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_MICMU               Reviewed;        1382 AA.
 Q2QL89;
 07-MAR-2006, integrated into UniProtKB/Swiss-Prot.
 24-JAN-2006, sequence version 1.
 23-FEB-2022, entry version 99.
 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;
 Microcebus murinus (Gray mouse lemur) (Lemur murinus).
 Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
 Eutheria; Euarchontoglires; Primates; Strepsirrhini; Lemuriformes;
 Cheirogaleidae; Microcebus.
 NCBI_TaxID=30608;
 [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 (NOV-2005) 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; DP000022; ABB89820.1; -; Genomic_DNA.
 RefSeq; XP_012616555.1; XM_012761101.1.
 SMR; Q2QL89; -.
 Ensembl; ENSMICT00000062442; ENSMICP00000048273; ENSMICG00000000697.
 GeneID; 105869368; -.
 KEGG; mmur:105869368; -.
 CTD; 4233; -.
 GeneTree; ENSGT00940000158022; -.
 OMA; DEEPGQC; -.
 OrthoDB; 408584at2759; -.
 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; 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; 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; 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_0000226363"
 TOPO_DOM        25..935
                 /note="Extracellular"
                 /evidence="ECO:0000255"
 TRANSMEM        936..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        100
                 /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;  154241 MW;  4046867B98D893D2 CRC64;
 MKASAVLAPG ILALLFTLVQ GSDGECHEAL AKSEMNVNMK YQLPNFTAET PIQNVVLHDH
 HIYLGATNYI YVLNDRDLQK VAEYKTGPVL EHPDCFPCQN CSDIANFSGG IWKDNINRAL
 LVDTYYDDQL ISCGSVNRGA CQRHVLPPDN PADIRSEVHC MFSPQADEEP GQCPDCVVSA
 LGAKVLLSVK DRFINFFVGN TLNSSYFPDH PLHSISVRRL KETQDGFKFL TDQSYIDVLP
 EFRDSYPIKY VHAFESNHFI YFLTVQRETL DAQTFHTRII RFCSVDSGLH SYMEMPLECI
 LTEKRRKRST REEVFNILQA AYVSKPGAQL AKQIGASLND DILFGVFAQS KPDSAEPMNR
 SAVCAFPIKY VNDFFNKIVN KNNVRCLQHF YGPHHEHCFN RTLLRNSSGC EVRKDEYRTE
 FTTALQRVDL FMGQFNQVLL TSISTFIKGD LTIANLGTSE GRFMQVVVSR SGSSTPHVNF
 QLDSHPVSPE VIVEHPLNQN GYTLVVTGKR ITKIPLNGLG CGHFQSCSQC LSAPSFVQCG
 WCHDKCVRSE ECPTGTWTQE ICLPAIHKVF PTSAPLEGGT MLTICGWDFG FRRNNKFDLK
 KTKVLLGNES CTLTLSESTT NMLKCTVGPA MSEHFNMSIV ISHGRGMTQY STFSYVDPVI
 TSISPSYGPK AGGTLLTLTG KYLNSGNSRH ISIGGKTCTL KSVSNSILEC YTPAQIISTE
 FPVKLKIDLA NRETSSFSYQ EDPVVYEIHP TKSFVSGGST ITGVGKNLNS VSVPRMVINV
 QEAGRNFTVA CQHRSNSEII CCTTPSLQQL NLQLPLKTKA FFMLDGILSK YFDLIYVHNP
 VFKPFEKPVM ISMGNENVLE IKGNDIDPEA VKGEVLKVGN KSCENIHSHS EAVLCTVPND
 LLKLNSELNI EWKQAVSSTV LGKVIVQPDQ NFTGLIVGVV SISIILLLLL GLFLWMKKRK
 QIKDLGSELV RYDARVHTPH LDRLVSARSV SPTTEMVSNE SVDYRATFPE DQFPNSSQNG
 SCRQVQYPLT DLSPILTSGD SDISSPLLQN TVHIDLSALN PELVQAVQHV VIGPSSLIVH
 FNEVIGRGHF GCVYHGTLLD NDGKKIHCAV KSLNRITDIG EVSQFLTEGI IMKDFSHPNV
 LSLLGICLRS EGSPLVVLPY MKHGDLRNFI RNETHNPTVK DLIGFGLQVA KGMKYLASKK
 FVHRDLAARN CMLDEKFTVK VADFGLARDM YDKEYYSVHN KTGAKLPVKW MALESLQTQK
 FTTKSDVWSF GVLLWELMTR GAPPYPDVNT FDITVYLLQG RRLLQPEYCP DPLYEVMLKC
 WHPKAEMRPS FSELVSRISA IFSTFIGEHY VHVNATYVNV KCVAPYPSLL SSQDNINGEV
 DT

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