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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