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MGP001909

UniProt Annotations

Entry Information
Gene NameMET proto-oncogene, receptor tyrosine kinase
Protein EntryMET_HUMAN
UniProt IDP08581
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=3; Comment=Additional soluble isoforms seem to exist.; Name=1; IsoId=P08581-1; Sequence=Displayed; Name=2; IsoId=P08581-2; Sequence=VSP_005005; Note=No experimental confirmation available.; Name=3; Synonyms=Soluble MET variant 4; IsoId=P08581-3; Sequence=VSP_042447, VSP_042448;
Catalytic ActivityATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. {ECO:0000255|PROSITE- ProRule:PRU10028}.
DiseaseHepatocellular carcinoma (HCC) [MIM:114550]: 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. {ECO:0000269|PubMed:9927037}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseaseNote=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.
DiseaseNote=Activation of MET after rearrangement with the TPR gene produces an oncogenic protein.
DiseaseNote=Defects in MET may be associated with gastric cancer.
DiseaseNote=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.
DiseaseRenal cell carcinoma papillary (RCCP) [MIM:605074]: 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. {ECO:0000269|PubMed:10327054, ECO:0000269|PubMed:10417759, ECO:0000269|PubMed:10433944, ECO:0000269|PubMed:9140397, ECO:0000269|PubMed:9563489}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DomainThe beta-propeller Sema domain mediates binding to HGF.
DomainThe kinase domain is involved in SPSB1 binding.
Enzyme RegulationIn 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.
FunctionActs as a receptor for Listeria internalin inlB, mediating entry of the pathogen into cells.
FunctionReceptor 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.
InteractionP22681:CBL; NbExp=15; IntAct=EBI-1039152, EBI-518228; Q96EY1-2:DNAJA3; NbExp=2; IntAct=EBI-1039152, EBI-3952284; P00533:EGFR; NbExp=7; IntAct=EBI-1039152, EBI-297353; P09769:FGR; NbExp=2; IntAct=EBI-1039152, EBI-1383732; P14210:HGF; NbExp=4; IntAct=EBI-1039152, EBI-1039104; P14210-6:HGF; NbExp=2; IntAct=EBI-1039152, EBI-6280319; P25147:inlB (xeno); NbExp=4; IntAct=EBI-1039152, EBI-1379295; O15357:INPPL1; NbExp=2; IntAct=EBI-1039152, EBI-1384248; P35968:KDR; NbExp=3; IntAct=EBI-1039152, EBI-1005487; P35918:Kdr (xeno); NbExp=3; IntAct=EBI-1039152, EBI-1555005; P06239:LCK; NbExp=3; IntAct=EBI-1039152, EBI-1348; P07948:LYN; NbExp=2; IntAct=EBI-1039152, EBI-79452; P15941:MUC1; NbExp=2; IntAct=EBI-1039152, EBI-2804728; P16333:NCK1; NbExp=2; IntAct=EBI-1039152, EBI-389883; O43639:NCK2; NbExp=2; IntAct=EBI-1039152, EBI-713635; P27986:PIK3R1; NbExp=6; IntAct=EBI-1039152, EBI-79464; O00459:PIK3R2; NbExp=11; IntAct=EBI-1039152, EBI-346930; Q92569:PIK3R3; NbExp=11; IntAct=EBI-1039152, EBI-79893; P19174:PLCG1; NbExp=10; IntAct=EBI-1039152, EBI-79387; 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; P18031:PTPN1; NbExp=3; IntAct=EBI-1039152, EBI-968788; Q06124:PTPN11; NbExp=13; IntAct=EBI-1039152, EBI-297779; P23467:PTPRB; NbExp=2; IntAct=EBI-1039152, EBI-1265766; Q12913:PTPRJ; NbExp=5; IntAct=EBI-1039152, EBI-2264500; P20936:RASA1; NbExp=15; IntAct=EBI-1039152, EBI-1026476; Q9UQQ2:SH2B3; NbExp=2; IntAct=EBI-1039152, EBI-7879749; O60880:SH2D1A; NbExp=3; IntAct=EBI-1039152, EBI-6983382; O14796:SH2D1B; NbExp=6; IntAct=EBI-1039152, EBI-3923013; Q9NP31:SH2D2A; NbExp=7; IntAct=EBI-1039152, EBI-490630; Q8N5H7:SH2D3C; NbExp=4; IntAct=EBI-1039152, EBI-745980; Q15464:SHB; NbExp=4; IntAct=EBI-1039152, EBI-4402156; P29353:SHC1; NbExp=5; IntAct=EBI-1039152, EBI-78835; P98077:SHC2; NbExp=2; IntAct=EBI-1039152, EBI-7256023; Q6S5L8:SHC4; NbExp=3; IntAct=EBI-1039152, EBI-9453524; Q96IW2:SHD; NbExp=2; IntAct=EBI-1039152, EBI-4402781; Q9H6Q3:SLA2; NbExp=4; IntAct=EBI-1039152, EBI-1222854; O75159:SOCS5; NbExp=2; IntAct=EBI-1039152, EBI-970130; O14544:SOCS6; NbExp=4; IntAct=EBI-1039152, EBI-3929549; P12931:SRC; NbExp=4; IntAct=EBI-1039152, EBI-621482; Q9ULZ2:STAP1; NbExp=3; IntAct=EBI-1039152, EBI-6083058; P43405:SYK; NbExp=3; IntAct=EBI-1039152, EBI-78302; P42680:TEC; NbExp=2; IntAct=EBI-1039152, EBI-1383480; Q63HR2:TENC1; NbExp=2; IntAct=EBI-1039152, EBI-949753; Q9HBL0:TNS1; NbExp=2; IntAct=EBI-1039152, EBI-3389814; Q68CZ2:TNS3; NbExp=3; IntAct=EBI-1039152, EBI-1220488; Q9UKW4:VAV3; NbExp=2; IntAct=EBI-1039152, EBI-297568; P07947:YES1; NbExp=3; IntAct=EBI-1039152, EBI-515331; P43403:ZAP70; NbExp=2; IntAct=EBI-1039152, EBI-1211276;
PtmAutophosphorylated 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. {ECO:0000269|PubMed:12475979, ECO:0000269|PubMed:15735664, ECO:0000269|PubMed:1655790, ECO:0000269|PubMed:18669648, ECO:0000269|PubMed:18691976, ECO:0000269|PubMed:18819921, ECO:0000269|PubMed:19369195, ECO:0000269|PubMed:7513258}.
PtmUbiquitinated. Ubiquitination by CBL regulates the receptor stability and activity through proteasomal degradation. {ECO:0000269|PubMed:12244174}.
SimilarityBelongs to the protein kinase superfamily. Tyr protein kinase family. {ECO:0000255|PROSITE-ProRule:PRU00159}.
SimilarityContains 1 protein kinase domain. {ECO:0000255|PROSITE-ProRule:PRU00159}.
SimilarityContains 1 Sema domain. {ECO:0000255|PROSITE- ProRule:PRU00352}.
SimilarityContains 3 IPT/TIG domains. {ECO:0000305}.
Subcellular LocationIsoform 3: Secreted.
Subcellular LocationMembrane; Single-pass type I membrane protein.
SubunitHeterodimer 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. Interacts with PTPN1 and PTPN2. {ECO:0000250, ECO:0000269|PubMed:10454568, ECO:0000269|PubMed:11063574, ECO:0000269|PubMed:12147692, ECO:0000269|PubMed:12198496, ECO:0000269|PubMed:14559966, ECO:0000269|PubMed:14684163, ECO:0000269|PubMed:15167892, ECO:0000269|PubMed:15314156, ECO:0000269|PubMed:15713673, ECO:0000269|PubMed:15735664, ECO:0000269|PubMed:1718989, ECO:0000269|PubMed:17662939, ECO:0000269|PubMed:18819921, ECO:0000269|PubMed:21784853, ECO:0000269|PubMed:7513258, ECO:0000269|PubMed:9440692}.
Tissue SpecificityExpressed 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. {ECO:0000269|PubMed:1719465, ECO:0000269|PubMed:1917129}.
Web ResourceName=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/METID131.html";
Web ResourceName=Wikipedia; Note=C-MET entry; URL="http://en.wikipedia.org/wiki/C-MET";
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