MET

Official Full Name

MET proto-oncogene, receptor tyrosine kinase

Organism

Homo sapiens

GeneID

4233

Background

This gene encodes a member of the receptor tyrosine kinase family of proteins and the product of the proto-oncogene MET. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that are linked via disulfide bonds to form the mature receptor. Further processing of the beta subunit results in the formation of the M10 peptide, which has been shown to reduce lung fibrosis. Binding of its ligand, hepatocyte growth factor, induces dimerization and activation of the receptor, which plays a role in cellular survival, embryogenesis, and cellular migration and invasion. Mutations in this gene are associated with papillary renal cell carcinoma, hepatocellular carcinoma, and various head and neck cancers. Amplification and overexpression of this gene are also associated with multiple human cancers. [provided by RefSeq, May 2016]

Synonyms

DA11; HGFR; AUTS9; RCCP2; c-Met; DFNB97;

Bio Chemical Class

Kinase

Protein Sequence

MKAPAVLAPGILVLLFTLVQRSNGECKEALAKSEMNVNMKYQLPNFTAETPIQNVILHEHHIFLGATNYIYVLNEEDLQKVAEYKTGPVLEHPDCFPCQDCSSKANLSGGVWKDNINMALVVDTYYDDQLISCGSVNRGTCQRHVFPHNHTADIQSEVHCIFSPQIEEPSQCPDCVVSALGAKVLSSVKDRFINFFVGNTINSSYFPDHPLHSISVRRLKETKDGFMFLTDQSYIDVLPEFRDSYPIKYVHAFESNNFIYFLTVQRETLDAQTFHTRIIRFCSINSGLHSYMEMPLECILTEKRKKRSTKKEVFNILQAAYVSKPGAQLARQIGASLNDDILFGVFAQSKPDSAEPMDRSAMCAFPIKYVNDFFNKIVNKNNVRCLQHFYGPNHEHCFNRTLLRNSSGCEARRDEYRTEFTTALQRVDLFMGQFSEVLLTSISTFIKGDLTIANLGTSEGRFMQVVVSRSGPSTPHVNFLLDSHPVSPEVIVEHTLNQNGYTLVITGKKITKIPLNGLGCRHFQSCSQCLSAPPFVQCGWCHDKCVRSEECLSGTWTQQICLPAIYKVFPNSAPLEGGTRLTICGWDFGFRRNNKFDLKKTRVLLGNESCTLTLSESTMNTLKCTVGPAMNKHFNMSIIISNGHGTTQYSTFSYVDPVITSISPKYGPMAGGTLLTLTGNYLNSGNSRHISIGGKTCTLKSVSNSILECYTPAQTISTEFAVKLKIDLANRETSIFSYREDPIVYEIHPTKSFISGGSTITGVGKNLNSVSVPRMVINVHEAGRNFTVACQHRSNSEIICCTTPSLQQLNLQLPLKTKAFFMLDGILSKYFDLIYVHNPVFKPFEKPVMISMGNENVLEIKGNDIDPEAVKGEVLKVGNKSCENIHLHSEAVLCTVPNDLLKLNSELNIEWKQAISSTVLGKVIVQPDQNFTGLIAGVVSISTALLLLLGFFLWLKKRKQIKDLGSELVRYDARVHTPHLDRLVSARSVSPTTEMVSNESVDYRATFPEDQFPNSSQNGSCRQVQYPLTDMSPILTSGDSDISSPLLQNTVHIDLSALNPELVQAVQHVVIGPSSLIVHFNEVIGRGHFGCVYHGTLLDNDGKKIHCAVKSLNRITDIGEVSQFLTEGIIMKDFSHPNVLSLLGICLRSEGSPLVVLPYMKHGDLRNFIRNETHNPTVKDLIGFGLQVAKGMKYLASKKFVHRDLAARNCMLDEKFTVKVADFGLARDMYDKEYYSVHNKTGAKLPVKWMALESLQTQKFTTKSDVWSFGVLLWELMTRGAPPYPDVNTFDITVYLLQGRRLLQPEYCPDPLYEVMLKCWHPKAEMRPSFSELVSRISAIFSTFIGEHYVHVNATYVNVKCVAPYPSLLSSEDNADDEVDTRPASFWETS

Open

Disease

Alzheimer disease, Biliary tract cancer, Brain cancer, Breast cancer, Cardiovascular disease, Chronic arterial occlusive disease, Colorectal cancer, Fibrosis, Glaucoma, Head and neck cancer, Heart disease, Injury, Liver cancer, Liver disease, Lung cancer, Melanoma, Metastatic lymph node neoplasm, Nasopharyngitis, Non-small-cell lung cancer, Ovarian cancer, Renal cell carcinoma, Sarcoma, Solid tumour/cancer, Stomach cancer, Thyroid cancer

Approved Drug

5 +

Clinical Trial Drug

44 +

Discontinued Drug

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Detailed Information

The MET proto-oncogene, located on chromosome 7q31.2, encodes the Hepatocyte Growth Factor (HGF) Receptor, a receptor tyrosine kinase (RTK). This gene belongs to a subfamily of RTKs characterized by a unique disulfide-linked heterodimeric structure, formed by the proteolytic cleavage of a single-chain precursor glycoprotein. The mature MET receptor consists of a 50 kDa extracellular alpha chain and a 145 kDa transmembrane beta chain. The extracellular region contains several domains: a Sema domain (important for ligand binding and receptor dimerization), a PSI domain, and four IPT repeats. The intracellular beta chain features a tyrosine kinase domain, a juxtamembrane (JM) domain, and a multifunctional docking site (Y1349VHVNATY1356VNV) in the C-terminal tail that recruits downstream signaling adaptors. Additionally, a proteolytic step within the beta chain generates the M10 peptide, which exhibits anti-fibrotic properties. MET shares structural homology and functional interplay with its paralog MST1R (RON). Gene Ontology annotations reflect its intrinsic protein tyrosine kinase activity and its role in pathways regulating GPCR signaling and apoptosis in specific cells, like synovial fibroblasts.

Biological Significance and Functional Mechanisms

MET is the high-affinity receptor for Hepatocyte Growth Factor/Scatter Factor (HGF/SF), a multifunctional cytokine produced by mesenchymal cells. The MET-HGF axis regulates a biological program termed "invasive growth," integrating proliferation, survival, motility, invasion, and morphogenesis. Ligand binding induces MET homodimerization and phosphorylation of tyrosine residues within the kinase domain and docking site (Y1349, Y1356). This phosphorylation creates binding sites for SH2 domain-containing adaptor proteins (e.g., GRB2, GAB1, PLCγ, SHP2, and PI3K p85), with GAB1 playing a critical role in amplifying the signal. Downstream signaling pathways activated include the RAS-MAPK (proliferation and morphogenesis), PI3K-AKT (survival and motility), and SRC-FAK (adhesion and cytoskeletal dynamics). Additionally, PLCγ activation generates second messengers for PKC activation and calcium mobilization, while STAT3 transcription factor recruitment contributes to specific transcriptional responses.

In embryonic development, MET signaling is essential for processes like gastrulation, myogenic precursor migration, and the formation of the placenta, liver, and kidney. In adults, MET expression is low but critical for tissue homeostasis, regeneration (e.g., liver regeneration, wound healing), and angiogenesis. MET also promotes epithelial-mesenchymal transition (EMT), a key process in cancer metastasis. Furthermore, Listeria monocytogenes exploits MET as an entry receptor for host cell invasion.

Clinical Relevance and Therapeutic Targeting

Dysregulation of the MET-HGF signaling pathway drives tumorigenesis and metastasis across many cancers. MET activation occurs via multiple mechanisms, each with diagnostic and therapeutic implications:

Gene Amplification and Overexpression: Common in gastric, esophageal, lung, and colorectal cancers, leading to receptor overexpression and constitutive kinase activation.
Activating Point Mutations: Mutations in the Sema domain (ligand binding/dimerization), juxtamembrane domain (negative regulation), and kinase domain. Germline mutations cause hereditary papillary renal cell carcinoma (HPRCC).
Exon 14 Skipping Mutations: Leads to JM domain deletion, impairing receptor downregulation and enhancing oncogenic potential, prevalent in lung adenocarcinomas, sarcomas, and other cancers.
Gene Fusions: Chromosomal rearrangements create fusion proteins that lead to ligand-independent dimerization and kinase activation, observed in glioblastoma, thyroid cancer, and lung cancer.
HGF Overexpression: Autocrine or paracrine loops sustain receptor activation, promoting tumor growth, survival, angiogenesis, and metastasis.

Figure 1. Mechanism of resistance to MET target therapies. (Rivas S, et al., 2022)

Several classes of MET inhibitors have been developed:

Monoclonal Antibodies (mAbs): Targeting the extracellular domain of MET or HGF, though clinical success with mAbs has been limited.
Tyrosine Kinase Inhibitors (TKIs): Small molecules targeting the MET kinase domain. Multitargeted TKIs inhibit MET alongside other targets but lack specificity.

Selective MET TKIs like Capmatinib and Tepotinib are FDA-approved for MET exon 14 skipping mutations in non-small cell lung cancer (NSCLC). Savolitinib is approved in China for METex14+ NSCLC. Ongoing development aims to overcome resistance mechanisms such as on-target kinase mutations (e.g., D1228, Y1230) and off-target bypass mechanisms.

The clinical success of selective MET inhibitors marks a major advance in precision oncology, emphasizing the need for molecular diagnostics to identify patients most likely to benefit from MET-targeted therapies.

References:

Rivas S, Marín A, Samtani S, et al. MET Signaling Pathways, Resistance Mechanisms, and Opportunities for Target Therapies. Int J Mol Sci. 2022 Nov 11;23(22):13898.
Comoglio PM, Trusolino L, Boccaccio C. Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy. Nat Rev Cancer. 2018 Jun;18(6):341-358.

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