression on aged human HSCs vs young; trogocytosis rate in aged marrow).

Mutations and disease associations

Mutation class	Representative variant	Disease	Mechanism
Loss-of-function (germline)	Multiple coding variants (e.g., Trp553ter)	Piebaldism	Absent KIT signalling → melanoblast migration/survival failure → patches of unpigmented skin and hair
Gain-of-function (somatic) — juxtamembrane	V559D, W557_K558del (exon 11)	GIST	Release of JMD auto-inhibition → constitutive kinase activation → ICC-lineage tumour ³
Gain-of-function (somatic) — kinase domain	D816V (exon 17)	Systemic mastocytosis; some AML	Activation-loop mutation → constitutive activity; D816V is imatinib-resistant (requires avapritinib/midostaurin)
Gain-of-function (somatic) — exon 9	A502_Y503dup	GIST (sunitinib-sensitive subtype)	Extracellular domain duplication promoting ligand-independent dimerisation

Piebaldism: KIT loss-of-function leads to white patches (ventral abdomen, forehead streak) due to failure of neural crest melanoblast migration and survival. The W locus in mice (Kit gene) has been the classical pigmentation genetics system since the early 20th century.

Pharmacology and druggability

KIT is among the most extensively targeted kinases in oncology. All approved drugs are for non-aging indications:

Drug	Generation	Main indication	KIT mutation sensitivity
Imatinib (Gleevec)	1st	GIST (exon 11 > exon 9), CML	Exon 11 >exon 9; D816V resistant
Sunitinib (Sutent)	2nd	Imatinib-resistant GIST	Exon 9 + some secondary resistance mutations
Regorafenib	3rd	Multi-resistant GIST	Broad but limited efficacy
Ripretinib (Qinlock)	4th	≥3rd line GIST	Broad spectrum via switch-control mechanism
Avapritinib (Ayvakit)	4th	D816V+ mastocytosis; exon 18 GIST	D816V-specific; most potent D816V inhibitor
Midostaurin	Multikinase	D816V systemic mastocytosis	D816V coverage; less selective than avapritinib

Aging-context tier = 2. No KIT inhibitor is FDA-approved or phase-3-tested for an aging-rejuvenation indication. Repurposing rationale would be speculative: KIT signalling supports stem cell maintenance (inhibition could worsen HSC/McSC exhaustion). Activation, not inhibition, might be more relevant for aging-associated stem cell loss, but no validated KIT agonist exists clinically. no-mechanism

Pathway membership

scf-kit-signaling — canonical ligand–receptor axis (stub; page not yet seeded)
pi3k-akt-pathway — survival branch downstream of Tyr-721
ras-mapk-pathway — proliferation/differentiation branch downstream of Tyr-568/703
jak-stat-pathway — transcriptional branch; STAT5 in HSCs
melanogenesis — melanocyte KIT → MAPK → MITF → tyrosinase axis

Key interactors

kitlg — ligand (SCF, stem cell factor); the cognate ligand page (R40 forward-ref; not yet seeded as of 2026-05-19)
grb2 — recruited to phospho-Tyr-703 in KID; bridges to RAS/RAF cascade
pi3k — p85 subunit recruited to phospho-Tyr-721; survival signalling
stat1 — activated downstream via JAK2 in mast cells and HSCs
PTPN6 (SHP-1) / PTPN11 (SHP-2) — phosphatases that limit KIT signal duration; not yet seeded

Limitations and gaps

KIT surface levels on aged human HSCs are not directly quantified in a well-powered cross-sectional study; the contribution of KIT signalling fidelity to HSC aging vs epigenetic drift remains unresolved. needs-replication
The KIT null result in solar lentigo (Hattori 2004) needs independent cohort replication with protein-level quantification across multiple ethnic skin phototypes. needs-replication
Aging-context druggability: no KIT modulator has been studied in a clinical aging trial; the on-target risk (HSC/McSC depletion by inhibitors) makes repurposing of existing KIT inhibitors counterintuitive. no-mechanism
scf-kit-signaling pathway page not yet seeded; the receptor–ligand axis lacks a dedicated pathway-level page. stub
kitlg protein page not yet seeded (R40 forward-ref flagged in hattori-2004-scf-solar-lentigo). stub
GenAge entry: KIT is not listed in the GenAge human aging gene database as of 2026-05-19; no formal longevity-gene annotation. needs-canonical-id — flag for periodic GenAge re-check.
GTEx aging correlation not populated; KIT is expressed in restricted cell types (not well-captured by bulk GTEx tissue data). needs-canonical-id

Cross-references

kitlg — cognate ligand (SCF / KITLG); not yet seeded
melanocytes — KIT-expressing effector cell for skin pigmentation
melanocyte-stem-cells — McSC pool maintenance; KIT is a key niche-retention signal
hematopoietic-stem-cells — HSC immunophenotype (LSK = Lin⁻Sca-1⁺c-Kit⁺ in mouse); KIT-trogocytosis niche model
skin-aging — solar lentigo (SCF/KIT ligand-driven focal hyperpigmentation)
melanogenesis — downstream effector process; SCF/KIT → MAPK → MITF → tyrosinase
stem-cell-exhaustion — hallmark; McSC depletion and KIT-dependent niche retention in HSCs
altered-intercellular-communication — hallmark; keratinocyte → melanocyte paracrine SCF axis exemplifies this hallmark in skin
hattori-2004-scf-solar-lentigo — primary anchor study; KIT mRNA unchanged 1.16-fold NS in lentigo

Footnotes

hattori-2004-scf-solar-lentigo · doi:10.1111/j.0022-202x.2004.22503.x · n=29 (per-assay n=7 RT-PCR, n=6 WB, n=4 GROα PCR, n=10 IHC) · observational, paired within-patient · model: human lentigo senilis biopsies, Japanese adults 35–85 yr · p<0.01 (SCF mRNA 3.9-fold), p<0.05 (membrane-bound SCF 1.6-fold), NS (c-KIT 1.16-fold) · local PDF confirmed in a local paper archive ↩ ↩² ↩³ ↩⁴
UniProt P10721 (KIT_HUMAN), accessed 2026-05-19 · review curated (Swiss-Prot) · Homo sapiens · 976 aa precursor ↩ ↩² ↩³
doi:10.1126/science.279.5350.577 · Hirota S et al. · Science 1998 · n=49 GIST tumours + n=6 sequenced for c-kit coding region · observational · 94% (46/49) of GISTs expressed KIT by IHC; c-kit coding region sequenced from 6 GISTs: 5/6 showed juxtamembrane domain (exon 11) gain-of-function mutations (deletions/substitutions near Lys-550–Val-560); constitutive kinase activation without SCF confirmed in 293T transfection assay; established KIT as driver oncogenic event in GIST · local PDF confirmed in a local paper archive · NOTE: the 94% figure is KIT expression, not mutation rate; exon-11 mutation frequency across larger GIST series is ~60–70% per subsequent literature ↩ ↩² ↩³
doi:10.1002/path.2503 · Hachiya A et al. · J Pathol 2009 · in-vitro + in-vivo (human follicle explants + mouse) · anti-KIT neutralising antibody suppressed melanogenic markers and caused reversible depigmentation; membrane-bound SCF expression peaks during anagen · model: human hair follicle explants + mouse · local PDF: not_oa (closed-access); no-fulltext-access ↩ ↩² ↩³
doi:10.1038/s41556-025-01769-9 · Mohri Y et al. (PMID 41053225) · Nat Cell Biol 2025 · in-vivo (mouse) + in-vitro · citation percentile 100th · DSB-induced seno-differentiation depletes KIT+ McSCs → hair greying; carcinogen-induced arachidonic acid + niche-SCF blocks differentiation → McSC expansion → melanoma risk · model: mouse genotoxic stress + human cell lines · local PDF: not_oa (closed-access); no-fulltext-access ↩ ↩²
doi:10.1126/science.adp2065 · Gao X et al. · Science 2024 · in-vivo (mouse + ex-vivo human BM) · citation percentile 100th · C-KIT receptor mediates trogocytosis-driven acquisition of macrophage surface markers by HSC subset, governing BM niche retention vs mobilisation · model: mouse BM + human BM · local PDF: PMC open access (PMC11533977) but download failed (a local paper archive PMC fetch pipeline issue — 0 candidate URLs after filtering); no-fulltext-access pending archive fix ↩

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