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Protein

Hepatocyte growth factor receptor

Gene

Met

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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). May regulate cortical bone osteogenesis (PubMed:26637977).By similarity2 Publications

Catalytic activityi

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-ProRule annotation

Enzyme regulationi

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).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei1001Required for ligand-induced CBL-mediated ubiquitinationBy similarity1
Binding sitei1108ATPPROSITE-ProRule annotation1
Active sitei1202Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi1082 – 1090ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • hepatocyte growth factor-activated receptor activity Source: MGI
  • protein kinase activity Source: MGI
  • protein phosphatase binding Source: MGI

GO - Biological processi

  • activation of MAPK activity Source: MGI
  • adult behavior Source: MGI
  • brain development Source: MGI
  • branching morphogenesis of an epithelial tube Source: MGI
  • cardiac muscle cell development Source: MGI
  • cardiac muscle contraction Source: MGI
  • chemical synaptic transmission Source: CACAO
  • endothelial cell morphogenesis Source: MGI
  • excitatory postsynaptic potential Source: BHF-UCL
  • glucose homeostasis Source: MGI
  • hepatocyte growth factor receptor signaling pathway Source: MGI
  • liver development Source: MGI
  • modulation of synaptic transmission Source: BHF-UCL
  • muscle cell migration Source: MGI
  • muscle organ development Source: MGI
  • myoblast proliferation Source: MGI
  • myotube differentiation Source: MGI
  • negative regulation of gene expression Source: MGI
  • negative regulation of hydrogen peroxide-mediated programmed cell death Source: MGI
  • negative regulation of transforming growth factor beta production Source: MGI
  • placenta development Source: MGI
  • positive chemotaxis Source: UniProtKB
  • positive regulation of endothelial cell chemotaxis Source: UniProtKB
  • positive regulation of glucose transport Source: MGI
  • positive regulation of p38MAPK cascade Source: MGI
  • positive regulation of transcription from RNA polymerase II promoter Source: MGI
  • protein autophosphorylation Source: MGI
  • reactive oxygen species metabolic process Source: MGI
  • regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling Source: MGI
  • regulation of cellular response to oxidative stress Source: MGI
  • regulation of interleukin-6 production Source: MGI
  • semaphorin-plexin signaling pathway Source: UniProtKB
  • skeletal muscle tissue development Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Receptor, Transferase, Tyrosine-protein kinase

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.1. 3474.

Names & Taxonomyi

Protein namesi
Recommended name:
Hepatocyte growth factor receptor (EC:2.7.10.1)
Short name:
HGF receptor
Alternative name(s):
HGF/SF receptor
Proto-oncogene c-Met
Scatter factor receptor
Short name:
SF receptor
Tyrosine-protein kinase Met
Gene namesi
Name:Met
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Unplaced

Organism-specific databases

MGIiMGI:96969. Met.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini25 – 931ExtracellularSequence analysisAdd BLAST907
Transmembranei932 – 954HelicalSequence analysisAdd BLAST23
Topological domaini955 – 1379CytoplasmicSequence analysisAdd BLAST425

GO - Cellular componenti

  • basal plasma membrane Source: MGI
  • cell surface Source: MGI
  • integral component of membrane Source: UniProtKB-KW
  • membrane Source: MGI
  • postsynapse Source: GOC
Complete GO annotation...

Keywords - Cellular componenti

Membrane

Pathology & Biotechi

Involvement in diseasei

Activation of Met after rearrangement with the TPR (translocated promoter) locus of chromosome 1 produces an oncogenic protein.

Keywords - Diseasei

Proto-oncogene

Chemistry databases

ChEMBLiCHEMBL5585.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 24Sequence analysisAdd BLAST24
ChainiPRO_000002444125 – 1379Hepatocyte growth factor receptorAdd BLAST1355

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi45N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi95 ↔ 101PROSITE-ProRule annotation
Disulfide bondi98 ↔ 160PROSITE-ProRule annotation
Glycosylationi106N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi133 ↔ 141PROSITE-ProRule annotation
Disulfide bondi171 ↔ 174PROSITE-ProRule annotation
Glycosylationi201N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi297 ↔ 362PROSITE-ProRule annotation
Glycosylationi357N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi384 ↔ 396PROSITE-ProRule annotation
Glycosylationi398N-linked (GlcNAc...)Sequence analysis1
Glycosylationi404N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi519 ↔ 537PROSITE-ProRule annotation
Disulfide bondi525 ↔ 560PROSITE-ProRule annotation
Disulfide bondi528 ↔ 544PROSITE-ProRule annotation
Disulfide bondi540 ↔ 550PROSITE-ProRule annotation
Glycosylationi606N-linked (GlcNAc...)Sequence analysis1
Glycosylationi634N-linked (GlcNAc...)Sequence analysis1
Glycosylationi784N-linked (GlcNAc...)Sequence analysis1
Glycosylationi878N-linked (GlcNAc...)Sequence analysis1
Modified residuei964PhosphoserineBy similarity1
Modified residuei975PhosphothreonineBy similarity1
Modified residuei988PhosphoserineBy similarity1
Modified residuei995PhosphoserineBy similarity1
Modified residuei998PhosphoserineBy similarity1
Modified residuei1001PhosphotyrosineBy similarity1
Modified residuei1228PhosphotyrosineBy similarity1
Modified residuei1232Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei1233Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei1287PhosphothreonineBy similarity1
Modified residuei1347Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei1354Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei1363PhosphotyrosineBy similarity1

Post-translational modificationi

Autophosphorylated in response to ligand binding on Tyr-1232 and Tyr-1233 in the kinase domain leading to further phosphorylation of Tyr-1347 and Tyr-1354 in the C-terminal multifunctional docking site. Dephosphorylated by PTPRJ at Tyr-1347 and Tyr-1363 (By similarity). Dephosphorylated by PTPN1 and PTPN2 (By similarity).By similarity
Ubiquitinated. Ubiquitination by CBL regulates MET endocytosis, resulting in decreasing plasma membrane receptor abundance, and in endosomal degradation and/or recycling of internalized receptors.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei306 – 307CleavageSequence analysis2

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiP16056.
PaxDbiP16056.
PeptideAtlasiP16056.
PRIDEiP16056.

PTM databases

iPTMnetiP16056.
PhosphoSitePlusiP16056.
SwissPalmiP16056.

Miscellaneous databases

PMAP-CutDBP16056.

Expressioni

Developmental stagei

Low though detectable expression at 10 dpc. From 15 dpc at least until 17 dpc, expression strongly increases. Down-regulated in the adult.1 Publication

Gene expression databases

CleanExiMM_MET.

Interactioni

Subunit structurei

Heterodimer made of an alpha chain (50 kDa) and a beta chain (145 kDa) which are disulfide linked (By similarity). Binds PLXNB1 (By similarity). Interacts when phosphorylated with downstream effectors including STAT3, PIK3R1, SRC, PCLG1, GRB2 and GAB1 (By similarity). When phosphorylated at Tyr-1354, interacts with INPPL1/SHIP2 (By similarity). Interacts with RANBP9 and RANBP10 (By similarity). Interacts with INPP5D/SHIP1. Interacts with SPSB1, SPSB2, SPSB4 and probably SPSB3. 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 (By similarity). Interacts with PTPN1 and PTPN2 (By similarity).By similarity

Binary interactionsi

WithEntry#Exp.IntActNotes
CblP226822EBI-1798780,EBI-640919
HGFP142102EBI-1798780,EBI-1039104From a different organism.
KdrP359183EBI-1798780,EBI-1555005

GO - Molecular functioni

Protein-protein interaction databases

IntActiP16056. 4 interactors.
MINTiMINT-137318.
STRINGi10090.ENSMUSP00000079324.

Chemistry databases

BindingDBiP16056.

Structurei

3D structure databases

ProteinModelPortaliP16056.
SMRiP16056.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini27 – 514SemaPROSITE-ProRule annotationAdd BLAST488
Domaini562 – 654IPT/TIG 1Add BLAST93
Domaini656 – 738IPT/TIG 2Add BLAST83
Domaini741 – 835IPT/TIG 3Add BLAST95
Domaini1076 – 1343Protein kinasePROSITE-ProRule annotationAdd BLAST268

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1210 – 1379Interaction with RANBP9By similarityAdd BLAST170
Regioni1318 – 1357Interaction with MUC20By similarityAdd BLAST40

Domaini

The kinase domain is involved in SPSB1 binding.By similarity
The beta-propeller Sema domain mediates binding to HGF.By similarity

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family.PROSITE-ProRule annotation
Contains 3 IPT/TIG domains.Curated
Contains 1 protein kinase domain.PROSITE-ProRule annotation
Contains 1 Sema domain.PROSITE-ProRule annotation

Keywords - Domaini

Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG1095. Eukaryota.
KOG3610. Eukaryota.
COG0515. LUCA.
HOGENOMiHOG000220900.
HOVERGENiHBG006348.
InParanoidiP16056.
PhylomeDBiP16056.

Family and domain databases

Gene3Di2.130.10.10. 1 hit.
2.60.40.10. 3 hits.
InterProiIPR013783. Ig-like_fold.
IPR014756. Ig_E-set.
IPR002909. IPT.
IPR011009. Kinase-like_dom.
IPR002165. Plexin_repeat.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR016201. PSI.
IPR001627. Semap_dom.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
IPR016244. Tyr_kinase_HGF/MSP_rcpt.
IPR015943. WD40/YVTN_repeat-like_dom.
[Graphical view]
PfamiPF07714. Pkinase_Tyr. 1 hit.
PF01437. PSI. 1 hit.
PF01403. Sema. 1 hit.
PF01833. TIG. 3 hits.
[Graphical view]
PIRSFiPIRSF000617. TyrPK_HGF-R. 1 hit.
PRINTSiPR00109. TYRKINASE.
SMARTiSM00429. IPT. 4 hits.
SM00423. PSI. 1 hit.
SM00630. Sema. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF101912. SSF101912. 1 hit.
SSF56112. SSF56112. 1 hit.
SSF81296. SSF81296. 3 hits.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
PS51004. SEMA. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P16056-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MKAPTVLAPG ILVLLLSLVQ RSHGECKEAL VKSEMNVNMK YQLPNFTAET
60 70 80 90 100
PIQNVVLHGH HIYLGATNYI YVLNDKDLQK VSEFKTGPVL EHPDCLPCRD
110 120 130 140 150
CSSKANSSGG VWKDNINMAL LVDTYYDDQL ISCGSVNRGT CQRHVLPPDN
160 170 180 190 200
SADIQSEVHC MFSPEEESGQ CPDCVVSALG AKVLLSEKDR FINFFVGNTI
210 220 230 240 250
NSSYPPGYSL HSISVRRLKE TQDGFKFLTD QSYIDVLPEF LDSYPIKYIH
260 270 280 290 300
AFESNHFIYF LTVQKETLDA QTFHTRIIRF CSVDSGLHSY MEMPLECILT
310 320 330 340 350
EKRRKRSTRE EVFNILQAAY VSKPGANLAK QIGASPSDDI LFGVFAQSKP
360 370 380 390 400
DSAEPVNRSA VCAFPIKYVN DFFNKIVNKN NVRCLQHFYG PNHEHCFNRT
410 420 430 440 450
LLRNSSGCEA RSDEYRTEFT TALQRVDLFM GRLNQVLLTS ISTFIKGDLT
460 470 480 490 500
IANLGTSEGR FMQVVLSRTA HLTPHVNFLL DSHPVSPEVI VEHPSNQNGY
510 520 530 540 550
TLVVTGKKIT KIPLNGLGCG HFQSCSQCLS APYFIQCGWC HNQCVRFDEC
560 570 580 590 600
PSGTWTQEIC LPAVYKVFPT SAPLEGGTVL TICGWDFGFR KNNKFDLRKT
610 620 630 640 650
KVLLGNESCT LTLSESTTNT LKCTVGPAMS EHFNVSVIIS NSRETTQYSA
660 670 680 690 700
FSYVDPVITS ISPRYGPQAG GTLLTLTGKY LNSGNSRHIS IGGKTCTLKS
710 720 730 740 750
VSDSILECYT PAQTTSDEFP VKLKIDLANR ETSSFSYRED PVVYEIHPTK
760 770 780 790 800
SFISGGSTIT GIGKTLNSVS LPKLVIDVHE VGVNYTVACQ HRSNSEIICC
810 820 830 840 850
TTPSLKQLGL QLPLKTKAFF LLDGILSKHF DLTYVHNPVF EPFEKPVMIS
860 870 880 890 900
MGNENVVEIK GNNIDPEAVK GEVLKVGNQS CESLHWHSGA VLCTVPSDLL
910 920 930 940 950
KLNSELNIEW KQAVSSTVLG KVIVQPDQNF AGLIIGAVSI SVVVLLLSGL
960 970 980 990 1000
FLWMRKRKHK DLGSELVRYD ARVHTPHLDR LVSARSVSPT TEMVSNESVD
1010 1020 1030 1040 1050
YRATFPEDQF PNSSQNGACR QVQYPLTDLS PILTSGDSDI SSPLLQNTVH
1060 1070 1080 1090 1100
IDLSALNPEL VQAVQHVVIG PSSLIVHFNE VIGRGHFGCV YHGTLLDNDG
1110 1120 1130 1140 1150
KKIHCAVKSL NRITDIEEVS QFLTEGIIMK DFSHPNVLSL LGICLRSEGS
1160 1170 1180 1190 1200
PLVVLPYMKH GDLRNFIRNE THNPTVKDLI GFGLQVAKGM KYLASKKFVH
1210 1220 1230 1240 1250
RDLAARNCML DEKFTVKVAD FGLARDMYDK EYYSVHNKTG AKLPVKWMAL
1260 1270 1280 1290 1300
ESLQTQKFTT KSDVWSFGVL LWELMTRGAP PYPDVNTFDI TIYLLQGRRL
1310 1320 1330 1340 1350
LQPEYCPDAL YEVMLKCWHP KAEMRPSFSE LVSRISSIFS TFIGEHYVHV
1360 1370
NATYVNVKCV APYPSLLPSQ DNIDGEGNT
Length:1,379
Mass (Da):153,549
Last modified:April 1, 1990 - v1
Checksum:iFC5CC87FDD8ADED8
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti1199V → I in AAA40015 (PubMed:2482828).Curated1
Sequence conflicti1255T → R in AAA40015 (PubMed:2482828).Curated1
Sequence conflicti1261K → T in AAA40015 (PubMed:2482828).Curated1
Sequence conflicti1269 – 1270VL → IP (PubMed:2482828).Curated2

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
Y00671 mRNA. Translation: CAA68680.1.
M33424 mRNA. Translation: AAA40015.1.
CCDSiCCDS19925.1.
PIRiS01254.
UniGeneiMm.86844.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
Y00671 mRNA. Translation: CAA68680.1.
M33424 mRNA. Translation: AAA40015.1.
CCDSiCCDS19925.1.
PIRiS01254.
UniGeneiMm.86844.

3D structure databases

ProteinModelPortaliP16056.
SMRiP16056.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiP16056. 4 interactors.
MINTiMINT-137318.
STRINGi10090.ENSMUSP00000079324.

Chemistry databases

BindingDBiP16056.
ChEMBLiCHEMBL5585.

PTM databases

iPTMnetiP16056.
PhosphoSitePlusiP16056.
SwissPalmiP16056.

Proteomic databases

MaxQBiP16056.
PaxDbiP16056.
PeptideAtlasiP16056.
PRIDEiP16056.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Organism-specific databases

MGIiMGI:96969. Met.

Phylogenomic databases

eggNOGiKOG1095. Eukaryota.
KOG3610. Eukaryota.
COG0515. LUCA.
HOGENOMiHOG000220900.
HOVERGENiHBG006348.
InParanoidiP16056.
PhylomeDBiP16056.

Enzyme and pathway databases

BRENDAi2.7.10.1. 3474.

Miscellaneous databases

ChiTaRSiMet. mouse.
PMAP-CutDBP16056.
PROiP16056.
SOURCEiSearch...

Gene expression databases

CleanExiMM_MET.

Family and domain databases

Gene3Di2.130.10.10. 1 hit.
2.60.40.10. 3 hits.
InterProiIPR013783. Ig-like_fold.
IPR014756. Ig_E-set.
IPR002909. IPT.
IPR011009. Kinase-like_dom.
IPR002165. Plexin_repeat.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR016201. PSI.
IPR001627. Semap_dom.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
IPR016244. Tyr_kinase_HGF/MSP_rcpt.
IPR015943. WD40/YVTN_repeat-like_dom.
[Graphical view]
PfamiPF07714. Pkinase_Tyr. 1 hit.
PF01437. PSI. 1 hit.
PF01403. Sema. 1 hit.
PF01833. TIG. 3 hits.
[Graphical view]
PIRSFiPIRSF000617. TyrPK_HGF-R. 1 hit.
PRINTSiPR00109. TYRKINASE.
SMARTiSM00429. IPT. 4 hits.
SM00423. PSI. 1 hit.
SM00630. Sema. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF101912. SSF101912. 1 hit.
SSF56112. SSF56112. 1 hit.
SSF81296. SSF81296. 3 hits.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
PS51004. SEMA. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiMET_MOUSE
AccessioniPrimary (citable) accession number: P16056
Secondary accession number(s): Q62125
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 1, 1990
Last sequence update: April 1, 1990
Last modified: November 30, 2016
This is version 175 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.