Hepatocyte growth factor receptor (HGF receptor) (EC 2.7.10.1) (HGF/SF receptor) (Proto-oncogene c-Met) (Scatter factor receptor) (SF receptor) (Tyrosine-protein kinase Met)

 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

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