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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