c-MET (MET receptor tyrosine kinase)

The receptor tyrosine kinase for hepatocyte growth factor (HGF), encoded by the MET proto-oncogene on chromosome 7q31.2. c-MET is the sole high-affinity receptor for HGF and transduces pleiotropic signals controlling epithelial proliferation, survival, migration, morphogenesis, and tissue regeneration. In cancer biology, MET is a well-validated oncogene (amplification, exon 14 skipping mutations, gene fusions); FDA-approved MET inhibitors now target these alterations. In aging biology, the HGF-c-MET axis plays emerging roles in satellite cell activation and skeletal muscle repair, with age-associated loss of paracrine HGF secretion from macrophages impairing c-MET-dependent muscle regeneration ¹. A critical caveat regarding the compound dihexa: the claim that Dihexa acts as a c-MET agonist rests entirely on a retracted paper and unpublished data — see the dedicated note below.

Identity

UniProt: P08581 (MET_HUMAN) — manually reviewed Swiss-Prot entry
NCBI Gene: 4233
HGNC: 7029 (symbol: MET)
Ensembl: ENSG00000105976 — confirmed via UniProt P08581 REST cross-reference (transcript ENST00000318493, protein ENSP00000317272)
Chromosomal locus: 7q31.2
Mouse ortholog: Met (one-to-one; high conservation)
GenAge ID: null — MET is not in GenAge curated aging-gene database as of 2026-05-09

Protein structure and processing

The MET gene encodes a single-pass transmembrane receptor tyrosine kinase. The canonical UniProt P08581 sequence is 1390 amino acids (mature chain after signal peptide cleavage of a 24 aa signal, chain residues 25–1390); the original Park 1987 cDNA ORF prediction was 1408 aa from the initiating Met. The pro-receptor is cleaved by furin at the Arg307–Ser308 bond (UniProt Site 307–308; Birchmeier 2003) to yield a disulfide-linked alpha-beta heterodimer:

Alpha subunit (~50 kDa): extracellular; contributes the Sema domain that forms the ligand-binding site
Beta subunit (~145 kDa): spans the membrane; contains the extracellular Sema/IPT domains (continued), a transmembrane helix, juxtamembrane region, kinase domain, and C-terminal multifunctional docking site

Key domains:

Domain	Location	Function
Sema	Extracellular (alpha + N-terminal beta)	HGF binding; dimerization interface
IPT/TIG (×3)	Extracellular beta	Structural; contributes to HGF affinity
Kinase	Intracellular beta	Catalytic; autophosphorylation
Juxtamembrane	Intracellular, near membrane	Regulatory; Tyr1003 — Cbl docking site; ubiquitin-mediated receptor degradation
Multifunctional docking	C-terminal tail	Adapter recruitment (GAB1, GRB2, Shc, SRC, STAT3)

Key phosphorylation sites (UniProt P08581 verified):

Tyr1234 / Tyr1235 — within the activation loop of the kinase domain; autophosphorylation by autocatalysis activates catalytic activity
Tyr1349 / Tyr1356 — C-terminal bidentate docking site; recruit Gab1 (directly via Gab1’s Met-binding site, and indirectly via Grb2) and other downstream effectors; also autocatalytic phosphorylation
Tyr1003 (juxtamembrane) — phosphorylated; Cbl E3 ubiquitin-ligase docking site; Cbl-mediated ubiquitination drives receptor endocytosis and degradation, attenuating signalling ². This is the site eliminated by METex14 skipping mutations. The previously listed Ser985 inhibitory site is not supported by UniProt P08581 or Birchmeier 2003 and has been removed. needs-replication — if a Ser985 PKC-mediated inhibitory phosphorylation has experimental support in another primary source, it should be re-added with that citation.

Activation mechanism

HGF binding promotes c-MET dimerization and trans-autophosphorylation at Tyr1234/Tyr1235, fully activating the kinase ². The phosphorylated bidentate docking site (pTyr1349/pTyr1356) then recruits the scaffold protein GAB1 — both directly via Gab1’s dedicated Met-binding site (MBS, a sequence of 13 amino acids unique to the Gab family) AND indirectly via grb2 (which can bind pTyr1356 and co-recruit Gab1 through a Grb2–Gab1 interaction). GRB2 can also bind the docking site directly. GAB1 acts as a primary signal amplifier recruiting ²:

PI3K → AKT — survival, proliferation (see pi3k-akt-pathway)
RAS → ERK/MAPK — proliferation, motility (see ras-mapk)
STAT3 — transcriptional programs for morphogenesis, regeneration (see jak-stat-pathway)
PLC-γ — calcium signalling
SRC — cytoskeletal reorganisation (cell scattering/motility)

The breadth of downstream connections is sometimes called the “multifunctional docking site” paradigm — unlike single-pathway RTKs, MET orchestrates parallel programs simultaneously, explaining its roles in both homeostatic morphogenesis (branching morphogenesis, wound healing) and pathological invasion (metastasis) ².

Aging-context biology

Satellite cell activation and muscle repair

Skeletal muscle repair depends on satellite-cell activation, which is triggered in part by HGF-c-MET signalling ³. A 2025 Aging Cell study by Koike et al. (C57BL/6J male mice; young = 8 weeks, aged = 24 months; n=4 per group for qPCR analyses) identified the Mac_1 macrophage subpopulation as a key regulator of satellite-cell proliferation via paracrine HGF/c-MET signalling that suppresses Cdkn1b expression in MuSCs. In aged mice, Hgf expression was significantly reduced in Mac_1 macrophages (p<0.05, unpaired two-tailed Student’s t-test; Fig 3L), impairing c-MET activation in satellite cells and thereby blunting muscle regeneration. Administration of exogenous HGF to macrophage-depleted young mice and to aged mice partially restored regeneration ¹. This places the HGF-c-MET axis upstream of stem-cell-exhaustion in the skeletal muscle context.

c-MET expression on satellite cells has been demonstrated to decrease upon aging-related stimulation ⁴, consistent with reduced receptor-level responsiveness.

Dimension	Status	Notes
Pathway conserved in humans?	yes	MET/HGF pathway identical in human satellite cells
Phenotype conserved in humans?	partial	Human muscle shows age-related regeneration decline; c-MET specifically not yet confirmed causal in human aging RCTs
Replicated in humans?	no	Koike 2025 is in mouse; no human mechanistic replication needs-human-replication

Liver regeneration

Hepatocyte proliferation after partial hepatectomy depends on HGF-c-MET signalling. Age-related decline in liver regenerative capacity is broadly attributed in part to dampened HGF-MET tone, though the mechanistic dissection in humans is limited. no-mechanism — specific contribution of c-MET receptor versus ligand availability versus downstream signalling not resolved.

Oncogenic risk in aging contexts

Chronic or ectopic c-MET activation is pro-tumorigenic. MET amplification and MET-activating mutations accumulate with age. Any therapeutic strategy aimed at augmenting HGF-c-MET signalling for regenerative purposes must account for this oncogenic risk — a major barrier to aging-indication drug development. This is not an aging-context druggability failure of MET inhibitors, which are productive cancer drugs (see Pharmacology below), but it does mean HGF/MET agonism faces a high safety bar. long-term-unknown — chronic low-level MET stimulation in aged humans has not been studied for cancer risk.

Cancer biology and druggability

MET is a tier-1 druggable target in oncology, with two FDA-approved kinase inhibitors for MET-altered NSCLC as of 2026:

Drug	Target alteration	FDA approval	Key trial
Capmatinib (Tabrecta)	METex14 skipping mutations	May 2020	GEOMETRY mono-1
Tepotinib (Tepmetko)	METex14 skipping mutations	Feb 2021 (FDA); Mar 2020 (Japan)	VISION trial ⁵
Crizotinib	MET amplification (ALK/ROS1 too)	Established; various	Not MET-specific
Amivantamab (Rybrevant)	EGFR-MET bispecific	May 2021	PAPILLON (EGFR exon 20); CHRYSALIS

MET exon 14 skipping (METex14): splice-site mutations that result in loss of transcription of exon 14, eliminating the juxtamembrane domain that contains the Cbl E3-ligase binding site at Tyr1003, thus preventing ubiquitin-mediated receptor degradation. The result is prolonged MET surface expression and constitutive downstream signalling. METex14 defines an NSCLC molecular subtype occurring in 3 to 4% of NSCLC patients ⁵.

MET amplification: focal amplification of the MET locus, found in primary tumors (~1-3% NSCLC) and as an acquired resistance mechanism to EGFR inhibitors.

Druggability-tier note (aging-context): The tier-1 designation reflects FDA-approved drugs that engage MET, but all are oncology indications. For aging-indication MET modulation, the target would need a novel context — most plausibly a tissue-restricted or episodic HGF-MET agonist strategy. No aging-indication clinical program for MET exists as of 2026-05-09. needs-human-replication for any aging intervention claim.

Historical context: MET cloning and ligand identification

The MET protooncogene was identified in 1987 by Park et al. via cDNA sequencing from a human osteogenic sarcoma (HOS) cell line; the 4224-nucleotide ORF predicted a 1408-aa protein with features of the tyrosine kinase growth factor receptor family, including a 24-aa signal peptide and a 23-aa transmembrane segment, but with no ligand-binding domain homology to other known receptors. The paper concluded MET is “a cell-surface receptor for an as-yet-unknown ligand.” ⁶ The ligand was identified as HGF in 1991: Bottaro et al. demonstrated biochemically that the 145 kDa tyrosyl phosphoprotein activated by HGF is the c-met product ⁷. Together these papers established the HGF-c-MET axis as a growth factor receptor system.

Dihexa / Benoist 2014 — retracted mechanism claim

RETRACTED CLAIM — do not cite for mechanistic support.

Benoist et al. 2014 (JPET) claimed that dihexa (an angiotensin IV-derived peptide) binds HGF, induces c-MET phosphorylation, and that its procognitive/synaptogenic effects are blocked by an HGF antagonist — supporting a c-MET agonist mechanism ⁸. This paper was retracted in April 2025. The retraction undermines the Dihexa-c-MET mechanistic framing. An earlier McCoy et al. paper on Dihexa’s synaptogenic activity attributes the c-MET connection to “Benoist, Kawas, Harding, unpublished data” — this unpublished data has never appeared in the literature and the retraction removes the only peer-reviewed corroboration. As of 2026-05-09, the claim that Dihexa is a c-MET agonist has no peer-reviewed support. See dihexa for the full retraction context.

Key interactors

hgf — sole high-affinity ligand; induces receptor dimerisation and transactivation
grb2 — adapter linking pTyr1356 docking site to RAS and GAB1
pi3k-akt-pathway — major survival/proliferation downstream effector
ras-mapk — proliferation and motility downstream
jak-stat-pathway — via STAT3 recruitment at pTyr1356

Pathway membership

hgf-met-signaling — canonical axis (planned page; currently stub)
pi3k-akt-pathway — HGF-c-MET signals strongly through PI3K → AKT → mTORC1
ras-mapk — RAS-ERK arm drives proliferation and motility programs
jak-stat-pathway — STAT3 arm mediates morphogenic and anti-apoptotic transcription

Limitations and gaps

#gap/needs-human-replication — Aging-relevant HGF-c-MET biology (satellite cell activation decline, macrophage-mediated HGF loss) is established in mouse models (C57BL/6J); no human mechanistic RCT or MR-validated causal evidence for c-MET in aging phenotypes.
#gap/no-mechanism — Liver regeneration decline with age: HGF-MET contribution is inferred from rodent data; which component of the axis (ligand availability, receptor expression, downstream signalling) declines predominantly in human aging is unresolved.
#gap/long-term-unknown — Oncogenic risk of chronic episodic HGF-c-MET agonism in aged humans has not been studied; this is a critical safety gap for any regenerative-aging intervention strategy.
#gap/needs-replication — Koike 2025 macrophage-HGF-satellite-cell axis is a single study in mouse (n=4/group); human replication and mechanistic confirmation pending.
#gap/needs-replication — Ser985 juxtamembrane inhibitory phosphorylation attributed to PKC: not confirmed in UniProt P08581 or Birchmeier 2003; this claim was removed pending a primary source. The well-supported juxtamembrane regulatory site is Tyr1003 (Cbl docking).
gtex-aging-correlation: null — GTEx API query for MET expression by age not performed on this pass.
mr-causal-evidence: partial — MET locus GWAS hits exist (cancer association studies, deafness DFNB97 locus); no published MR study has leveraged these instruments for aging phenotypes.

Footnotes

doi:10.1111/acel.70042 · Koike H, Sugimura M, Ouchi R, Yoshimoto Y, Manabe I, Oishi Y · Aging Cell 2025 · n=4 per group (qPCR; C57BL/6J male; young=8 wk, aged=24 mo) · in-vivo + 3D muscle organoid · scRNA-seq identified Mac_1 macrophage subpopulation as key regulator of MuSC proliferation via HGF/c-MET signalling suppressing Cdkn1b; Hgf expression significantly reduced in aged Mac_1 macrophages (p<0.05); exogenous HGF partially rescued regeneration defect in aged and macrophage-depleted mice ↩ ↩²
doi:10.1038/nrm1261 · Birchmeier C et al. · Nat Rev Mol Cell Biol 2003 · review · comprehensive mechanistic review of MET/HGF signalling, docking site architecture, GAB1 scaffold biology, morphogenesis vs metastasis programs · 2577 citations; local PDF available at DOI lookup ↩ ↩² ↩³ ↩⁴
doi:10.1111/j.1740-0929.2009.00712.x · Tatsumi R et al. · Animal Science Journal 2010 · review/mechanistic · describes mechanosensing cascade: stretch → NO → HGF release → c-met activation → satellite cell activation; role of HGF-c-MET in myogenesis reviewed · not_oa locally ↩
doi:10.1152/japplphysiol.00437.2003 · Barani AE et al. · J Appl Physiol 2003 · in-vitro/ex-vivo (muscle-derived cells) · age-related decline in c-met responsiveness in satellite cell preparations; reduced mitotic characteristics in aged cells · not_oa locally ↩
doi:10.1056/NEJMoa2004407 · Paik PK et al. · N Engl J Med 2020 · n=152 (safety population); n=99 (efficacy/combined-biopsy population with ≥9 mo follow-up) · phase-2, single-arm, open-label (VISION trial; NCT02864992) · tepotinib 500 mg/day in advanced NSCLC with METex14 skipping mutations; objective response rate 46% (95% CI 36–57) by independent review in combined-biopsy group; 68% (95% CI 48–84) in treatment-naive patients (n=28); median duration of response 11.1 mo; METex14 occurs in 3–4% of NSCLC; peripheral edema most common grade ≥3 AE (7%) ↩ ↩²
doi:10.1073/pnas.84.18.6379 · Park M, Dean M, Kaul K, Braun MJ, Gonda MA, Vande Woude G · PNAS 1987 · n=not applicable (molecular cloning) · in-vitro (cDNA library, HOS cell line, sequence analysis) · sequenced MET protooncogene cDNA; 4224-nt ORF predicting 1408-aa receptor tyrosine kinase; 24-aa signal peptide, 23-aa TM domain, 435-aa intracellular domain; no ligand identified; concluded MET is a cell-surface receptor for an unknown ligand ↩
doi:10.1126/science.1846706 · Bottaro DP et al. · Science 1991 · n=not applicable (biochemical) · in-vitro (immunoprecipitation, cross-linking) · identified c-met product as the cell-surface receptor activated by HGF; established the HGF-c-MET ligand-receptor pairing · 2232 citations; not_oa locally ↩
RETRACTED — doi:10.1124/jpet.114.218735 · Benoist CC et al. · JPET 2014 · retracted April 2025 · originally claimed Dihexa/Nle1-AngIV binds HGF with high affinity and induces c-MET phosphorylation, with procognitive effects blocked by HGF antagonist; retraction removes the only peer-reviewed support for the Dihexa-c-MET mechanism. Do NOT cite for mechanistic claims. ↩

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