Q108U6 (MET_LOXAF) 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

Loxodonta africana (African elephant) [Reference proteome]

Taxonomic identifier

9785 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Afrotheria › Proboscidea › Elephantidae › Loxodonta

Protein attributes

Sequence length	1382 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Inferred from homology

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. 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 By similarity.
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	activation of MAPK activity Inferred from electronic annotation. Source: Compara adult behavior Inferred from electronic annotation. Source: Compara brain development Inferred from electronic annotation. Source: Compara branching morphogenesis of an epithelial tube Inferred from electronic annotation. Source: Compara glucose homeostasis Inferred from electronic annotation. Source: Compara liver development Inferred from electronic annotation. Source: Compara muscle cell migration Inferred from electronic annotation. Source: Compara myoblast proliferation Inferred from electronic annotation. Source: Compara myotube differentiation Inferred from electronic annotation. Source: Compara negative regulation of hydrogen peroxide-mediated programmed cell death Inferred from electronic annotation. Source: Compara placenta development Inferred from electronic annotation. Source: Compara positive regulation of glucose transport Inferred from electronic annotation. Source: Compara protein autophosphorylation Inferred from electronic annotation. Source: Compara regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling Inferred from electronic annotation. Source: Compara
Cellular_component	basal plasma membrane Inferred from electronic annotation. Source: Compara 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 electronic annotation. Source: Compara
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_0000250465
Regions
	Topological domain	25 – 935	911	Extracellular Potential
	Transmembrane	936 – 956	21	Helical; Potential
	Topological domain	957 – 1382	426	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	450	1	N-linked (GlcNAc...) Potential
	Glycosylation	608	1	N-linked (GlcNAc...) Potential
	Glycosylation	636	1	N-linked (GlcNAc...) Potential
	Glycosylation	751	1	N-linked (GlcNAc...) Potential
	Glycosylation	786	1	N-linked (GlcNAc...) Potential
	Glycosylation	880	1	N-linked (GlcNAc...) Potential
	Glycosylation	931	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

Sequences

	Sequence		Length	Mass (Da)
	Q108U6 [UniParc]. Last modified August 22, 2006. Version 1. Checksum: B22F334F1CC126BC	FASTA	1,382	154,684
	10 20 30 40 50 60 MKAPAVLAPG VLVLLFTLVR KSHGECEEAL AKSKMNVNMK YQLPNFTADT PIQNVVLHEH 70 80 90 100 110 120 HIFLGAINNI YVLNDKDLQK VAEYKTGPVL EHPDCLPCQD CSSKANLSGS VWKDNINMAL 130 140 150 160 170 180 LVDTYYDDQL ITCGSVNRGT CQRHVLPPDN PADIHSKVHC MYSPQADEEP SKCPDCVVSA 190 200 210 220 230 240 LGTKVLLTEK DRFINFFVGN TVNSSYLPDH SLHSISVRRL KETQDGFKFL TDQSYIDVLP 250 260 270 280 290 300 EFRDSYPIKY VHAFKHNQFI YFLTVQRETL ESQTFHTRII RFCSVDSGLH SYMEMPLECI 310 320 330 340 350 360 LTEKRRKRSA REEVFNILQA AYVSKPGAYL AKQIGALPDD DILYGVFAQS KLDSAEPMNR 370 380 390 400 410 420 SAVCAFPIKY VNDFFNKIVN KNNVRCLQHF YGPNHEHCFN RTLLRNSSGC EVRRDEYRTE 430 440 450 460 470 480 FTTALQRVDL FTGQFNQVLL TSISTFIKGN LTIANLGTSE GRFMQVVVSR SGLTTPHVNF 490 500 510 520 530 540 RLDSHAVSPE VILEHPLNQN GYTLVITGKK ITKIPLDGLG CDHFQSCSQC LSAPSFVQCG 550 560 570 580 590 600 WCHNKCARAE ECPNGMWTQE ICLPTIYEVF PTSAPLEGGT TLTVCGWDFG FRRNNKFDLK 610 620 630 640 650 660 KTRVLIGNDS CTLTLSESTT NTLKCTVGPA MNKHFNLSII ISNGRGTARY RTFSYVEPVI 670 680 690 700 710 720 TSISPSYGPK AGGTLVTLTG KYLNSGNSRH ISIGGKTCTL KSVSDSVLEC YTPAQSISTD 730 740 750 760 770 780 FPVKLKIDLA NREAYSFSYQ EDPTVYEIHP NKSFISGGST ITGIGKNLNS VSVPRMVINV 790 800 810 820 830 840 QEAGRNFTVA CQHRSNSEII CCTTPSLQQL NLQLPLKTKA FFMLDGIHSN YFDLIYVHNP 850 860 870 880 890 900 VFKPFKKPVM ISMGNENVLE IKGDYIDPEA VKGEVLKVGN KSCENIHLQS EAVLCTVPND 910 920 930 940 950 960 LLKLNSELNI EWKQAVSSTV LGKVIVQPDQ NFTGLIVGVV SISIILLLLL GLFLWLKKRK 970 980 990 1000 1010 1020 QIKDLGSELV RYDARVHTPH LDRLVSARSV SPTTEMVSNE SVDYRATFPE DQFPNSSQNG 1030 1040 1050 1060 1070 1080 SCRQVQYPLT DMSPILTNGD SDSSIPLLQN NVHIDLSALN PELVQAVQHV VIGPSSLIVH 1090 1100 1110 1120 1130 1140 FNEVIGRGHF GCVYHGTLLD NGDKKIHCAV KSLNRITDIG EVSQFLTEGI IMKDFSHPNV 1150 1160 1170 1180 1190 1200 LSLLGICLRS EGSPLVVLPY MKHGDLRNFI RNETHNPTVK DLIGFGLQVA KGMKYLASKK 1210 1220 1230 1240 1250 1260 FVHRDLAARN CMLDEKFTVK VADFGLARDV YDKEYYSVHN KTGAKLPVKW MALESLQTQK 1270 1280 1290 1300 1310 1320 FTTKSDVWSF GVLLWELMTR GAPPYPDVNT FDITVYLLQG RRLLQPEYCP DPLYEVMLKC 1330 1340 1350 1360 1370 1380 WHPKAEMRPS FSELVSRISA IFSTFIGEHY VHVNTTYVNV KCVAPYPSLL SSQDSVDDEV DT

References

[1]

"NISC comparative sequencing initiative." 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. Submitted (JUL-2006) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].

Cross-references

Sequence databases
EMBL GenBank DDBJ	DP000087 Genomic DNA. Translation: ABG66646.1.
RefSeq	XP_003407277.1. XM_003407229.1.
3D structure databases
ProteinModelPortal	Q108U6.
SMR	Q108U6. Positions 40-742, 1047-1347.
ModBase	Search...
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
GeneID	100656285.
Phylogenomic databases
HOGENOM	HOG000220900.
HOVERGEN	HBG006348.
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...

Entry information

Entry name

MET_LOXAF

Accession

Primary (citable) accession number: Q108U6

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 3, 2006
Last sequence update:	August 22, 2006
Last modified:	May 1, 2013
This is version 58 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program