MET_RHIFE
ID MET_RHIFE Reviewed; 1381 AA.
AC Q2IBC0;
DT 28-NOV-2006, integrated into UniProtKB/Swiss-Prot.
DT 07-MAR-2006, sequence version 1.
DT 03-AUG-2022, entry version 88.
DE RecName: Full=Hepatocyte growth factor receptor;
DE Short=HGF receptor;
DE EC=2.7.10.1;
DE AltName: Full=HGF/SF receptor;
DE AltName: Full=Proto-oncogene c-Met;
DE AltName: Full=Scatter factor receptor;
DE Short=SF receptor;
DE AltName: Full=Tyrosine-protein kinase Met;
DE Flags: Precursor;
GN Name=MET;
OS Rhinolophus ferrumequinum (Greater horseshoe bat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Chiroptera; Microchiroptera; Rhinolophidae;
OC Rhinolophinae; Rhinolophus.
OX NCBI_TaxID=59479;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Antonellis A., Ayele K., Benjamin B., Blakesley R.W., Boakye A.,
RA Bouffard G.G., Brinkley C., Brooks S., Chu G., Coleman H., Engle J.,
RA Gestole M., Greene A., Guan X., Gupta J., Haghighi P., Han J., Hansen N.,
RA Ho S.-L., Hu P., Hunter G., Hurle B., Idol J.R., Kwong P., Laric P.,
RA Larson S., Lee-Lin S.-Q., Legaspi R., Madden M., Maduro Q.L., Maduro V.B.,
RA Margulies E.H., Masiello C., Maskeri B., McDowell J., Mojidi H.A.,
RA Mullikin J.C., Oestreicher J.S., Park M., Portnoy M.E., Prasad A., Puri O.,
RA Reddix-Dugue N., Schandler K., Schueler M.G., Sison C., Stantripop S.,
RA Stephen E., Taye A., Thomas J.W., Thomas P.J., Tsipouri V., Ung L.,
RA Vogt J.L., Wetherby K.D., Young A., Green E.D.;
RT "NISC comparative sequencing initiative.";
RL Submitted (JAN-2006) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Receptor tyrosine kinase that transduces signals from the
CC extracellular matrix into the cytoplasm by binding to hepatocyte growth
CC factor/HGF ligand. Regulates many physiological processes including
CC proliferation, scattering, morphogenesis and survival. Ligand binding
CC at the cell surface induces autophosphorylation of MET on its
CC intracellular domain that provides docking sites for downstream
CC signaling molecules. Following activation by ligand, interacts with the
CC PI3-kinase subunit PIK3R1, PLCG1, SRC, GRB2, STAT3 or the adapter GAB1.
CC Recruitment of these downstream effectors by MET leads to the
CC activation of several signaling cascades including the RAS-ERK, PI3
CC kinase-AKT, or PLCgamma-PKC. The RAS-ERK activation is associated with
CC the morphogenetic effects while PI3K/AKT coordinates prosurvival
CC effects. During embryonic development, MET signaling plays a role in
CC gastrulation, development and migration of muscles and neuronal
CC precursors, angiogenesis and kidney formation. In adults, participates
CC in wound healing as well as organ regeneration and tissue remodeling.
CC Promotes also differentiation and proliferation of hematopoietic cells
CC (By similarity). {ECO:0000250}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10028};
CC -!- ACTIVITY REGULATION: In its inactive state, the C-terminal tail
CC interacts with the catalytic domain and inhibits the kinase activity.
CC Upon ligand binding, the C-terminal tail is displaced and becomes
CC phosphorylated, thus increasing the kinase activity (By similarity).
CC {ECO:0000250}.
CC -!- SUBUNIT: Heterodimer made of an alpha chain (50 kDa) and a beta chain
CC (145 kDa) which are disulfide linked. Binds PLXNB1. Interacts when
CC phosphorylated with downstream effectors including STAT3, PIK3R1, SRC,
CC PCLG1, GRB2 and GAB1. Interacts with SPSB1, SPSB2 and SPSB4. Interacts
CC with INPP5D/SHIP1. When phosphorylated at Tyr-1356, interacts with
CC INPPL1/SHIP2. Interacts with RANBP9 and RANBP10, as well as SPSB1,
CC SPSB2, SPSB3 and SPSB4. SPSB1 binding occurs in the presence and in the
CC absence of HGF, however HGF treatment has a positive effect on this
CC interaction. Interacts with MUC20; prevents interaction with GRB2 and
CC suppresses hepatocyte growth factor-induced cell proliferation.
CC Interacts with GRB10. Interacts with PTPN1 and PTPN2. Interacts with
CC HSP90AA1 and HSP90AB1; the interaction suppresses MET kinase activity.
CC {ECO:0000250|UniProtKB:P08581, ECO:0000250|UniProtKB:P16056}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000250}; Single-pass type I
CC membrane protein {ECO:0000250}.
CC -!- DOMAIN: The kinase domain is involved in SPSB1 binding. {ECO:0000250}.
CC -!- DOMAIN: The beta-propeller Sema domain mediates binding to HGF.
CC {ECO:0000250}.
CC -!- PTM: Autophosphorylated in response to ligand binding on Tyr-1234 and
CC Tyr-1235 in the kinase domain leading to further phosphorylation of
CC Tyr-1349 and Tyr-1356 in the C-terminal multifunctional docking site.
CC Dephosphorylated by PTPRJ at Tyr-1349 and Tyr-1365. Dephosphorylated by
CC PTPN1 and PTPN2 (By similarity). {ECO:0000250}.
CC -!- PTM: Ubiquitinated. Ubiquitination by CBL regulates the receptor
CC stability and activity through proteasomal degradation (By similarity).
CC {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. {ECO:0000255|PROSITE-ProRule:PRU00159}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; DP000028; ABC87472.1; -; Genomic_DNA.
DR AlphaFoldDB; Q2IBC0; -.
DR SMR; Q2IBC0; -.
DR Proteomes; UP000472240; Unplaced.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0017154; F:semaphorin receptor activity; IEA:InterPro.
DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0050918; P:positive chemotaxis; ISS:UniProtKB.
DR GO; GO:2001028; P:positive regulation of endothelial cell chemotaxis; ISS:UniProtKB.
DR GO; GO:0071526; P:semaphorin-plexin signaling pathway; ISS:UniProtKB.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IEA:InterPro.
DR Gene3D; 2.130.10.10; -; 1.
DR Gene3D; 2.60.40.10; -; 3.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR014756; Ig_E-set.
DR InterPro; IPR002909; IPT_dom.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR031148; Plexin.
DR InterPro; IPR002165; Plexin_repeat.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR016201; PSI.
DR InterPro; IPR001627; Semap_dom.
DR InterPro; IPR036352; Semap_dom_sf.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR InterPro; IPR016244; Tyr_kinase_HGF/MSP_rcpt.
DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom_sf.
DR PANTHER; PTHR22625; PTHR22625; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR Pfam; PF01437; PSI; 1.
DR Pfam; PF01403; Sema; 1.
DR Pfam; PF01833; TIG; 3.
DR PIRSF; PIRSF000617; TyrPK_HGF-R; 1.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00429; IPT; 4.
DR SMART; SM00423; PSI; 1.
DR SMART; SM00630; Sema; 1.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF101912; SSF101912; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR SUPFAM; SSF81296; SSF81296; 3.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
DR PROSITE; PS51004; SEMA; 1.
PE 3: Inferred from homology;
KW ATP-binding; Disulfide bond; Glycoprotein; Kinase; Membrane;
KW Nucleotide-binding; Phosphoprotein; Proto-oncogene; Receptor;
KW Reference proteome; Repeat; Signal; Transferase; Transmembrane;
KW Transmembrane helix; Tyrosine-protein kinase; Ubl conjugation.
FT SIGNAL 1..24
FT /evidence="ECO:0000255"
FT CHAIN 25..1381
FT /note="Hepatocyte growth factor receptor"
FT /id="PRO_0000260431"
FT TOPO_DOM 25..932
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 933..955
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 956..1381
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 27..515
FT /note="Sema"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
FT DOMAIN 563..655
FT /note="IPT/TIG 1"
FT DOMAIN 657..739
FT /note="IPT/TIG 2"
FT DOMAIN 742..836
FT /note="IPT/TIG 3"
FT DOMAIN 1078..1345
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1212..1381
FT /note="Interaction with RANBP9"
FT /evidence="ECO:0000250"
FT REGION 1320..1359
FT /note="Interaction with MUC20"
FT /evidence="ECO:0000250"
FT ACT_SITE 1204
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10028"
FT BINDING 1084..1092
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 1110
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT SITE 307..308
FT /note="Cleavage"
FT /evidence="ECO:0000255"
FT MOD_RES 966
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT MOD_RES 977
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT MOD_RES 990
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT MOD_RES 997
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT MOD_RES 1000
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT MOD_RES 1003
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT MOD_RES 1230
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT MOD_RES 1234
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT MOD_RES 1235
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT MOD_RES 1289
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT MOD_RES 1349
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT MOD_RES 1356
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT MOD_RES 1365
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT CARBOHYD 45
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 74
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 106
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 358
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 399
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 607
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 635
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 785
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 879
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 930
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 95..101
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
FT DISULFID 98..159
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
FT DISULFID 133..141
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
FT DISULFID 172..175
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
FT DISULFID 298..363
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
FT DISULFID 385..397
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
FT DISULFID 520..538
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
FT DISULFID 526..561
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
FT DISULFID 529..545
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
FT DISULFID 541..551
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
SQ SEQUENCE 1381 AA; 153861 MW; 17A551306FB41788 CRC64;
MKALAVLGPG LLVHLLTLVQ KSGGECKEAL VKSAMNVDMK YQLPNFTAET PIQNVVVHQH
YIYLGAVNYI YVLNDTDLQK VAEYRTGPVL EHPECLPCQD CSHKANASGG VWADNVNMAL
LVDTYYDDQL ISCGSVRRGT CRRHVLRSDA ADIRSEVHCM FSPQADEEPG RCPDCVVSAL
GTKVLLSEKD RFINFFVGNT ISSAHLPGRA LHSISVRRLK ETQDGFKFLT DQSYIDVLPE
FRDSYPIKYV HAFESNHFIY FLTVQRETLD AQTFHTRIVR FCSVDSGLHS YVEMPLECIL
TEKRRRRSAR SEVFNILQAA YVGKPGTHLA NQIGVNLDDD ILYAVFAQSK PDSAEPMNRS
AVCAFPIKLV NEFFNKIVNK NNVRCLQHFY GPNHEPCFNR TLLRIPSGCE VRSDEYRTEF
TTALQRVDLF MGQFNRVLLT SVSTFIAGDL TIANLGTSEG RFMQVVVFRS GSSTPHVNFR
LDSHPVSPEM IVQHPLNQNG YTLVVTGKTI TKIPLNGLGC EHFQSCSQCL SAPPFVQCGW
CHNKCVRSEE CPSGVWTQDV CHPTIYEVFP TTAPLEGGTT LTICGWDFGF RRNNKFDLKK
TRILLGNESC TLTLSESTAN TLKCTVGPAM SEHLNLSIII SSGRGTAQYT AFSYVDPIIT
SVSPSYGPKT GGTLLTLTGK YLNSGNSRHI SIGGKTCSLK SVSESVLECY TPAQTTTTEF
PIKLKIDLAN RETNSFNYRE DPIVDEIHPT KSFISGGSTI TGVGKNLNSV SGLRMVISVR
EAGRNFTVAC QHRSNSEIIC CTTPSLQQLN LQLPLTTKAF FMLDGIHSKY FDLIYVHDPV
FKLFEKPVMI SIGNENVLEI KGNDIDPEAV KGEVLKVGNK SCENVHSHSE AVLCTVPSDL
LKLNSELNIE WKQAVSSTIL GKVIVQPDQN FTGLIVGVIS ISVLLSLLFG LFLWLKRRKQ
IKDLGSELVR YDARIHTPHL DRLVSARSIS PTTEMVSNES VDYRATFPED QFANSSQNGS
CRQVQCPLMD LSPILPGGDS DISSPLLQNT VRIDLSALNP ELVQAVQHVV IGPSRLIVHF
NEVIGRGHFG CVYHGTLLDN DDKKIHCAVK SLNRITDIGE VSQFLTEGII MKDFSHPNVL
SLLGICLRSE GSPLVVLPYM KHGDLRNFIR NETHNPTVKD LIGFGLQVAK GMKYLASKKF
VHRDLAARNC MLDENFTVKV ADFGLARDVY DKEYYSVHNK TGAKLPVKWM ALESLQTQKF
TTKSDVWSFG VLLWELMTRG APPYPDVNTF DITVYLLQGR RLLQPEYCPD HLYEVMLKCW
HPKAEQRPSF AELVSRISAI FSAFIGEHYV HVNATYVNVK CVAPYPCLLS SQDHVDGEGD
T
