ID:MET_HUMAN DESCRIPTION: RecName: Full=Hepatocyte growth factor receptor; Short=HGF receptor; EC=2.7.10.1; AltName: Full=HGF/SF receptor; AltName: Full=Proto-oncogene c-Met; AltName: Full=Scatter factor receptor; Short=SF receptor; AltName: Full=Tyrosine-protein kinase Met; Flags: Precursor; 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. FUNCTION: Acts as a receptor for Listeria internalin inlB, mediating entry of the pathogen into cells. CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. ENZYME REGULATION: In its inactive state, the C-terminal tail interacts with the catalytic domain and inhibits the kinase activity. Upon ligand binding, the C-terminal tail is displaced and becomes phosphorylated, thus increasing the kinase activity. SUBUNIT: Heterodimer made of an alpha chain (50 kDa) and a beta chain (145 kDa) which are disulfide linked. Binds PLXNB1. Interacts when phosphorylated with downstream effectors including STAT3, PIK3R1, SRC, PCLG1, GRB2 and GAB1. Interacts with SPSB1, SPSB2 and SPSB4 (By similarity). Interacts with INPP5D/SHIP1. When phosphorylated at Tyr-1356, interacts with INPPL1/SHIP2. Interacts with RANBP9 and RANBP10, as well as SPSB1, SPSB2, SPSB3 and SPSB4. SPSB1 binding occurs in the presence and in the absence of HGF, however HGF treatment has a positive effect on this interaction. Interacts with MUC20; prevents interaction with GRB2 and suppresses hepatocyte growth factor-induced cell proliferation. Interacts with GRB10. INTERACTION: Q96EY1-2:DNAJA3; NbExp=2; IntAct=EBI-1039152, EBI-3952284; P00533:EGFR; NbExp=4; IntAct=EBI-1039152, EBI-297353; P14210:HGF; NbExp=2; IntAct=EBI-1039152, EBI-1039104; P25147:inlB (xeno); NbExp=4; IntAct=EBI-1039152, EBI-1379295; P35968:KDR; NbExp=3; IntAct=EBI-1039152, EBI-1005487; P35918:Kdr (xeno); NbExp=3; IntAct=EBI-1039152, EBI-1555005; O43157:PLXNB1; NbExp=7; IntAct=EBI-1039152, EBI-1111488; O15031:PLXNB2; NbExp=2; IntAct=EBI-1039152, EBI-722004; Q9ULL4:PLXNB3; NbExp=2; IntAct=EBI-1039152, EBI-311073; Q00944:PTK2 (xeno); NbExp=5; IntAct=EBI-1039152, EBI-2896409; SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane protein. SUBCELLULAR LOCATION: Isoform 3: Secreted. TISSUE SPECIFICITY: Expressed in normal hepatocytes as well as in epithelial cells lining the stomach, the small and the large intestine. Found also in basal keratinocytes of esophagus and skin. High levels are found in liver, gastrointestinal tract, thyroid and kidney. Also present in the brain. DOMAIN: The kinase domain is involved in SPSB1 binding. DOMAIN: The beta-propeller Sema domain mediates binding to HGF. 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. PTM: Dephosphorylated by PTPRJ at Tyr-1349 and Tyr-1365. PTM: Ubiquitinated. Ubiquitination by CBL regulates the receptor stability and activity through proteasomal degradation. DISEASE: Note=Activation of MET after rearrangement with the TPR gene produces an oncogenic protein. DISEASE: Note=Defects in MET may be associated with gastric cancer. DISEASE: Defects in MET are a cause of hepatocellular carcinoma (HCC) [MIM:114550]. DISEASE: Defects in MET are a cause of renal cell carcinoma papillary (RCCP) [MIM:605074]. It is 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. It is subclassified into common renal cell carcinoma (clear cell, non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma. DISEASE: Note=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. DISEASE: Note=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. SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein kinase family. SIMILARITY: Contains 3 IPT/TIG domains. SIMILARITY: Contains 1 protein kinase domain. SIMILARITY: Contains 1 Sema domain. WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/METID131.html"; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/MET"; WEB RESOURCE: Name=Wikipedia; Note=C-MET entry; URL="http://en.wikipedia.org/wiki/C-MET";
ModBase Predicted Comparative 3D Structure on P08581
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Other Names for This Gene
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Methods, Credits, and Use Restrictions
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