Basic Information | Overview of PTM Sites | Experimental PTM Sites | Protein-Protein Interactions | Drug and Disease Associations | Related Literatures
Basic Information
Protein Name :  Hepatocyte growth factor receptor  

UniProtKB / Swiss-Prot ID :  MET_HUMAN

Gene Name (Synonyms) : 
MET  

Species :  Homo sapiens (Human). 

Subcellular Localization :  Membrane; Single-pass type I membrane protein. Isoform 3: Secreted. 

Protein 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. Acts as a receptor for Listeria internalin inlB, mediating entry of the pathogen into cells. 

Transmembrane Topology (topPTM) : MET_HUMAN 

Protein Sequence MKAPAVLAPGILVLLFTLVQRSNGECKEALAKSEMNVNMKYQLPNFTAETPIQNVILHEHHIFLGATNYI...
Predicted Secondary Structure CCCCCCHHHHHHHHHHHHHCCCCCCCHHHHHHCCCCEEEEEECCCCCCCCEEEEEEEECCEEEEEEEEEE...
Protein Variant
LocationDescription
143R -> Q (in dbSNP:rs35469582). VAR_041738
150H -> Y (found in a case of cancer ofunknown primary origin; the mutated
156S -> L (in dbSNP:rs56311081). VAR_041739
168E -> D (found in a case of cancer ofunknown primary origin; the mutated
238L -> S (in dbSNP:rs34349517). VAR_032478
316I -> M (in dbSNP:rs35225896). VAR_032479
320A -> V (in dbSNP:rs35776110). VAR_006285
375N -> S (in dbSNP:rs33917957). VAR_032480
385C -> Y (found in a case of cancer ofunknown primary origin; the mutated
773P -> L (in gastric cancer). VAR_032481
970R -> C (in dbSNP:rs34589476). VAR_032482
991P -> S (in gastric cancer; prolongedtyrosine phosphorylation in response to
992T -> I (found in a case of cancer ofunknown primary origin; the mutated
1092V -> I (in RCCP; constitutiveautophosphorylation).
1094H -> L (in RCCP; constitutiveautophosphorylation; causes malignant
1094H -> R (in RCCP; causes malignanttransformation in cell lines).
1094H -> Y (in RCCP; constitutiveautophosphorylation; causes malignant
1106H -> D (in RCCP; constitutiveautophosphorylation; causes malignant
1131M -> T (in RCCP; germline mutation). VAR_006286
1173T -> I (in HCC). VAR_032490
1188V -> L (in RCCP; germline mutation). VAR_006287
1195L -> V (in RCCP; somatic mutation). VAR_006288
1220V -> I (in RCCP; germline mutation). VAR_006289
1228D -> H (in RCCP; somatic mutation). VAR_006291
1228D -> N (in RCCP; germline mutation). VAR_006290
1230Y -> C (in RCCP; germline mutation). VAR_006292
1230Y -> D (in RCCP; constitutiveautophosphorylation; causes malignant
1230Y -> H (in RCCP; somatic mutation). VAR_006293
1244K -> R (in HCC). VAR_032492
1250M -> I (in HCC). VAR_032493
1250M -> T (in RCCP; somatic mutation). VAR_006294
1294V -> I (found in a case of cancer ofunknown primary origin; the mutated
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Overview of Protein Modification Sites with Functional and Structural Information
Accessible Surface Area (ASA)
Pred. Secondary
Real Secondary
Disorder Prediction
Protein Domain
&
Experimental PTM Sites
Predicted PTM Sites
Protein Variant
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Experimental Post-Translational Modification Sites Download
Locations
Modification
Substrate Sites
&
Secondary Structure
Accessible Surface Area (%)
Resource
Reference
Structural Characterization
Orthologous
Protein Cluster
106N-linked (GlcNAc...).SSKANLSGG
CCCCCCCCC
38.18UniProtKB
Link-
189Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)LSSVKDRFI
EECCCCCCE
45.17Phosphositeplus
Link-
223Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)LKETKDGFM
CCCCCHHHH
57.87Phosphositeplus
Link-
324Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)AYVSKPGAQ
ECCCCHHHH
37.11Phosphositeplus
Link-
765Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)TGVGKNLNS
EEEEECCCE
56.72Phosphositeplus
Link-
830PhosphotyrosineILSKYFDLI
CCCCCEEEE
10.03PhosphoELM
Link-
830PhosphotyrosineILSKYFDLI
CCCCCEEEE
10.03Phosphositeplus
Link-
962Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)RKQIKDLGS
HHHHHHHHH
44.39Phosphositeplus
Link-
966PhosphoserineKDLGSELVR
HHHHHHHHH
34.75HPRD
Link-
966PhosphoserineKDLGSELVR
HHHHHHHHH
34.75Phosphositeplus
Link-
966PhosphoserineKDLGSELVR
HHHHHHHHH
34.75SysPTM
Link-
966Phosphoserine.KDLGSELVR
HHHHHHHHH
34.75UniProtKB
Link-
977PhosphothreonineARVHTPHLD
CEECCCCCC
15.00PhosphoELM
Link-
977PhosphothreonineARVHTPHLD
CEECCCCCC
15.00Phosphositeplus
Link-
977PhosphothreonineARVHTPHLD
CEECCCCCC
15.00SysPTM
Link-
977Phosphothreonine (MET)ARVHTPHLD
CEECCCCCC
15.00HPRD
Link-
977Phosphothreonine.ARVHTPHLD
CEECCCCCC
15.00UniProtKB
Link-
985PhosphoserineDRLVSARSV
CCCCCCCCC
23.66HPRD
Link-
985PhosphoserineDRLVSARSV
CCCCCCCCC
23.66Phosphositeplus
Link-
985Phosphoserine (PKC_group;PKC_delta;PKC_epsilon)DRLVSARSV
CCCCCCCCC
23.66PhosphoELM
Link-
988PhosphoserineVSARSVSPT
CCCCCCCCC
27.02PhosphoELM
Link-
988PhosphoserineVSARSVSPT
CCCCCCCCC
27.02Phosphositeplus
Link-
988PhosphoserineVSARSVSPT
CCCCCCCCC
27.02SysPTM
Link-
988Phosphoserine (MET)VSARSVSPT
CCCCCCCCC
27.02HPRD
Link-
988Phosphoserine.VSARSVSPT
CCCCCCCCC
27.02UniProtKB
Link-
990PhosphoserineARSVSPTTE
CCCCCCCCC
20.13PhosphoELM
Link-
990PhosphoserineARSVSPTTE
CCCCCCCCC
20.13Phosphositeplus
Link-
990PhosphoserineARSVSPTTE
CCCCCCCCC
20.13SysPTM
Link-
990Phosphoserine (MET)ARSVSPTTE
CCCCCCCCC
20.13HPRD
Link-
990Phosphoserine.ARSVSPTTE
CCCCCCCCC
20.13UniProtKB
Link-
992PhosphothreonineSVSPTTEMV
CCCCCCCCC
28.07HPRD
Link-
992PhosphothreonineSVSPTTEMV
CCCCCCCCC
28.07PhosphoELM
Link-
992PhosphothreonineSVSPTTEMV
CCCCCCCCC
28.07Phosphositeplus
Link-
993PhosphothreonineVSPTTEMVS
CCCCCCCCC
26.01HPRD
Link-
993PhosphothreonineVSPTTEMVS
CCCCCCCCC
26.01PhosphoELM
Link-
993PhosphothreonineVSPTTEMVS
CCCCCCCCC
26.01Phosphositeplus
Link-
997PhosphoserineTEMVSNESV
CCCCCCCCC
33.30HPRD
Link-
997PhosphoserineTEMVSNESV
CCCCCCCCC
33.30PhosphoELM
Link-
997PhosphoserineTEMVSNESV
CCCCCCCCC
33.30Phosphositeplus
Link-
997PhosphoserineTEMVSNESV
CCCCCCCCC
33.30SysPTM
Link-
997Phosphoserine.TEMVSNESV
CCCCCCCCC
33.30UniProtKB
Link-
1000PhosphoserineVSNESVDYR
CCCCCCCEE
25.25HPRD
Link-
1000PhosphoserineVSNESVDYR
CCCCCCCEE
25.25PhosphoELM
Link-
1000PhosphoserineVSNESVDYR
CCCCCCCEE
25.25Phosphositeplus
Link-
1000PhosphoserineVSNESVDYR
CCCCCCCEE
25.25SysPTM
Link-
1000Phosphoserine.VSNESVDYR
CCCCCCCEE
25.25UniProtKB
Link-
1003PhosphotyrosineESVDYRATF
CCCCEEEEC
10.45HPRD
Link-
1003PhosphotyrosineESVDYRATF
CCCCEEEEC
10.45PhosphoELM
Link-
1003PhosphotyrosineESVDYRATF
CCCCEEEEC
10.45Phosphositeplus
Link-
1003PhosphotyrosineESVDYRATF
CCCCEEEEC
10.45SysPTM
Link-
1003Phosphotyrosine.ESVDYRATF
CCCCEEEEC
10.45UniProtKB
Link-
1093PhosphotyrosineFGCVYHGTL
CCEEEEEEE
9.90Phosphositeplus
Link-
1161Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)LPYMKHGDL
EEECCCCCH
38.30Phosphositeplus
Link-
1190Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)LQVAKGMKY
HHHHHHHHH
61.76Phosphositeplus
Link-
1230PhosphotyrosineARDMYDKEY
EEECCCCCC
28.31HPRD
Link-
1230PhosphotyrosineARDMYDKEY
EEECCCCCC
28.31Phosphositeplus
Link-
1230Phosphotyrosine (Met)ARDMYDKEY
EEECCCCCC
28.31PhosphoELM
Link-
1230Phosphotyrosine.ARDMYDKEY
EEECCCCCC
28.31UniProtKB
Link-
1232Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)DMYDKEYYS
ECCCCCCEE
30.08Phosphositeplus
Link-
1234PhosphotyrosineYDKEYYSVH
CCCCCEEEE
13.54HPRD
Link-
1234PhosphotyrosineYDKEYYSVH
CCCCCEEEE
13.54Phosphositeplus
Link-
1234Phosphotyrosine (Met;Met;Met)YDKEYYSVH
CCCCCEEEE
13.54PhosphoELM
Link-
1234Phosphotyrosine; by autocatalysis.YDKEYYSVH
CCCCCEEEE
13.54UniProtKB
Link-
1235PhosphotyrosineDKEYYSVHN
CCCCEEEEE
12.81HPRD
Link-
1235PhosphotyrosineDKEYYSVHN
CCCCEEEEE
12.81Phosphositeplus
Link-
1235Phosphotyrosine (Met)DKEYYSVHN
CCCCEEEEE
12.81PhosphoELM
Link-
1235Phosphotyrosine; by autocatalysis.DKEYYSVHN
CCCCEEEEE
12.81UniProtKB
Link-
1236PhosphoserineKEYYSVHNK
CCCEEEEEE
18.92Phosphositeplus
Link-
1240Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)SVHNKTGAK
EEEEECCCC
33.20Phosphositeplus
Link-
1289PhosphothreoninePDVNTFDIT
CCCCHHHHH
23.64Phosphositeplus
Link-
1289Phosphothreonine.PDVNTFDIT
CCCCHHHHH
23.64UniProtKB
Link-
1295PhosphotyrosineDITVYLLQG
HHHHHHHHC
7.95HPRD
Link-
1313PhosphotyrosinePDPLYEVML
CHHHHHHHH
16.33PhosphoELM
Link-
1313PhosphotyrosinePDPLYEVML
CHHHHHHHH
16.33Phosphositeplus
Link-
1331PhosphoserineRPSFSELVS
CCCHHHHHH
34.07HPRD
Link-
1338PhosphoserineVSRISAIFS
HHHHHHHHH
17.75HPRD
Link-
1349DePhosphotyrosineIGEHYVHVN
CCCCCCCCC
6.48HPRD
Link-
1349PhosphotyrosineIGEHYVHVN
CCCCCCCCC
6.48HPRD
Link-
1349PhosphotyrosineIGEHYVHVN
CCCCCCCCC
6.48Phosphositeplus
Link-
1349Phosphotyrosine (Met;Met;Met)IGEHYVHVN
CCCCCCCCC
6.48PhosphoELM
Link-
1349Phosphotyrosine; by autocatalysis.IGEHYVHVN
CCCCCCCCC
6.48UniProtKB
Link-
1355PhosphothreonineHVNATYVNV
CCCHHHCCC
23.85Phosphositeplus
Link
1356DePhosphotyrosineVNATYVNVK
CCHHHCCCC
6.39HPRD
Link
1356PhosphotyrosineVNATYVNVK
CCHHHCCCC
6.39HPRD
Link
1356PhosphotyrosineVNATYVNVK
CCHHHCCCC
6.39Phosphositeplus
Link
1356Phosphotyrosine (Met;Met;Met)VNATYVNVK
CCHHHCCCC
6.39PhosphoELM
Link
1356Phosphotyrosine; by autocatalysis.VNATYVNVK
CCHHHCCCC
6.39UniProtKB
Link
1365PhosphotyrosineCVAPYPSLL
CCCCCCCCC
8.84HPRD
Link-
1365PhosphotyrosineCVAPYPSLL
CCCCCCCCC
8.84PhosphoELM
Link-
1365PhosphotyrosineCVAPYPSLL
CCCCCCCCC
8.84Phosphositeplus
Link-
1365Phosphotyrosine.CVAPYPSLL
CCCCCCCCC
8.84UniProtKB
Link-
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Protein-Protein Interactions
      Interacting Protein      
Interaction type
Source ID
      Resource      
      Pubmed ID      
Domain-Domain Interactions
PLXB1_HUMANphosphorylation reactionMINT-49668MINT12198496
CBL_HUMANphysical interactionMINT-16046MINT11894096
CBL_HUMANubiquitination reactionMINT-14027MINT11894096
RANB9_HUMANphysical interactionMINT-14119MINT12147692
RANB9_HUMANphysical interactionMINT-18300MINT12147692
RANB9_HUMANphysical interactionMINT-18299MINT12147692
HGFA_HUMANphysical interactionDIP:10921EDIP9537587
HGF_HUMANdirect interaction
direct interaction
EBI-1554953
EBI-1039192
intact17981115
15167892
STAT3_HUMANin vivoHPRD:01280HPRD9440692
GRB2_HUMANin vitro
in vivo
yeast 2-hybrid
HPRD:01280HPRD11439336
8662889
9660480
7511210
15546961
HGF_HUMANin vivoHPRD:01280HPRD1655405
GAB1_HUMANin vitro
in vivo
HPRD:01280HPRD10995442
10734310
CNR1_HUMANin vitroHPRD:01280HPRD11894096
MET_HUMANin vitro
in vivo
HPRD:01280HPRD1655790
1655405
P85A_HUMANin vitroHPRD:01280HPRD7513258
PLCG1_HUMANin vitroHPRD:01280HPRD7513258
8662733
CASP3_HUMANin vitro
in vivo
HPRD:01280HPRD15542841
SPSB1_HUMANin vivoHPRD:01280HPRD15713673
SRC8_HUMANin vitro
in vivo
HPRD:01280HPRD11439336
S25BP_HUMANyeast 2-hybridHPRD:01280HPRD15546961
PHS2_HUMANyeast 2-hybridHPRD:01280HPRD15546961
VAV_HUMANyeast 2-hybridHPRD:01280HPRD15546961
SNX2_HUMANyeast 2-hybridHPRD:01280HPRD15546961
DAPK3_HUMANyeast 2-hybridHPRD:01280HPRD15546961
SMC1A_HUMANyeast 2-hybridHPRD:01280HPRD15546961
DNJA3_HUMANyeast 2-hybridHPRD:01280HPRD15546961
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Disease Reference
Kegg disease
H00018 Gastric cancer
H00021 Renal cell carcinoma
H00046 Cholangiocarcinoma
OMIM disease
Note=Activation of MET after rearrangement with the TPR gene produces an oncogenic protein.
114550
605074Renal cell carcinoma papillary (RCCP)
Drug Reference
Kegg drug
D09618 Foretinib (USAN/INN)
D09941 Onartuzumab (USAN/INN)
D10173 Tivantinib (USAN/INN)
D10224 Golvatinib (USAN)
There are no disease associations of PTM sites.
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Related Literatures of Post-Translational Modification
N-linked Glycosylation
ReferencePubMed
"Identification of N-glycosylation sites on secreted proteins of humanhepatocellular carcinoma cells with a complementary proteomicsapproach.";
Cao J., Shen C., Wang H., Shen H., Chen Y., Nie A., Yan G., Lu H.,Liu Y., Yang P.;
J. Proteome Res. 8:662-672(2009).
Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-106, AND MASSSPECTROMETRY.
Phosphorylation
ReferencePubMed
"Identification of the major autophosphorylation site of theMet/hepatocyte growth factor receptor tyrosine kinase.";
Ferracini R., Longati P., Naldini L., Vigna E., Comoglio P.M.;
J. Biol. Chem. 266:19558-19564(1991).
Cited for: PHOSPHORYLATION AT TYR-1235, AND ATP-BINDING SITE LYS-1110.
"A multifunctional docking site mediates signaling and transformationby the hepatocyte growth factor/scatter factor receptor family.";
Ponzetto C., Bardelli A., Zhen Z., Maina F., dalla Zonca P.,Giordano S., Graziani A., Panayotou G., Comoglio P.M.;
Cell 77:261-271(1994).
Cited for: AUTOPHOSPHORYLATION AT TYR-1349 AND TYR-1356, AND INTERACTION WITHSRC; PLCG1 AND GRB2.
"Hepatocyte growth factor receptor tyrosine kinase met is a substrateof the receptor protein-tyrosine phosphatase DEP-1.";
Palka H.L., Park M., Tonks N.K.;
J. Biol. Chem. 278:5728-5735(2003).
Cited for: PHOSPHORYLATION AT TYR-1230; TYR-1234; TYR-1235; TYR-1349 ANDTYR-1365, AND DEPHOSPHORYLATION BY PTPRJ AT TYR-1349 AND TYR-1365.
"The SH2-domian-containing inositol 5-phosphatase (SHIP)-2 binds to c-Met directly via tyrosine residue 1356 and involves hepatocyte growthfactor (HGF)-induced lamellipodium formation, cell scattering and cellspreading.";
Koch A., Mancini A., El Bounkari O., Tamura T.;
Oncogene 24:3436-3447(2005).
Cited for: PHOSPHORYLATION AT TYR-1356, AND INTERACTION WITH INPPL1.
"Global survey of phosphotyrosine signaling identifies oncogenickinases in lung cancer.";
Rikova K., Guo A., Zeng Q., Possemato A., Yu J., Haack H., Nardone J.,Lee K., Reeves C., Li Y., Hu Y., Tan Z., Stokes M., Sullivan L.,Mitchell J., Wetzel R., Macneill J., Ren J.M., Yuan J.,Bakalarski C.E., Villen J., Kornhauser J.M., Smith B., Li D., Zhou X.,Gygi S.P., Gu T.-L., Polakiewicz R.D., Rush J., Comb M.J.;
Cell 131:1190-1203(2007).
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-1003; TYR-1230; TYR-1234AND TYR-1235, AND MASS SPECTROMETRY.
"Proteomics analysis of protein kinases by target class-selectiveprefractionation and tandem mass spectrometry.";
Wissing J., Jaensch L., Nimtz M., Dieterich G., Hornberger R.,Keri G., Wehland J., Daub H.;
Mol. Cell. Proteomics 6:537-547(2007).
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-977; SER-988; SER-990AND TYR-1003, AND MASS SPECTROMETRY.
"Kinase-selective enrichment enables quantitative phosphoproteomics ofthe kinome across the cell cycle.";
Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,Greff Z., Keri G., Stemmann O., Mann M.;
Mol. Cell 31:438-448(2008).
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-966; THR-977; SER-988;SER-990; SER-997; SER-1000 AND TYR-1003, AND MASS SPECTROMETRY.
"A quantitative atlas of mitotic phosphorylation.";
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,Elledge S.J., Gygi S.P.;
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-990; SER-997 ANDSER-1000, AND MASS SPECTROMETRY.
"An extensive survey of tyrosine phosphorylation revealing new sitesin human mammary epithelial cells.";
Heibeck T.H., Ding S.-J., Opresko L.K., Zhao R., Schepmoes A.A.,Yang F., Tolmachev A.V., Monroe M.E., Camp D.G. II, Smith R.D.,Wiley H.S., Qian W.-J.;
J. Proteome Res. 8:3852-3861(2009).
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-1234, AND MASSSPECTROMETRY.
"Large-scale proteomics analysis of the human kinome.";
Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,Mann M., Daub H.;
Mol. Cell. Proteomics 8:1751-1764(2009).
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-966; THR-977; SER-988;SER-990; SER-997; SER-1000; TYR-1003; TYR-1234 AND THR-1289, AND MASSSPECTROMETRY.
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Basic Information | Overview of PTM Sites | Experimental PTM Sites | Protein-Protein Interactions | Drug and Disease Associations | Related Literatures