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_MUSPF               Reviewed;        1382 AA.
 Q07E24;
 28-NOV-2006, integrated into UniProtKB/Swiss-Prot.
 31-OCT-2006, sequence version 1.
 25-MAY-2022, entry version 89.
 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;
 Mustela putorius furo (European domestic ferret) (Mustela furo).
 Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
 Eutheria; Laurasiatheria; Carnivora; Caniformia; Mustelidae; Mustelinae;
 Mustela.
 NCBI_TaxID=9669;
 [1]
 NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
 Antonellis A., Ayele K., Benjamin B., Blakesley R.W., Boakye A.,
 Bouffard G.G., Brinkley C., Brooks S., Chu G., Coleman H., Engle J.,
 Gestole M., Greene A., Guan X., Gupta J., Haghighi P., Han J., Hansen N.,
 Ho S.-L., Hu P., Hunter G., Hurle B., Idol J.R., Kwong P., Laric P.,
 Larson S., Lee-Lin S.-Q., Legaspi R., Madden M., Maduro Q.L., Maduro V.B.,
 Margulies E.H., Masiello C., Maskeri B., McDowell J., Mojidi H.A.,
 Mullikin J.C., Oestreicher J.S., Park M., Portnoy M.E., Prasad A., Puri O.,
 Reddix-Dugue N., Schandler K., Schueler M.G., Sison C., Stantripop S.,
 Stephen E., Taye A., Thomas J.W., Thomas P.J., Tsipouri V., Ung L.,
 Vogt J.L., Wetherby K.D., Young A., Green E.D.;
 "NISC comparative sequencing initiative.";
 Submitted (SEP-2006) to the EMBL/GenBank/DDBJ databases.
 -!- 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-1357, 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-1235 and
     Tyr-1236 in the kinase domain leading to further phosphorylation of
     Tyr-1350 and Tyr-1357 in the C-terminal multifunctional docking site.
     Dephosphorylated by PTPRJ at Tyr-1350 and Tyr-1366. 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; DP000183; ABI93652.1; -; Genomic_DNA.
 RefSeq; XP_004741975.1; XM_004741918.2.
 AlphaFoldDB; Q07E24; -.
 SMR; Q07E24; -.
 STRING; 9668.ENSMPUP00000007141; -.
 GeneID; 101675655; -.
 KEGG; mpuf:101675655; -.
 CTD; 4233; -.
 eggNOG; KOG0836; Eukaryota.
 eggNOG; KOG1095; Eukaryota.
 eggNOG; KOG3610; Eukaryota.
 InParanoid; Q07E24; -.
 Proteomes; UP000000715; Unassembled WGS sequence.
 GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
 GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
 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; IEA:UniProtKB-EC.
 GO; GO:0050918; P:positive chemotaxis; ISS:UniProtKB.
 GO; GO:2001028; P:positive regulation of endothelial cell chemotaxis; ISS:UniProtKB.
 GO; GO:0071526; P:semaphorin-plexin signaling pathway; ISS:UniProtKB.
 GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IEA:InterPro.
 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..1382
                 /note="Hepatocyte growth factor receptor"
                 /id="PRO_0000260426"
 TOPO_DOM        25..933
                 /note="Extracellular"
                 /evidence="ECO:0000255"
 TRANSMEM        934..956
                 /note="Helical"
                 /evidence="ECO:0000255"
 TOPO_DOM        957..1382
                 /note="Cytoplasmic"
                 /evidence="ECO:0000255"
 DOMAIN          27..516
                 /note="Sema"
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
 DOMAIN          564..656
                 /note="IPT/TIG 1"
 DOMAIN          658..740
                 /note="IPT/TIG 2"
 DOMAIN          743..837
                 /note="IPT/TIG 3"
 DOMAIN          1079..1346
                 /note="Protein kinase"
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
 NP_BIND         1085..1093
                 /note="ATP"
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
 REGION          1213..1382
                 /note="Interaction with RANBP9"
                 /evidence="ECO:0000250"
 REGION          1321..1360
                 /note="Interaction with MUC20"
                 /evidence="ECO:0000250"
 ACT_SITE        1205
                 /note="Proton acceptor"
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
                 ECO:0000255|PROSITE-ProRule:PRU10028"
 BINDING         1111
                 /note="ATP"
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
 SITE            308..309
                 /note="Cleavage"
                 /evidence="ECO:0000255"
 MOD_RES         967
                 /note="Phosphoserine"
                 /evidence="ECO:0000250|UniProtKB:P08581"
 MOD_RES         978
                 /note="Phosphothreonine"
                 /evidence="ECO:0000250|UniProtKB:P08581"
 MOD_RES         991
                 /note="Phosphoserine"
                 /evidence="ECO:0000250|UniProtKB:P08581"
 MOD_RES         998
                 /note="Phosphoserine"
                 /evidence="ECO:0000250|UniProtKB:P08581"
 MOD_RES         1001
                 /note="Phosphoserine"
                 /evidence="ECO:0000250|UniProtKB:P08581"
 MOD_RES         1004
                 /note="Phosphotyrosine"
                 /evidence="ECO:0000250|UniProtKB:P08581"
 MOD_RES         1231
                 /note="Phosphotyrosine"
                 /evidence="ECO:0000250|UniProtKB:P08581"
 MOD_RES         1235
                 /note="Phosphotyrosine; by autocatalysis"
                 /evidence="ECO:0000250|UniProtKB:P08581"
 MOD_RES         1236
                 /note="Phosphotyrosine; by autocatalysis"
                 /evidence="ECO:0000250|UniProtKB:P08581"
 MOD_RES         1290
                 /note="Phosphothreonine"
                 /evidence="ECO:0000250|UniProtKB:P08581"
 MOD_RES         1350
                 /note="Phosphotyrosine; by autocatalysis"
                 /evidence="ECO:0000250|UniProtKB:P08581"
 MOD_RES         1357
                 /note="Phosphotyrosine; by autocatalysis"
                 /evidence="ECO:0000250|UniProtKB:P08581"
 MOD_RES         1366
                 /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        203
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        359
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        400
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        406
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        608
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        636
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        786
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        880
                 /note="N-linked (GlcNAc...) asparagine"
                 /evidence="ECO:0000255"
 CARBOHYD        931
                 /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        173..176
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
 DISULFID        299..364
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
 DISULFID        386..398
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
 DISULFID        521..539
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
 DISULFID        527..562
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
 DISULFID        530..546
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
 DISULFID        542..552
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00352"
 SEQUENCE   1382 AA;  154655 MW;  FA94AFA93BCD9681 CRC64;
 MRAPAVLAPG ILVLLFTLVQ RSCGECKEAL VKSEMNVNMK YQLPNFTAET PIQNVVLHKH
 HIYLGAVNYI YVLNDKDLQK VAEYKTGPVL EHPDCSPCQD CSHKANLSGA VWKDNINMAL
 LIDIYYDDQL ISCGSVQRGT CQRHVLPRSN TADIQSEVHC MYSPQADEEP GQCPDCVVSA
 LGTKVLISEK TRFINFFVGN TINSSSHPDH SLHSISVRRL KETQDGFKFL TDQSYIDVLP
 EFRDSYPIKY VHAFESNHFI YFLTVQRETL DAQTFHTRVI RFCSVDSGLH SYMEMPLECI
 LTEKRRKRST REEVFNILQA AYVGKPGAHL AKQIGANLND DILYGVFARS QPDSAEPMNR
 SAVCAFPIKY VNEFFNKIVN KNNVRCLQHF YGPNHEHCFN RTLLRNSSGC EVRSDEYRTE
 FTTALQRVDL FMGQFNQVLL TSISTFIKGD LTIANLGTSE GRFMQVVVSR SGSSTPHVNF
 RLDSHPVSPE AIVEHPLNQN GYTLVVTGKK ITKIPLNGLG CEHFQSCSQC LSAPPFVQCG
 WCHDKCVQLE ECPTGTWTQE ICLPTIYEVF PTSAPLEGGT MLTICGWDFG FRRNNKFDLK
 KTKVLLGNES CTLTLSESTT NMLKCTVGPA VNEHFNISII IANGRGTAQY SKFSYVDPII
 TSISPSYGPK TGGTLLTLNG KYLNSGNSRH ISIGGETCTL KSVSDSILEC YTPAQTTPTE
 FPIKLKIDLA NREMNSFSYQ EDPIVYAIHP TKSFISGGST ITAIGKNLHS VSVLRMGINV
 HEARRNFTVA CQHRSNSEII CCTTPSLQQL SLQLPLKTKA FFMLDGIHSK YFDLIYVHNP
 VFKPFEKPVM ISIGNENVLE IKGNDIDPEA VKGEVLKVGN KSCETIYSDS EAVLCKVPND
 LLKLNNELNI EWKQAVSSTI LGKVIVQPDQ NFTGLIVGVI SISLIVLLLL GLFLWLKRRK
 QIKDLGSELV RYDARVHTPH LDRLVSARSV SPTTEMVSNE SVDYRATFPE DQFPNSSQNG
 SCRQVQYPLT DLSPMLTSGD SDISSPLLQN TVHIDLSALN PELVQAVQHV VIGPSSLIVH
 FNEVIGRGHF GCVYHGTLLD NDDKKIHCAV KSLNRITDIG EVSQFLTEGI IMKDFSHPNV
 LSLLGICLRS EGSPLVVLPY MKHGDLRNFI RNETHNPTVK DLIGFGLQVA KGMKYLASKK
 FVHRDLAARN CMLDEKFTVK VADFGLARDM YDKEYYSVHN KTGAKLPVKW MALESLQTQK
 FTTKSDVWSF GVLLWELMTR GAPPYPDVNT FDITVYLLQG RRLLQPEYCP DPLYEVMLKC
 WHPKAELRPS FSELVSRISA IFSTFIGEHY VHVNATYVNV KCVAPYPSLL SSQDIIDGEG
 DT

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