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MET_PLEMO
ID   MET_PLEMO               Reviewed;        1381 AA.
AC   Q2QLC0;
DT   07-MAR-2006, integrated into UniProtKB/Swiss-Prot.
DT   24-JAN-2006, sequence version 1.
DT   03-AUG-2022, entry version 92.
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   Plecturocebus moloch (Dusky titi monkey) (Callicebus moloch).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Platyrrhini;
OC   Pitheciidae; Callicebinae; Plecturocebus.
OX   NCBI_TaxID=9523;
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 (NOV-2005) 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}.
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DR   EMBL; DP000019; ABB89789.1; -; Genomic_DNA.
DR   AlphaFoldDB; Q2QLC0; -.
DR   SMR; Q2QLC0; -.
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; 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; 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..1381
FT                   /note="Hepatocyte growth factor receptor"
FT                   /id="PRO_0000226360"
FT   TOPO_DOM        25..934
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        935..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        106
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        149
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        202
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..160
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;  154623 MW;  43C77E2A3BC1016B CRC64;
     MKAPAVLAPG ILVLLFTLVQ RSNGECKEAL TKSEMNVNMK YQLPNFTAET PIQNVVLHEH
     HIFLGATNYI YVLNEEDLQK VAEHRTGPVL EHPDCFPCQD CSSKANLSGG VWKDNINMAL
     VVDTYYDDQL ISCGSVNRGT CQRHVFPHNH TADIQSDVHC IFSPQIEEPS QCPDCVVSAL
     GTKVLLSVKD RFLNFFVGNT VNSSYFPDHS LHSISVRRLK ETKNGFMFLT DQSYVDVLPE
     FRDSYPIKYV HAFESNNFIY FLTVQRETLN AQTFHTRIIR FCSINSALHS YMEMPLECIL
     TEKRKKRSTK KEVFNILQAA YVSKPGAQLA RQIGASLNDD ILFGVFAQSK PDSAEPMDRS
     AVCAFPIKYV NDFFNKIVNK NNVRCLQHFY GPNHEHCFNR TFQRNLLGCE ARRDEYRTEF
     TTALQRIDLF AGQFNKVLLT SISTFVKGDL TIANLGTSEG RFIQIVVSRS VPSTPHVNFL
     LDSHPVSPEV IVEQPLNQDG YTLVVTGKKI TKIPLNGLGC RHFQSCSQCL SAPSFVQCGW
     CHDKCVRSEE CSSGTWTQET CLPAIYKVFP TSAPLEGGTR LTICGWDFGF RRNNKFDLKK
     TRVLLGNESC TLTSSESTMN TLKCTIGPAM NEHFNMSIII SNSHGTTQYS TFSYVDPIIT
     SISPRYGPMS GGTLLTLTGN YLNSGNSRHI SIGGKTCTLK SVSNSILECY TPAQTISTEF
     PVKLKIDLAN RETSIFSYLE DPIVYEIHPT KSFISGGSTI TGIGKNLNSV SVPRMVINLH
     EARRNFTVAC QHRSNSEIIC CTTPSLQQLN LQLPLKTKAF FMLDGILSKY FDLIYVHNPV
     FKPFEKPVMI SMGNENVLEI KGNDIDPEAV KGEVLKVGNK SCENIHLHSE AVLCTVPSDL
     LKLNSELNIE WKQAISSTVL GKVIVQPDQN FTGLIAGVVS ISIALLLLLA FFLWLKKRKQ
     IKDLGSELVR YDARVHTPHL DRLVSARSVS PTTEMVSNES VDYRATFPED QFPNSSQNGS
     CRQVQYPLPD 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 SQDNADGEVD
     T
 
 
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