P16056 (MET_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Hepatocyte growth factor receptor
Short name=HGF receptor
EC=2.7.10.1

Alternative name(s):
HGF/SF receptor
Proto-oncogene c-Met
Scatter factor receptor
Short name=SF receptor
Tyrosine-protein kinase Met

Gene names

Name:

Met

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	1379 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

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. Ref.4
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Enzyme 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.
Subunit structure	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. Ref.5 Ref.6 Ref.7
Subcellular location	Membrane; Single-pass type I membrane protein.
Domain	The kinase domain is involved in SPSB1 binding By similarity. The beta-propeller Sema domain mediates binding to HGF By similarity.
Post-translational modification	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 By similarity. Dephosphorylated by PTPRJ at Tyr-1347 and Tyr-1363 By similarity. Ubiquitinated. Ubiquitination by CBL regulates the receptor stability and activity through proteasomal degradation By similarity.
Involvement in disease	Activation of Met after rearrangement with the TPR (translocated promoter) locus of chromosome 1 produces an oncogenic protein.
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. Contains 3 IPT/TIG domains. Contains 1 protein kinase domain. Contains 1 Sema domain.

Ontologies

Keywords
Cellular component	Membrane
Disease	Proto-oncogene
Domain	Repeat Signal Transmembrane Transmembrane helix
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Receptor Transferase Tyrosine-protein kinase
PTM	Disulfide bond Glycoprotein Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	activation of MAPK activity Inferred from physical interaction Ref.6. Source: MGI adult behavior Inferred from mutant phenotype PubMed 12397180. Source: MGI brain development Inferred from mutant phenotype PubMed 12397180. Source: MGI glucose homeostasis Inferred from mutant phenotype PubMed 16049329. Source: MGI liver development Inferred from mutant phenotype Ref.4. Source: MGI muscle cell migration Inferred from mutant phenotype Ref.4. Source: MGI myoblast proliferation Inferred from mutant phenotype PubMed 11061428. Source: MGI myotube differentiation Inferred from mutant phenotype Ref.4. Source: MGI placenta development Inferred from mutant phenotype Ref.4. Source: MGI positive regulation of glucose transport Inferred from mutant phenotype PubMed 16049329. Source: MGI protein autophosphorylation Inferred from direct assay Ref.6. Source: MGI regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling Inferred from mutant phenotype PubMed 14517989. Source: MGI regulation of excitatory postsynaptic membrane potential Inferred from mutant phenotype PubMed 21490227. Source: BHF-UCL regulation of synaptic transmission Inferred from mutant phenotype PubMed 21490227. Source: BHF-UCL
Cellular_component	basal plasma membrane Inferred from sequence orthology Ref.6. Source: MGI integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW hepatocyte growth factor-activated receptor activity Inferred from direct assay Ref.6. Source: MGI
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
HGF	P14210	2	EBI-1798780,EBI-1039104	From a different organism.
Kdr	P35918	3	EBI-1798780,EBI-1555005

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 24	24	Potential
	Chain	25 – 1379	1355	Hepatocyte growth factor receptor		PRO_0000024441
Regions
	Topological domain	25 – 931	907	Extracellular Potential
	Transmembrane	932 – 954	23	Helical; Potential
	Topological domain	955 – 1379	425	Cytoplasmic Potential
	Domain	27 – 514	488	Sema
	Domain	562 – 654	93	IPT/TIG 1
	Domain	656 – 738	83	IPT/TIG 2
	Domain	741 – 835	95	IPT/TIG 3
	Domain	1076 – 1343	268	Protein kinase
	Nucleotide binding	1082 – 1090	9	ATP By similarity
	Region	1210 – 1379	170	Interaction with RANBP9 By similarity
	Region	1318 – 1357	40	Interaction with MUC20 By similarity
Sites
	Active site	1202	1	Proton acceptor By similarity
	Binding site	1108	1	ATP By similarity
	Site	306 – 307	2	Cleavage Potential
Amino acid modifications
	Modified residue	975	1	Phosphothreonine By similarity
	Modified residue	988	1	Phosphoserine By similarity
	Modified residue	995	1	Phosphoserine By similarity
	Modified residue	998	1	Phosphoserine By similarity
	Modified residue	1001	1	Phosphotyrosine By similarity
	Modified residue	1228	1	Phosphotyrosine By similarity
	Modified residue	1232	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1233	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1287	1	Phosphothreonine By similarity
	Modified residue	1347	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1354	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1363	1	Phosphotyrosine By similarity
	Glycosylation	45	1	N-linked (GlcNAc...) Potential
	Glycosylation	106	1	N-linked (GlcNAc...) Potential
	Glycosylation	201	1	N-linked (GlcNAc...) Potential
	Glycosylation	357	1	N-linked (GlcNAc...) Potential
	Glycosylation	398	1	N-linked (GlcNAc...) Potential
	Glycosylation	404	1	N-linked (GlcNAc...) Potential
	Glycosylation	606	1	N-linked (GlcNAc...) Potential
	Glycosylation	634	1	N-linked (GlcNAc...) Potential
	Glycosylation	784	1	N-linked (GlcNAc...) Potential
	Glycosylation	878	1	N-linked (GlcNAc...) Potential
	Disulfide bond	95 ↔ 101		By similarity
	Disulfide bond	98 ↔ 160		By similarity
	Disulfide bond	133 ↔ 141		By similarity
	Disulfide bond	171 ↔ 174		By similarity
	Disulfide bond	297 ↔ 362		By similarity
	Disulfide bond	384 ↔ 396		By similarity
	Disulfide bond	519 ↔ 537		By similarity
	Disulfide bond	525 ↔ 560		By similarity
	Disulfide bond	528 ↔ 544		By similarity
	Disulfide bond	540 ↔ 550		By similarity
Experimental info
	Sequence conflict	1199	1	V → I in AAA40015. Ref.2
	Sequence conflict	1255	1	T → R in AAA40015. Ref.2
	Sequence conflict	1261	1	K → T in AAA40015. Ref.2
	Sequence conflict	1269 – 1270	2	VL → IP Ref.2

Sequences

	Sequence		Length	Mass (Da)
	P16056 [UniParc]. Last modified April 1, 1990. Version 1. Checksum: FC5CC87FDD8ADED8	FASTA	1,379	153,549
	10 20 30 40 50 60 MKAPTVLAPG ILVLLLSLVQ RSHGECKEAL VKSEMNVNMK YQLPNFTAET PIQNVVLHGH 70 80 90 100 110 120 HIYLGATNYI YVLNDKDLQK VSEFKTGPVL EHPDCLPCRD CSSKANSSGG VWKDNINMAL 130 140 150 160 170 180 LVDTYYDDQL ISCGSVNRGT CQRHVLPPDN SADIQSEVHC MFSPEEESGQ CPDCVVSALG 190 200 210 220 230 240 AKVLLSEKDR FINFFVGNTI NSSYPPGYSL HSISVRRLKE TQDGFKFLTD QSYIDVLPEF 250 260 270 280 290 300 LDSYPIKYIH AFESNHFIYF LTVQKETLDA QTFHTRIIRF CSVDSGLHSY MEMPLECILT 310 320 330 340 350 360 EKRRKRSTRE EVFNILQAAY VSKPGANLAK QIGASPSDDI LFGVFAQSKP DSAEPVNRSA 370 380 390 400 410 420 VCAFPIKYVN DFFNKIVNKN NVRCLQHFYG PNHEHCFNRT LLRNSSGCEA RSDEYRTEFT 430 440 450 460 470 480 TALQRVDLFM GRLNQVLLTS ISTFIKGDLT IANLGTSEGR FMQVVLSRTA HLTPHVNFLL 490 500 510 520 530 540 DSHPVSPEVI VEHPSNQNGY TLVVTGKKIT KIPLNGLGCG HFQSCSQCLS APYFIQCGWC 550 560 570 580 590 600 HNQCVRFDEC PSGTWTQEIC LPAVYKVFPT SAPLEGGTVL TICGWDFGFR KNNKFDLRKT 610 620 630 640 650 660 KVLLGNESCT LTLSESTTNT LKCTVGPAMS EHFNVSVIIS NSRETTQYSA FSYVDPVITS 670 680 690 700 710 720 ISPRYGPQAG GTLLTLTGKY LNSGNSRHIS IGGKTCTLKS VSDSILECYT PAQTTSDEFP 730 740 750 760 770 780 VKLKIDLANR ETSSFSYRED PVVYEIHPTK SFISGGSTIT GIGKTLNSVS LPKLVIDVHE 790 800 810 820 830 840 VGVNYTVACQ HRSNSEIICC TTPSLKQLGL QLPLKTKAFF LLDGILSKHF DLTYVHNPVF 850 860 870 880 890 900 EPFEKPVMIS MGNENVVEIK GNNIDPEAVK GEVLKVGNQS CESLHWHSGA VLCTVPSDLL 910 920 930 940 950 960 KLNSELNIEW KQAVSSTVLG KVIVQPDQNF AGLIIGAVSI SVVVLLLSGL FLWMRKRKHK 970 980 990 1000 1010 1020 DLGSELVRYD ARVHTPHLDR LVSARSVSPT TEMVSNESVD YRATFPEDQF PNSSQNGACR 1030 1040 1050 1060 1070 1080 QVQYPLTDLS PILTSGDSDI SSPLLQNTVH IDLSALNPEL VQAVQHVVIG PSSLIVHFNE 1090 1100 1110 1120 1130 1140 VIGRGHFGCV YHGTLLDNDG KKIHCAVKSL NRITDIEEVS QFLTEGIIMK DFSHPNVLSL 1150 1160 1170 1180 1190 1200 LGICLRSEGS PLVVLPYMKH GDLRNFIRNE THNPTVKDLI GFGLQVAKGM KYLASKKFVH 1210 1220 1230 1240 1250 1260 RDLAARNCML DEKFTVKVAD FGLARDMYDK EYYSVHNKTG AKLPVKWMAL ESLQTQKFTT 1270 1280 1290 1300 1310 1320 KSDVWSFGVL LWELMTRGAP PYPDVNTFDI TIYLLQGRRL LQPEYCPDAL YEVMLKCWHP 1330 1340 1350 1360 1370 KAEMRPSFSE LVSRISSIFS TFIGEHYVHV NATYVNVKCV APYPSLLPSQ DNIDGEGNT

References

[1]	"Characterization of the mouse met proto-oncogene." Chan A.M.-L., King H.W.S., Deakin E.A., Tempest P.R., Hilkens J., Kroezen V., Edwards D.R., Wills A.J., Brookes P., Cooper C.S. Oncogene 2:593-599(1988) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"The application of the polymerase chain reaction to cloning members of the protein tyrosine kinase family." Wilks A.F., Kurban R.R., Hovens C.M., Ralph S.J. Gene 85:67-74(1989) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1199-1270.
[3]	"The Met receptor tyrosine kinase transduces motility, proliferation, and morphogenic signals of scatter factor/hepatocyte growth factor in epithelial cells." Weidner K.M., Sachs M., Birchmeier W. J. Cell Biol. 121:145-154(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 924-935.
[4]	"Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud." Bladt F., Riethmacher D., Isenmann S., Aguzzi A., Birchmeier C. Nature 376:768-771(1995) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN DEVELOPMENT.
[5]	"The SH2-containing inositol 5-phosphatase (SHIP)-1 is implicated in the control of cell-cell junction and induces dissociation and dispersion of MDCK cells." Mancini A., Koch A., Wilms R., Tamura T. Oncogene 21:1477-1484(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH INPP5D.
[6]	"MUC20 suppresses the hepatocyte growth factor-induced Grb2-Ras pathway by binding to a multifunctional docking site of met." Higuchi T., Orita T., Katsuya K., Yamasaki Y., Akiyama K., Li H., Yamamoto T., Saito Y., Nakamura M. Mol. Cell. Biol. 24:7456-7468(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH MUC20.
[7]	"The SPRY domain of SSB-2 adopts a novel fold that presents conserved Par-4-binding residues." Masters S.L., Yao S., Willson T.A., Zhang J.-G., Palmer K.R., Smith B.J., Babon J.J., Nicola N.A., Norton R.S., Nicholson S.E. Nat. Struct. Mol. Biol. 13:77-84(2006) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SPSB1; SPSB2 AND SPSB4.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	Y00671 mRNA. Translation: CAA68680.1. M33424 mRNA. Translation: AAA40015.1.
IPI	IPI00130420.
PIR	S01254.
UniGene	Mm.86844.
3D structure databases
ProteinModelPortal	P16056.
SMR	P16056. Positions 40-740, 1044-1376.
ModBase	Search...
Protein-protein interaction databases
IntAct	P16056. 2 interactions.
MINT	MINT-137318.
PTM databases
PhosphoSite	P16056.
Proteomic databases
PaxDb	P16056.
PRIDE	P16056.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Organism-specific databases
MGI	MGI:96969. Met.
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000220900.
HOVERGEN	HBG006348.
InParanoid	P16056.
OrthoDB	EOG466VK2.
Enzyme and pathway databases
BRENDA	2.7.10.1. 3474.
Gene expression databases
CleanEx	MM_MET.
Genevestigator	P16056.
GermOnline	ENSMUSG00000009376. Mus musculus.
Family and domain databases
Gene3D	2.130.10.10. 1 hit. 2.60.40.10. 3 hits.
InterPro	IPR013783. Ig-like_fold. IPR014756. Ig_E-set. IPR002909. IPT_TIG_rcpt. IPR011009. Kinase-like_dom. IPR003659. Plexin-like. IPR016201. Plexin-like_fold. IPR002165. Plexin_repeat. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR001627. Semaphorin/CD100_Ag. 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]
Pfam	PF07714. Pkinase_Tyr. 1 hit. PF01437. PSI. 1 hit. PF01403. Sema. 1 hit. PF01833. TIG. 3 hits. [Graphical view]
PIRSF	PIRSF000617. TyrPK_HGF-R. 1 hit.
PRINTS	PR00109. TYRKINASE.
SMART	SM00429. IPT. 4 hits. SM00423. PSI. 1 hit. SM00630. Sema. 1 hit. SM00219. TyrKc. 1 hit. [Graphical view]
SUPFAM	SSF81296. Ig_E-set. 3 hits. SSF56112. Kinase_like. 1 hit. SSF103575. Plexin-like_fold. 1 hit. SSF101912. Sema. 1 hit.
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00109. PROTEIN_KINASE_TYR. 1 hit. PS51004. SEMA. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChEMBL	CHEMBL5585.
ChiTaRS	MET. mouse.
PMAP-CutDB	P16056.
SOURCE	Search...

Entry information

Entry name

MET_MOUSE

Accession

Primary (citable) accession number: P16056
Secondary accession number(s): Q62125

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 1, 1990
Last sequence update:	April 1, 1990
Last modified:	May 1, 2013
This is version 140 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program