P97523 (MET_RAT) 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

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [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 › Rattus

Protein attributes

Sequence length	1382 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.
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. Binds PLXNB1. Interacts when phosphorylated with downstream effectors including STAT3, PIK3R1, SRC, PCLG1, GRB2 and GAB1. Interacts with SPSB1, SPSB2 and SPSB4 By similarity. 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 By similarity.
Subcellular location	Membrane; Single-pass type I membrane protein.
Tissue specificity	Expressed at highest levels in lung, liver and kidney, also expressed in stomach, intestine, spleen, testis and brain. Not expressed in heart or muscle.
Developmental stage	Expression is down-regulated during pregnancy and is virtually undetectable during lactation. Expression progressively increases post-lactation.
Induction	By interleukin-6 and acute acid-induced gastric injury. Inhibited by prolactin.
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-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 By similarity. Dephosphorylated by PTPRJ at Tyr-1350 and Tyr-1366 By similarity. Ubiquitinated. Ubiquitination by CBL regulates the receptor stability and activity through proteasomal degradation By similarity.
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	brain development Inferred from expression pattern PubMed 12106690. Source: RGD cell aging Inferred from expression pattern PubMed 18202313. Source: RGD cellular response to arsenic-containing substance Inferred from expression pattern PubMed 16876216. Source: RGD cellular response to glucose stimulus Inferred from expression pattern PubMed 17124385. Source: RGD cellular response to growth factor stimulus Inferred from expression pattern PubMed 7526865. Source: RGD cellular response to inorganic substance Inferred from expression pattern PubMed 12839939. Source: RGD cellular response to interleukin-6 Inferred from expression pattern Ref.2. Source: RGD cellular response to peptide hormone stimulus Inferred from expression pattern PubMed 17035232. Source: RGD central nervous system neuron differentiation Inferred from expression pattern PubMed 18262389. Source: RGD lactation Inferred from expression pattern Ref.4. Source: RGD liver development Inferred from expression pattern PubMed 8506951. Source: RGD male gonad development Inferred from expression pattern PubMed 11316747. Source: RGD negative regulation of peptidyl-threonine phosphorylation Inferred from mutant phenotype PubMed 18262389. Source: RGD negative regulation of transcription from RNA polymerase II promoter Inferred from mutant phenotype PubMed 17427161. Source: RGD neuron migration Inferred from direct assay PubMed 12106690. Source: RGD oligodendrocyte development Inferred from expression pattern PubMed 17382307. Source: RGD pancreas development Inferred from expression pattern PubMed 8954115. Source: RGD positive regulation of DNA replication Inferred from mutant phenotype PubMed 17427161. Source: RGD positive regulation of dendrite morphogenesis Inferred from mutant phenotype PubMed 18262389. Source: RGD positive regulation of mitosis Inferred from mutant phenotype PubMed 17427161. Source: RGD positive regulation of neuron projection development Inferred from mutant phenotype PubMed 18262389. Source: RGD positive regulation of peptidyl-serine phosphorylation Inferred from mutant phenotype PubMed 18262389. Source: RGD positive regulation of peptidyl-threonine phosphorylation Inferred from mutant phenotype PubMed 18262389. Source: RGD positive regulation of transcription from RNA polymerase II promoter Inferred from mutant phenotype PubMed 17427161. Source: RGD protein autophosphorylation Inferred from direct assay PubMed 7499789PubMed 8208547. Source: RGD response to acid Inferred from expression pattern PubMed 7729276. Source: RGD response to drug Inferred from expression pattern PubMed 18652820. Source: RGD response to organic cyclic compound Inferred from expression pattern PubMed 19638569. Source: RGD response to wounding Inferred from expression pattern PubMed 19213039. Source: RGD sperm motility Inferred from mutant phenotype PubMed 12399538. Source: RGD
Cellular_component	cytoplasm Inferred from direct assay PubMed 18794800. Source: RGD excitatory synapse Inferred from direct assay PubMed 16861928. Source: RGD extracellular space Inferred from direct assay PubMed 19794968. Source: RGD integral to membrane Non-traceable author statement Ref.2. Source: RGD neuronal cell body Inferred from direct assay PubMed 16861928. Source: RGD plasma membrane Inferred from direct assay PubMed 18202313. Source: RGD postsynaptic density Inferred from direct assay PubMed 16861928. Source: RGD postsynaptic membrane Inferred from direct assay PubMed 16861928. Source: RGD sperm flagellum Inferred from direct assay PubMed 12399538. Source: RGD
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW hepatocyte growth factor-activated receptor activity Inferred from mutant phenotype PubMed 18262389. Source: RGD phosphatidylinositol 3-kinase binding Inferred from direct assay PubMed 7499789. Source: RGD protein complex binding Inferred from direct assay PubMed 17065554. Source: RGD protein heterodimerization activity Inferred from direct assay PubMed 8833090. Source: RGD
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 24	24	Potential
	Chain	25 – 1382	1358	Hepatocyte growth factor receptor		PRO_0000024442
Regions
	Topological domain	25 – 935	911	Extracellular Potential
	Transmembrane	936 – 956	21	Helical; Potential
	Topological domain	957 – 1379	423	Cytoplasmic Potential
	Domain	27 – 516	490	Sema
	Domain	564 – 656	93	IPT/TIG 1
	Domain	658 – 740	83	IPT/TIG 2
	Domain	743 – 837	95	IPT/TIG 3
	Domain	1079 – 1346	268	Protein kinase
	Nucleotide binding	1085 – 1093	9	ATP By similarity
	Region	1213 – 1382	170	Interaction with RANBP9 By similarity
	Region	1321 – 1360	40	Interaction with MUC20 By similarity
Sites
	Active site	1205	1	Proton acceptor By similarity
	Binding site	1111	1	ATP By similarity
	Site	308 – 309	2	Cleavage Potential
Amino acid modifications
	Modified residue	978	1	Phosphothreonine By similarity
	Modified residue	991	1	Phosphoserine By similarity
	Modified residue	998	1	Phosphoserine By similarity
	Modified residue	1001	1	Phosphoserine By similarity
	Modified residue	1004	1	Phosphotyrosine By similarity
	Modified residue	1231	1	Phosphotyrosine By similarity
	Modified residue	1235	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1236	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1290	1	Phosphothreonine By similarity
	Modified residue	1350	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1357	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1366	1	Phosphotyrosine By similarity
	Glycosylation	45	1	N-linked (GlcNAc...) Potential
	Glycosylation	106	1	N-linked (GlcNAc...) Potential
	Glycosylation	203	1	N-linked (GlcNAc...) Potential
	Glycosylation	359	1	N-linked (GlcNAc...) Potential
	Glycosylation	400	1	N-linked (GlcNAc...) Potential
	Glycosylation	406	1	N-linked (GlcNAc...) Potential
	Glycosylation	608	1	N-linked (GlcNAc...) Potential
	Glycosylation	636	1	N-linked (GlcNAc...) Potential
	Glycosylation	786	1	N-linked (GlcNAc...) Potential
	Glycosylation	880	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	173 ↔ 176		By similarity
	Disulfide bond	299 ↔ 364		By similarity
	Disulfide bond	386 ↔ 398		By similarity
	Disulfide bond	521 ↔ 539		By similarity
	Disulfide bond	527 ↔ 562		By similarity
	Disulfide bond	530 ↔ 546		By similarity
	Disulfide bond	542 ↔ 552		By similarity
Experimental info
	Sequence conflict	53	1	H → Q in AAB19189. Ref.2
	Sequence conflict	58	1	P → H in AAB19189. Ref.2
	Sequence conflict	240	1	P → G in AAB19189. Ref.2
	Sequence conflict	427	1	R → A in AAB19189. Ref.2
	Sequence conflict	485	1	Y → H in AAB19189. Ref.2
	Sequence conflict	490 – 495	6	EVIVEH → GAAGIR Ref.3
	Sequence conflict	533	1	P → A in AAB19189. Ref.2
	Sequence conflict	740	1	R → G in AAB19189. Ref.2
	Sequence conflict	744	1	V → F in AAB19189. Ref.2
	Sequence conflict	808	1	R → Q in AAB19189. Ref.2
	Sequence conflict	890 – 893	4	SEAL → TASV in CAA86508. Ref.4
	Sequence conflict	907	1	Missing in CAA86508. Ref.4
	Sequence conflict	924	1	K → E in CAA86508. Ref.4
	Sequence conflict	934	1	A → R in CAA86508. Ref.4
	Sequence conflict	1028	1	L → P in AAB19189. Ref.2
	Sequence conflict	1068	1	P → Q in AAB19189. Ref.2
	Sequence conflict	1197	1	V → A Ref.2
	Sequence conflict	1197	1	V → A Ref.5
	Sequence conflict	1331	1	V → F in AAB19189. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	P97523 [UniParc]. Last modified May 1, 1997. Version 1. Checksum: 66B8F2C88FE34427	FASTA	1,382	153,941
	10 20 30 40 50 60 MKAPTALAPG ILLLLLTLAQ RSHGECKEAL VKSEMNVNMK YQLPNFTAET PIHNVVLPGH 70 80 90 100 110 120 HIYLGATNYI YVLNDKDLQK VSEFKTGPVV EHPDCFPCQD CSSKANVSGG VWKDNVNMAL 130 140 150 160 170 180 LVDTYYDDQL ISCGSVNRGT CQRHVLPPDN AADIQSEVHC MFSPLAEEES GQCPDCVVSA 190 200 210 220 230 240 LGAKVLLSEK DRFINFFVGN TINSSYPPDY SLHSISVRRL KETQDGFKFL TDQSYIDVLP 250 260 270 280 290 300 EFRDSYPIKY IHAFESNHFI YFLTVQKETL DAQTFHTRII RFCSVDSGLH SYMEMPLECI 310 320 330 340 350 360 LTEKRRKRST REEVFNILQA AYVSKPGANL AKQIGASPYD DILYGVFAQS KPDSAEPMNR 370 380 390 400 410 420 SAVCAFPIKY VNDFFNKIVN KNNVRCLQHF YGPNHEHCFN RTLLRNSSGC EVRSDEYRTE 430 440 450 460 470 480 FTTALQRVDL FMGRLNHVLL TSISTFIKGD LTIANLGTSE GRFMQVVLSR TAHFTPHVNF 490 500 510 520 530 540 LLDSYPVSPE VIVEHPSNQN GYTLVVTGKK ITKIPLNGLG CGHFQSCSQC LSPPYFIQCG 550 560 570 580 590 600 WCHNRCVHSN ECPSGTWTQE ICLPAVYKVF PTSAPLEGGT MLTICGWDFG FKKNNKFDLR 610 620 630 640 650 660 KTKVLLGNES CTLTLSESTT NTLKCTVGPA MSEHFNVSVI VSNSRETTQY SAFSYVDPVI 670 680 690 700 710 720 TSISPRYGPH AGGTLLTLTG KYLNSGNSRH ISIGGKTCTL KSVSDSILEC YTPGHTVSAE 730 740 750 760 770 780 FPVKLKIDLA DRVTSSFSYR EDPVVSEIHP TKSFISGGST ITGIGKNLNS VSTPKLVIEV 790 800 810 820 830 840 HDVGVNYTVA CQHRSSSEII CCTTPSLRQL DLQLPLKTKA FFLLDGILSK HFDLTYVHDP 850 860 870 880 890 900 MFKPFEKPVM ISMGNENVVE IKGDDIDPEA VKGEVLKVGN KSCENLHWHS EALLCTVPSD 910 920 930 940 950 960 LLKLNGGELN IEWKQAVSST VLGKVIVQPD QNFAGLIIGA VSISVVVLLV SGLFLWLRKR 970 980 990 1000 1010 1020 KHKDLGSELV RYDARVHTPH LDRLVSARSV SPTTEMVSNE SVDYRATFPE DQFPNSSQNG 1030 1040 1050 1060 1070 1080 ACRQVQYLLT DLSPILTSGD SDISSPLLQN TVHIDLSALN PELVQAVPHV VIGPSSLIVH 1090 1100 1110 1120 1130 1140 FNEVIGRGHF GCVYHGTLLD SDGKKIHCAV KSLNRITDIE EVSQFLTEGI IMKDFSHPNV 1150 1160 1170 1180 1190 1200 LSLLGICLRS EGSPLVVLPY MKHGDLRNFI RNETHNPTVK DLIGFGLQVA KGMKYLVSKK 1210 1220 1230 1240 1250 1260 FVHRDLAARN CMLDEKFTVK VADFGLARDM YDKEYYSVHN KTGAKLPVKW MALESLQTQK 1270 1280 1290 1300 1310 1320 FTTKSDVWSF GVLLWELMTR GAPPYPDVNT FDITIYLLQG RRLLQPEYCP DALYEVMLKC 1330 1340 1350 1360 1370 1380 WHPKAEMRPS VSELVSRISS IFSTFIGEHY VHVNATYVNV KCVAPYPSLL PSQDNIDGEA NT

References

[1]	"Chromosomal localization of rat hepatocyte growth factor (Hgf) and HGF receptor (Met) and characterization of HGF receptor cDNA." Wallenius V.R., Rawet H., Skrtic S., Helou K., Qiu Y., Levan G., Ekberg S., Carlsson B., Isaksson O.G.P., Nakamura T., Jansson J.-O. Mamm. Genome 8:661-667(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: Sprague-Dawley. Tissue: Liver.
[2]	"Primary structure of rat HGF receptor and induced expression in glomerular mesangial cells." Liu Y., Tolbert E.M., Sun A.M., Dworkin L.D. Am. J. Physiol. 271:F679-F688(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], CHARACTERIZATION. Strain: Sprague-Dawley. Tissue: Kidney.
[3]	"Increased expression of c-met messenger RNA following acute gastric injury in rats." Tsujii M., Kawano S., Tsuji S., Ito T., Hayashi N., Horimoto M., Mita E., Nagano K., Masuda E., Hayashi N., Fusamoto H., Kamada T. Biochem. Biophys. Res. Commun. 200:536-541(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 364-495. Strain: Sprague-Dawley. Tissue: Gastric mucosa.
[4]	"Modulation of hepatocyte growth factor and c-met in the rat mammary gland during pregnancy, lactation, and involution." Pepper M.S., Soriano J.V., Menoud P.-A., Sappino A.-P., Orci L., Montesano R. Exp. Cell Res. 219:204-210(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 851-1002. Tissue: Intestine.
[5]	Kikuchi Y. Submitted (MAR-1998) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1129-1267.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	X96786 mRNA. Translation: CAA65582.1. U65007 mRNA. Translation: AAB19189.1. S69881 mRNA. Translation: AAB30575.1. Z46374 mRNA. Translation: CAA86508.1. AB012281 Genomic DNA. Translation: BAA28171.1.
IPI	IPI00326236.
PIR	PC2131.
RefSeq	NP_113705.1. NM_031517.2.
UniGene	Rn.10617.
3D structure databases
ProteinModelPortal	P97523.
SMR	P97523. Positions 40-742, 1047-1347.
ModBase	Search...
PTM databases
PhosphoSite	P97523.
Proteomic databases
PaxDb	P97523.
PRIDE	P97523.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
GeneID	24553.
KEGG	rno:24553.
UCSC	RGD:3082. rat.
Organism-specific databases
CTD	4233.
RGD	3082. Met.
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000220900.
HOVERGEN	HBG006348.
InParanoid	P97523.
KO	K05099.
OrthoDB	EOG466VK2.
Enzyme and pathway databases
BRENDA	2.7.10.1. 5301.
Gene expression databases
ArrayExpress	P97523.
Genevestigator	P97523.
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
NextBio	603662.

Entry information

Entry name

MET_RAT

Accession

Primary (citable) accession number: P97523
Secondary accession number(s): P97579, Q63119, Q63964

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 27, 2001
Last sequence update:	May 1, 1997
Last modified:	May 1, 2013
This is version 131 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program