MET_ECHTE
ID MET_ECHTE Reviewed; 1380 AA.
AC A1X150;
DT 06-MAR-2007, integrated into UniProtKB/Swiss-Prot.
DT 06-FEB-2007, sequence version 1.
DT 03-AUG-2022, entry version 79.
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 Echinops telfairi (Lesser hedgehog tenrec).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Afrotheria; Tenrecidae; Tenrecinae; Echinops.
OX NCBI_TaxID=9371;
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 (DEC-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-1355, 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-1233 and
CC Tyr-1234 in the kinase domain leading to further phosphorylation of
CC Tyr-1348 and Tyr-1355 in the C-terminal multifunctional docking site.
CC Dephosphorylated by PTPRJ at Tyr-1348 and Tyr-1364. 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}.
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DR EMBL; DP000274; ABL76166.1; -; Genomic_DNA.
DR AlphaFoldDB; A1X150; -.
DR SMR; A1X150; -.
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; Repeat;
KW Signal; Transferase; Transmembrane; Transmembrane helix;
KW Tyrosine-protein kinase; Ubl conjugation.
FT SIGNAL 1..24
FT /evidence="ECO:0000255"
FT CHAIN 25..1380
FT /note="Hepatocyte growth factor receptor"
FT /id="PRO_0000280067"
FT TOPO_DOM 25..931
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 932..954
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 955..1380
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 27..513
FT /note="Sema"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
FT DOMAIN 561..654
FT /note="IPT/TIG 1"
FT DOMAIN 656..738
FT /note="IPT/TIG 2"
FT DOMAIN 741..835
FT /note="IPT/TIG 3"
FT DOMAIN 1077..1344
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1211..1380
FT /note="Interaction with RANBP9"
FT /evidence="ECO:0000250"
FT REGION 1319..1358
FT /note="Interaction with MUC20"
FT /evidence="ECO:0000250"
FT ACT_SITE 1203
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10028"
FT BINDING 1083..1091
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 1109
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT SITE 305..306
FT /note="Cleavage"
FT /evidence="ECO:0000255"
FT MOD_RES 965
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT MOD_RES 976
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT MOD_RES 989
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT MOD_RES 996
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT MOD_RES 999
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT MOD_RES 1002
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT MOD_RES 1229
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT MOD_RES 1233
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT MOD_RES 1234
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT MOD_RES 1288
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT MOD_RES 1348
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT MOD_RES 1355
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT MOD_RES 1364
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P08581"
FT CARBOHYD 45
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 200
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 397
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 403
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 551
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 592
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 605
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 633
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 784
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 878
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 929
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 95..101
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
FT DISULFID 98..156
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
FT DISULFID 129..137
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
FT DISULFID 170..173
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
FT DISULFID 296..361
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
FT DISULFID 383..395
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
FT DISULFID 518..536
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
FT DISULFID 524..559
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
FT DISULFID 527..543
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
FT DISULFID 539..549
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
SQ SEQUENCE 1380 AA; 153466 MW; 32D24F67032BF2D8 CRC64;
MKAPAALAPG ILVLLLTLVQ KGGGECREAL AKSEMNVNMR YRLPNFTADT PIQNVVVHEG
HVFLGAINSI YVLRERDLQQ VSEYKTGPVW EHPDCLPCQA CGLAGGQWRE NVNMALLVET
YYDDQLISCG SVHRGTCQRH VLPRDNPADI QAEVHCMHSP RADEDEASQC PDCVVSALGT
KVLLAEKQRF VNFFVGNTLN GSSLPGHALH SISVRRIKET QDGFKFLTDK SYIDVLPEFQ
ASYPIKYIHA FESNRFIYFL TVQRETLDSP SFHTRIIRFC SADSGLRSYM EMPLECILTE
KRRKRALRSE VFNVLQAAYV GKPGAQLAKQ IGASAHDDIL YGVFSQSRPD SAEPTDRSAL
CAFPVKYVDE FFHRIVNKNN VRCLQHFYGP NHLHCFNRTL LRNSSGCEVR SDEYRTEFTT
ALQRIDLSAG HFSQVLLTSI STFIKGDLTI ANLGTSEGRF MQVVVSRSGS WTPHVDFRLD
SHAVSPEVIV EHPVNQNGYT LVVTGKKITK IPLDGLGCEH FQSCSQCLSA PPFVQCGWCH
DKCARAEDCP NGTWTQEICL PTIYEVFPAS APLEGGTTLT VCGWDFGFRR NNKSDFKRTR
VLIGNESCPL TLSESTPNML KCTVGPAMSE HSNLSIIISN VRGTAPQYRT FSYVDPEITS
ISPSYGPKAG GTLVTLTGKY LNSGNSRHIS IGGKTCTLKS VSDSVLECYT PAQSISADFP
VKLKIDLANR EAYSFSYQEN PLVVEIHPTK SFVSGGSTIT VVGKNLNSVS VPRMIINVHE
VEMNFTVACQ QRSNSELICC TTPSLQQLDL QLPLKATAFF MLDGIHSRDF DLIYVPNPVF
KLFEKPVMIS MGNENVLEIK GNDIDPEAVK GEVLKVGNKS CENIHSYPES VLCTVPNDLL
KLNSELNIEW KQAVSSTVLG KVIVQPDQNF TGLIVGVVSI SVILLSSLGL FLWLKKRKQI
KDLGSELVCY DARVHTPHLD RLVSARSVSP TTEMVSNESV DYRATFPEDQ FPNSSQNGSC
RQVQYPLPDL SPILTSGDSD ISSPLLQNTV HIDLSALNPE LVQAVQHVVI GPSSLIVHFN
EVIGRGHFGC VYHGTLLDND DRKIHCAVKS LNRITDIGEV SQFLTEGIIM KDFSHPNVLS
LLGICLRSEG SPLVVLPYMK HGDLRNFIRN ETHSPTVKDL IGFGLQVAKG MKYLASKKFV
HRDLAARNCM LDGKFTVKVA DFGLARDMYD KEYYSVHNKT GAKLPVKWMA LESLQTQKFT
TKSDVWSFGV LLWELMTRGA PPYPDVNTFD ITVYLLQGRR LLQPEYCPDP LYEVMLKCWH
PKAEMRPSFT ELVSRISAIF STFIGEHYVH VNATYVNVKC VAPYPSLLSS HDTVDGEVDT
