MET
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]
Full Name
MET Proto-Oncogene, Receptor Tyrosine Kinase
Function
Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand. Regulates many physiological processes including proliferation, scattering, morphogenesis and survival. Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1, SRC, GRB2, STAT3 or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. The RAS-ERK activation is associated with the morphogenetic effects while PI3K/AKT coordinates prosurvival effects. During embryonic development, MET signaling plays a role in gastrulation, development and migration of muscles and neuronal precursors, angiogenesis and kidney formation. In adults, participates in wound healing as well as organ regeneration and tissue remodeling. Promotes also differentiation and proliferation of hematopoietic cells. May regulate cortical bone osteogenesis (By similarity).
(Microbial infection) Acts as a receptor for Listeria monocytogenes internalin InlB, mediating entry of the pathogen into cells.
Biological Process
Branching morphogenesis of an epithelial tube Source: UniProtKB
Cell migration Source: GO_Central
Cell surface receptor signaling pathway Source: UniProtKB
Endothelial cell morphogenesis Source: UniProtKB
Entry of bacterium into host cell Source: Reactome
Establishment of skin barrier Source: CAFA
Liver development Source: GO_Central
MAPK cascade Source: Reactome
Multicellular organism development Source: GO_Central
Negative regulation of autophagy Source: ParkinsonsUK-UCL
Negative regulation of guanyl-nucleotide exchange factor activity Source: CAFA
Negative regulation of hydrogen peroxide-mediated programmed cell death Source: BHF-UCL
Negative regulation of Rho protein signal transduction Source: CAFA
Negative regulation of stress fiber assembly Source: CAFA
Negative regulation of thrombin-activated receptor signaling pathway Source: CAFA
Nervous system development Source: GO_Central
Neuron differentiation Source: GO_Central
Pancreas development Source: GO_Central
Phagocytosis Source: GO_Central
Positive chemotaxis Source: UniProtKB
Positive regulation of endothelial cell chemotaxis Source: UniProtKB
Positive regulation of kinase activity Source: GO_Central
Positive regulation of microtubule polymerization Source: CAFA
Positive regulation of protein kinase B signaling Source: GO_Central
Positive regulation of transcription by RNA polymerase II Source: BHF-UCL
Semaphorin-plexin signaling pathway Source: UniProtKB
Signal transduction Source: ProtInc
Transmembrane receptor protein tyrosine kinase signaling pathway Source: GO_Central
Cellular Location
Membrane
Isoform 3: Secreted
Involvement in disease
Activation of MET after rearrangement with the TPR gene produces an oncogenic protein.
Defects in MET may be associated with gastric cancer.
Hepatocellular carcinoma (HCC):
A primary malignant neoplasm of epithelial liver cells. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes.
Renal cell carcinoma papillary (RCCP):
A subtype of renal cell carcinoma tending to show a tubulo-papillary architecture formed by numerous, irregular, finger-like projections of connective tissue. Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium.
A common allele in the promoter region of the MET shows genetic association with susceptibility to autism in some families. Functional assays indicate a decrease in MET promoter activity and altered binding of specific transcription factor complexes.
MET activating mutations may be involved in the development of a highly malignant, metastatic syndrome known as cancer of unknown primary origin (CUP) or primary occult malignancy. Systemic neoplastic spread is generally a late event in cancer progression. However, in some instances, distant dissemination arises at a very early stage, so that metastases reach clinical relevance before primary lesions. Sometimes, the primary lesions cannot be identified in spite of the progresses in the diagnosis of malignancies.
Deafness, autosomal recessive, 97 (DFNB97):
A form of non-syndromic sensorineural hearing loss with prelingual onset. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information.
Osteofibrous dysplasia (OSFD):
Disease susceptibility is associated with variants affecting the gene represented in this entry. Disease-associated variants identified in 4 families cause the deletion of exon 14. This results in the exclusion of an ubiquitination target site within the cytoplasmic domain, hence in protein stabilization. The persistent presence of MET at the cell surface in conditions of ligand-dependent activation retards osteoblastic differentiation.
A congenital disorder of osteogenesis characterized by non-neoplastic, radiolucent lesions that affect the cortical bone immediately under the periosteum. It usually manifests as a painless swelling or anterior bowing of the long bones, most commonly the tibia and fibula.
Topology
Extracellular: 25-932
Helical: 933-955
Cytoplasmic: 956-1390
PTM
Autophosphorylated in response to ligand binding on Tyr-1234 and Tyr-1235 in the kinase domain leading to further phosphorylation of Tyr-1349 and Tyr-1356 in the C-terminal multifunctional docking site. Dephosphorylated by PTPRJ at Tyr-1349 and Tyr-1365. Dephosphorylated by PTPN1 and PTPN2.
Ubiquitinated. Ubiquitination by CBL regulates MET endocytosis, resulting in decreasing plasma membrane receptor abundance, and in endosomal degradation and/or recycling of internalized receptors.
(Microbial infection) Tyrosine phosphorylation is stimulated by L.monocytogenes InlB. Tyrosine phosphorylation is maximal 10-20 minutes after treatment with InlB and disappears by 60 minutes. The phosphorylated residues were not identified.
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