MET_HUMAN » Hepatocyte growth factor receptor

MET_HUMAN » Hepatocyte growth factor receptor
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Topology in Plasma membrane
Topologyextracellular side
cytoplasmic side
MET_HUMAN » Hepatocyte growth factor receptor » HGF receptor; HGF/SF receptor;Proto-oncogene c-Met;Scatter factor receptor;SF receptor; Tyrosine-protein kinase Met;
Hydrophobic Thickness 34.0 ± 2.2 Å
Tilt Angle 0 ± 2°
ΔGtransfer -42.2 kcal/mol
ΔGfold -21.6 kcal/mol
Links UniProtKB, Pfam, Interpro, iHOP, STRING, HGNC, Reactome
Topology Out
TM Segments 931-955 (927-959)
Pathways

Adherens junction (KEGG)

Axon guidance (KEGG)

Bacterial invasion of epithelial cells (KEGG)

Cytokine-cytokine receptor interaction (KEGG)

Developmental Biology (Reactome)

Endocytosis (KEGG)

Epithelial cell signaling in Helicobacter pylori infection (KEGG)

Focal adhesion (KEGG)

glucose and glucose-1-phosphate degradation (BioCyc)

Malaria (KEGG)

Melanoma (KEGG)

methionine degradation I (to homocysteine) (BioCyc)

methylmalonyl pathway (BioCyc)

Pathways in cancer (KEGG)

PI3K-Akt signaling pathway (KEGG)

Proteoglycans in cancer (KEGG)

Renal cell carcinoma (KEGG)

Transcriptional misregulation in cancer (KEGG)

PDB 3vw8 (1024-1352), 4eev (1038-1346), 3rhk (1038-1346), 4gg5 (1038-1346), 2g15 (1038-1346), 4gg7 (1038-1346), 4mxc (1038-1346), 3q6w (1048-1348), 3q6u (1048-1348), 4iwd (1048-1348), 3r7o (1048-1348), 4xmo (1048-1350), 3cd8 (1048-1350), 3ccn (1048-1350), 3i5n (1048-1350), 4deh (1048-1351), 4dei (1048-1351), 2rfs (1048-1351), 4xyf (1048-1351), 2rfn (1048-1351), 4deg (1048-1351), 3l8v (1049-1360), 3f82 (1049-1360), 3dkg (1049-1360), 3dkf (1049-1360), 1r0p (1049-1360), 1r1w (1049-1360), 3a4p (1049-1360), 3c1x (1049-1360), 3ce3 (1049-1360), 3cth (1049-1360), 3ctj (1049-1360), 3dkc (1049-1360), 3qti (1050-1360), 3zze (1051-1348), 3zcl (1051-1348), 3zxz (1051-1348), 4aoi (1051-1348), 4ap7 (1051-1348), 3zc5 (1051-1348), 3zbx (1051-1348), 2wgj (1051-1348), 3lq8 (1051-1348), 2wkm (1051-1348), 3f66 (1052-1349), 2wd1 (1055-1346), 4knb (1060-1346), 1ssl (519-562), 3efj (A/B=1048-1351), 3efk (A/B=1048-1351), 3bux (A/C=997-1009), 3u6h (A=1048-1351), 3u6i (A=1048-1351), 2uzy (B/D=25-740), 2uzx (B/D=25-740), 4o3u (B=25-567), 4o3t (B=25-567), 1shy (B=25-567), 4k3j (B=39-564), 1fyr (I/J/K/L=1356-1359)
OPM none
Complexes

MET:MET_HUMAN

Interactions

CADH1, Complex: CADH1:MET, PubMed

CD44, Complex: CD44:MET, PubMed

EGFR, Complex: MET:EGFR, PubMed

ITB4, Complex: MET:ITB4, PubMed

LRIG1, Complex: MET:LRIG1, PubMed

MET, Complex: Homodimer of hepatocyte growth factor receptor, PDBID: 3EFJ

MUC1, Complex: MUC1:MET, PubMed

PLXB1, Complex: PLXB1:MET, PubMed

PLXB2, Complex: MET:PLXB2

PLXB3, Complex: MET:PLXB3

PTPRB, Complex: MET:PTPRB, PubMed

PTPRC, Complex: PTPRC:MET

PTPRG, Complex: MET:PTPRG

PTPRJ, Complex: PTPRJ:MET, PubMed

PTPRK, Complex: PTPRK:MET

PTPRO, Complex: MET:PTPRO

TNR6, Complex: TNR6:MET, PubMed

VGFR2, Complex: MET:VGFR2, PubMed

Domains

AA: 55-496, PDBID: 1SHY, Subunit B, Seq Identity:100%, Sema domain

AA: 519-562, PDBID: 1SHY, Subunit B, Seq Identity:100%, Plexin repeat

AA: 563-654, PDBID: 2UZX, Subunit B, Seq Identity:100%, IPT/TIG domain

AA: 657-738, PDBID: 2UZY, Subunit B, Seq Identity:100%, IPT/TIG domain

AA: 742-831, PDBID: 2UZY, Subunit B, Seq Identity:27%, IPT/TIG domain

AA: 1078-1337, PDBID: 1R0P, Subunit A, Seq Identity:100%, Protein tyrosine kinase

UniProt annotation for MET_HUMAN » Hepatocyte growth factor receptor
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. Interacts with PTPN1 and PTPN2.

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.

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: Hepatocellular carcinoma (HCC) OMIM: 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. caused by mutations affecting the gene represented in this entry.

DISEASE: Renal cell carcinoma papillary (RCCP) OMIM: 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. mutations affecting the gene represented in this entry.

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.

UniProt features for MET_HUMAN » Hepatocyte growth factor receptor
SIGNAL 1 24 Potential.
CHAIN 25 1390 Hepatocyte growth factor receptor.
DOMAIN 27 515 Sema.
DOMAIN 563 655 IPT/TIG 1.
DOMAIN 657 739 IPT/TIG 2.
DOMAIN 742 836 IPT/TIG 3.
DOMAIN 1078 1345 Protein kinase.
REGION 1212 1390 Interaction with RANBP9.
REGION 1320 1359 Interaction with MUC20.
ACT_SITE 1204 1204 Proton acceptor (By similarity).
SITE 307 308 Cleavage (Potential).
SITE 1009 1010 Breakpoint for translocation to form TPR- MET oncogene.
DISULFID 95 101
DISULFID 98 160
DISULFID 133 141
DISULFID 172 175
DISULFID 298 363
DISULFID 385 397
DISULFID 520 538
DISULFID 526 561
DISULFID 529 545
DISULFID 541 551
Amino Acid Sequence for MET_HUMAN » Hepatocyte growth factor receptor
MKAPAVLAPG ILVLLFTLVQ RSNGECKEAL AKSEMNVNMK YQLPNFTAET PIQNVILHEH HIFLGATNYI YVLNEEDLQK VAEYKTGPVL EHPDCFPCQD CSSKANLSGG VWKDNINMAL VVDTYYDDQL ISCGSVNRGT CQRHVFPHNH TADIQSEVHC IFSPQIEEPS QCPDCVVSAL GAKVLSSVKD RFINFFVGNT INSSYFPDHP LHSISVRRLK ETKDGFMFLT DQSYIDVLPE FRDSYPIKYV HAFESNNFIY FLTVQRETLD AQTFHTRIIR FCSINSGLHS YMEMPLECIL TEKRKKRSTK KEVFNILQAA YVSKPGAQLA RQIGASLNDD ILFGVFAQSK PDSAEPMDRS AMCAFPIKYV NDFFNKIVNK NNVRCLQHFY GPNHEHCFNR TLLRNSSGCE ARRDEYRTEF TTALQRVDLF MGQFSEVLLT SISTFIKGDL TIANLGTSEG RFMQVVVSRS GPSTPHVNFL LDSHPVSPEV IVEHTLNQNG YTLVITGKKI TKIPLNGLGC RHFQSCSQCL SAPPFVQCGW CHDKCVRSEE CLSGTWTQQI CLPAIYKVFP NSAPLEGGTR LTICGWDFGF RRNNKFDLKK TRVLLGNESC TLTLSESTMN TLKCTVGPAM NKHFNMSIII SNGHGTTQYS TFSYVDPVIT SISPKYGPMA GGTLLTLTGN YLNSGNSRHI SIGGKTCTLK SVSNSILECY TPAQTISTEF AVKLKIDLAN RETSIFSYRE DPIVYEIHPT KSFISGGSTI TGVGKNLNSV SVPRMVINVH EAGRNFTVAC QHRSNSEIIC CTTPSLQQLN LQLPLKTKAF FMLDGILSKY FDLIYVHNPV FKPFEKPVMI SMGNENVLEI KGNDIDPEAV KGEVLKVGNK SCENIHLHSE AVLCTVPNDL LKLNSELNIE WKQAISSTVL GKVIVQPDQN FTGLIAGVVS ISTALLLLLG FFLWLKKRKQ IKDLGSELVR YDARVHTPHL DRLVSARSVS PTTEMVSNES VDYRATFPED QFPNSSQNGS CRQVQYPLTD MSPILTSGDS DISSPLLQNT VHIDLSALNP ELVQAVQHVV IGPSSLIVHF NEVIGRGHFG CVYHGTLLDN DGKKIHCAVK SLNRITDIGE VSQFLTEGII MKDFSHPNVL SLLGICLRSE GSPLVVLPYM KHGDLRNFIR NETHNPTVKD LIGFGLQVAK GMKYLASKKF VHRDLAARNC MLDEKFTVKV ADFGLARDMY DKEYYSVHNK TGAKLPVKWM ALESLQTQKF TTKSDVWSFG VLLWELMTRG APPYPDVNTF DITVYLLQGR RLLQPEYCPD PLYEVMLKCW HPKAEMRPSF SELVSRISAI FSTFIGEHYV HVNATYVNVK CVAPYPSLLS SEDNADDEVD TRPASFWETS