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MET_PANTR Reviewed; 1390 AA.
Q2QLF1;
07-MAR-2006, integrated into UniProtKB/Swiss-Prot.
24-JAN-2006, sequence version 1.
23-FEB-2022, entry version 123.
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;
Name=MET;
Pan troglodytes (Chimpanzee).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
Pan.
NCBI_TaxID=9598;
[1]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=12917688; DOI=10.1038/nature01858;
Thomas J.W., Touchman J.W., Blakesley R.W., Bouffard G.G.,
Beckstrom-Sternberg S.M., Margulies E.H., Blanchette M., Siepel A.C.,
Thomas P.J., McDowell J.C., Maskeri B., Hansen N.F., Schwartz M.S.,
Weber R.J., Kent W.J., Karolchik D., Bruen T.C., Bevan R., Cutler D.J.,
Schwartz S., Elnitski L., Idol J.R., Prasad A.B., Lee-Lin S.-Q.,
Maduro V.V.B., Summers T.J., Portnoy M.E., Dietrich N.L., Akhter N.,
Ayele K., Benjamin B., Cariaga K., Brinkley C.P., Brooks S.Y., Granite S.,
Guan X., Gupta J., Haghighi P., Ho S.-L., Huang M.C., Karlins E.,
Laric P.L., Legaspi R., Lim M.J., Maduro Q.L., Masiello C.A.,
Mastrian S.D., McCloskey J.C., Pearson R., Stantripop S., Tiongson E.E.,
Tran J.T., Tsurgeon C., Vogt J.L., Walker M.A., Wetherby K.D.,
Wiggins L.S., Young A.C., Zhang L.-H., Osoegawa K., Zhu B., Zhao B.,
Shu C.L., De Jong P.J., Lawrence C.E., Smit A.F., Chakravarti A.,
Haussler D., Green P., Miller W., Green E.D.;
"Comparative analyses of multi-species sequences from targeted genomic
regions.";
Nature 424:788-793(2003).
-!- 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
(By similarity). {ECO:0000250}.
-!- CATALYTIC ACTIVITY:
Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
[protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1;
Evidence={ECO:0000255|PROSITE-ProRule:PRU10028};
-!- ACTIVITY 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 (By similarity).
{ECO:0000250}.
-!- 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. 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. Interacts with
HSP90AA1 and HSP90AB1; the interaction suppresses MET kinase activity.
{ECO:0000250|UniProtKB:P08581, ECO:0000250|UniProtKB:P16056}.
-!- SUBCELLULAR LOCATION: Membrane {ECO:0000250}; Single-pass type I
membrane protein {ECO:0000250}.
-!- DOMAIN: The kinase domain is involved in SPSB1 binding. {ECO:0000250}.
-!- DOMAIN: The beta-propeller Sema domain mediates binding to HGF.
{ECO:0000250}.
-!- 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 (By similarity). {ECO:0000250}.
-!- PTM: Ubiquitinated. Ubiquitination by CBL regulates the receptor
stability and activity through proteasomal degradation (By similarity).
{ECO:0000250}.
-!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
kinase family. {ECO:0000255|PROSITE-ProRule:PRU00159}.
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EMBL; DP000016; AAR16247.2; -; Genomic_DNA.
RefSeq; NP_001129302.1; NM_001135830.1.
SMR; Q2QLF1; -.
STRING; 9598.ENSPTRP00000057112; -.
PaxDb; Q2QLF1; -.
GeneID; 463671; -.
KEGG; ptr:463671; -.
CTD; 4233; -.
eggNOG; KOG1095; Eukaryota.
eggNOG; KOG3610; Eukaryota.
HOGENOM; CLU_005158_0_0_1; -.
InParanoid; Q2QLF1; -.
OrthoDB; 408584at2759; -.
TreeFam; TF317402; -.
Proteomes; UP000002277; Unplaced.
Bgee; ENSPTRG00000019614; Expressed in liver and 6 other tissues.
GO; GO:0009925; C:basal plasma membrane; IBA:GO_Central.
GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
GO; GO:0043235; C:receptor complex; IBA:GO_Central.
GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
GO; GO:0005008; F:hepatocyte growth factor-activated receptor activity; IBA:GO_Central.
GO; GO:0004712; F:protein serine/threonine/tyrosine kinase activity; IEA:RHEA.
GO; GO:0017154; F:semaphorin receptor activity; IEA:InterPro.
GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IBA:GO_Central.
GO; GO:0016477; P:cell migration; IBA:GO_Central.
GO; GO:0001889; P:liver development; IBA:GO_Central.
GO; GO:0007399; P:nervous system development; IBA:GO_Central.
GO; GO:0030182; P:neuron differentiation; IBA:GO_Central.
GO; GO:0031016; P:pancreas development; IBA:GO_Central.
GO; GO:0006909; P:phagocytosis; IBA:GO_Central.
GO; GO:0050918; P:positive chemotaxis; ISS:UniProtKB.
GO; GO:2001028; P:positive regulation of endothelial cell chemotaxis; ISS:UniProtKB.
GO; GO:0033674; P:positive regulation of kinase activity; IBA:GO_Central.
GO; GO:0051897; P:positive regulation of protein kinase B signaling; IBA:GO_Central.
GO; GO:0071526; P:semaphorin-plexin signaling pathway; ISS:UniProtKB.
GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central.
Gene3D; 2.130.10.10; -; 1.
Gene3D; 2.60.40.10; -; 3.
InterPro; IPR013783; Ig-like_fold.
InterPro; IPR014756; Ig_E-set.
InterPro; IPR002909; IPT_dom.
InterPro; IPR011009; Kinase-like_dom_sf.
InterPro; IPR031148; Plexin.
InterPro; IPR002165; Plexin_repeat.
InterPro; IPR000719; Prot_kinase_dom.
InterPro; IPR017441; Protein_kinase_ATP_BS.
InterPro; IPR016201; PSI.
InterPro; IPR001627; Semap_dom.
InterPro; IPR036352; Semap_dom_sf.
InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
InterPro; IPR008266; Tyr_kinase_AS.
InterPro; IPR020635; Tyr_kinase_cat_dom.
InterPro; IPR016244; Tyr_kinase_HGF/MSP_rcpt.
InterPro; IPR015943; WD40/YVTN_repeat-like_dom_sf.
PANTHER; PTHR22625; PTHR22625; 1.
Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
Pfam; PF01437; PSI; 1.
Pfam; PF01403; Sema; 1.
Pfam; PF01833; TIG; 3.
PIRSF; PIRSF000617; TyrPK_HGF-R; 1.
PRINTS; PR00109; TYRKINASE.
SMART; SM00429; IPT; 4.
SMART; SM00423; PSI; 1.
SMART; SM00630; Sema; 1.
SMART; SM00219; TyrKc; 1.
SUPFAM; SSF101912; SSF101912; 1.
SUPFAM; SSF56112; SSF56112; 1.
SUPFAM; SSF81296; SSF81296; 3.
PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
PROSITE; PS51004; SEMA; 1.
3: Inferred from homology;
ATP-binding; Disulfide bond; Glycoprotein; Kinase; Membrane;
Nucleotide-binding; Phosphoprotein; Proto-oncogene; Receptor;
Reference proteome; Repeat; Signal; Transferase; Transmembrane;
Transmembrane helix; Tyrosine-protein kinase; Ubl conjugation.
SIGNAL 1..24
/evidence="ECO:0000255"
CHAIN 25..1390
/note="Hepatocyte growth factor receptor"
/id="PRO_0000226057"
TOPO_DOM 25..932
/note="Extracellular"
/evidence="ECO:0000255"
TRANSMEM 933..955
/note="Helical"
/evidence="ECO:0000255"
TOPO_DOM 956..1390
/note="Cytoplasmic"
/evidence="ECO:0000255"
DOMAIN 27..515
/note="Sema"
/evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
DOMAIN 563..655
/note="IPT/TIG 1"
DOMAIN 657..739
/note="IPT/TIG 2"
DOMAIN 742..836
/note="IPT/TIG 3"
DOMAIN 1078..1345
/note="Protein kinase"
/evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
NP_BIND 1084..1092
/note="ATP"
/evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
REGION 1212..1390
/note="Interaction with RANBP9"
/evidence="ECO:0000250"
REGION 1320..1359
/note="Interaction with MUC20"
/evidence="ECO:0000250"
ACT_SITE 1204
/note="Proton acceptor"
/evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
ECO:0000255|PROSITE-ProRule:PRU10028"
BINDING 1110
/note="ATP"
/evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
SITE 307..308
/note="Cleavage"
/evidence="ECO:0000255"
MOD_RES 966
/note="Phosphoserine"
/evidence="ECO:0000250|UniProtKB:P08581"
MOD_RES 977
/note="Phosphothreonine"
/evidence="ECO:0000250|UniProtKB:P08581"
MOD_RES 990
/note="Phosphoserine"
/evidence="ECO:0000250|UniProtKB:P08581"
MOD_RES 997
/note="Phosphoserine"
/evidence="ECO:0000250|UniProtKB:P08581"
MOD_RES 1000
/note="Phosphoserine"
/evidence="ECO:0000250|UniProtKB:P08581"
MOD_RES 1003
/note="Phosphotyrosine"
/evidence="ECO:0000250|UniProtKB:P08581"
MOD_RES 1230
/note="Phosphotyrosine"
/evidence="ECO:0000250|UniProtKB:P08581"
MOD_RES 1234
/note="Phosphotyrosine; by autocatalysis"
/evidence="ECO:0000250|UniProtKB:P08581"
MOD_RES 1235
/note="Phosphotyrosine; by autocatalysis"
/evidence="ECO:0000250|UniProtKB:P08581"
MOD_RES 1289
/note="Phosphothreonine"
/evidence="ECO:0000250|UniProtKB:P08581"
MOD_RES 1349
/note="Phosphotyrosine; by autocatalysis"
/evidence="ECO:0000250|UniProtKB:P08581"
MOD_RES 1356
/note="Phosphotyrosine; by autocatalysis"
/evidence="ECO:0000250|UniProtKB:P08581"
MOD_RES 1365
/note="Phosphotyrosine"
/evidence="ECO:0000250|UniProtKB:P08581"
CARBOHYD 45
/note="N-linked (GlcNAc...) asparagine"
/evidence="ECO:0000255"
CARBOHYD 106
/note="N-linked (GlcNAc...) asparagine"
/evidence="ECO:0000255"
CARBOHYD 149
/note="N-linked (GlcNAc...) asparagine"
/evidence="ECO:0000255"
CARBOHYD 202
/note="N-linked (GlcNAc...) asparagine"
/evidence="ECO:0000255"
CARBOHYD 399
/note="N-linked (GlcNAc...) asparagine"
/evidence="ECO:0000255"
CARBOHYD 405
/note="N-linked (GlcNAc...) asparagine"
/evidence="ECO:0000255"
CARBOHYD 607
/note="N-linked (GlcNAc...) asparagine"
/evidence="ECO:0000255"
CARBOHYD 635
/note="N-linked (GlcNAc...) asparagine"
/evidence="ECO:0000255"
CARBOHYD 785
/note="N-linked (GlcNAc...) asparagine"
/evidence="ECO:0000255"
CARBOHYD 879
/note="N-linked (GlcNAc...) asparagine"
/evidence="ECO:0000255"
CARBOHYD 930
/note="N-linked (GlcNAc...) asparagine"
/evidence="ECO:0000255"
DISULFID 95..101
/evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
DISULFID 98..160
/evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
DISULFID 133..141
/evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
DISULFID 172..175
/evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
DISULFID 298..363
/evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
DISULFID 385..397
/evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
DISULFID 520..538
/evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
DISULFID 526..561
/evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
DISULFID 529..545
/evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
DISULFID 541..551
/evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
SEQUENCE 1390 AA; 155569 MW; 81C0349AE225B31F CRC64;
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 TLLRNSSSCE ARRDEYRTEF
TTALQRVDLF MGQFSEVLLT SISTFIKGDL TIANLGTSEG RFMQVVVSRS GPSTPHVNFL
LDSHPVSPEV IVEHTLNQNG YTLVVTGKKI 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 ISIALLLLLG 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