Reviewed, UniProtKB/Swiss-Prot P08581 (MET_HUMAN)

Names and origin

Protein names

Recommended name:
    Hepatocyte growth factor receptor
      Short name=HGF receptor
    EC=2.7.10.1
Alternative name(s):
    Scatter factor receptor
      Short name=SF receptor
    HGF/SF receptor
    Met proto-oncogene tyrosine kinase
    c-Met

Gene names

Name:

MET

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	1390 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 for hepatocyte growth factor and scatter factor. Has a tyrosine-protein kinase activity.
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Subunit structure	Heterodimer formed of an alpha chain (50 kDa) and a beta chain (145 kDa) which are disulfide linked. Binds PLXNB1 and GRB2. Interacts with SPSB1, SPSB2 and SPSB4 By similarity. Interacts with INPP5D/SHIP1. When phosphorylated at Tyr-1356, 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.
Subcellular location	Membrane; Single-pass type I membrane protein.
Domain	The kinase domain is involved in SPSB1 binding.
Involvement in disease	Activation of MET after rearrangement with the TPR gene produces an oncogenic protein. Defects in MET may be associated with gastric cancer. Defects in MET are a cause of hepatocellular carcinoma (HCC) [MIM:114550]. Defects in MET are a cause of hereditary papillary renal carcinoma (HPRC) [MIM:605074]; also known as papillary renal cell carcinoma 2 (RCCP2). HPRC is a form of inherited kidney cancer characterized by a predisposition to develop multiple, bilateral papillary renal tumors. The pattern of inheritance is consistent with autosomal dominant transmission with reduced penetrance. Genetic variations in MET may be associated with susceptibility to autism type 1B (AUTS1B) [MIM:608636]. Autism is a neurodevelopmental disorder characterized by disturbance in language, perception and socialization. The disorder is classically defined by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypical, and ritualized patterns of interests and behavior.
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
Coding sequence diversity	Alternative splicing Chromosomal rearrangement Polymorphism
Disease	Disease mutation Proto-oncogene
Domain	Repeat Signal Transmembrane
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Receptor Transferase Tyrosine-protein kinase
PTM	Glycoprotein Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	cell proliferation Traceable author statement. Source: ProtInc cell surface receptor linked signal transduction Ref.1 Non-traceable author statement. Source: UniProtKB
Cellular component	integral to plasma membrane Ref.7 Traceable author statement. Source: ProtInc
Molecular function	hepatocyte growth factor receptor activity Traceable author statement. Source: ProtInc protein binding Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
HGF	P14210	2	EBI-1039152,EBI-1039104
inlB	P25147	3	EBI-1039152,EBI-1379295	From a different organism.
YWHAZ	P63104	1	EBI-1039152,EBI-347088

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P08581-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P08581-2)

The sequence of this isoform differs from the canonical sequence as follows:
     755-755: S → STWWKEPLNIVSFLFCFAS

Notes: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Molecule processing

Signal peptide

1 – 24

24

Potential

Chain

25 – 1390

1366

Hepatocyte growth factor receptor

Regions

Topological domain

25 – 932

908

Extracellular Potential

Transmembrane

933 – 955

23

Potential

Topological domain

956 – 1390

435

Cytoplasmic Potential

Domain

27 – 515

489

Sema

Domain

563 – 655

93

IPT/TIG 1

Domain

657 – 739

83

IPT/TIG 2

Domain

742 – 836

95

IPT/TIG 3

Domain

1078 – 1345

268

Protein kinase

Nucleotide binding

1084 – 1092

9

ATP By similarity

Region

1212 – 1390

179

Interaction with RANBP9

Sites

Active site

1204

1

Proton acceptor By similarity

Binding site

1110

1

ATP

Site

307 – 308

2

Cleavage Potential

Site

1009 – 1010

2

Breakpoint for translocation to form TPR-MET oncogene

Amino acid modifications

Modified residue

977

1

Phosphothreonine

Modified residue

988

1

Phosphoserine

Modified residue

990

1

Phosphoserine

Modified residue

1003

1

Phosphotyrosine

Modified residue

1230

1

Phosphotyrosine

Modified residue

1234

1

Phosphotyrosine

Modified residue

1235

1

Phosphotyrosine; by autocatalysis

Modified residue

1356

1

Phosphotyrosine

Glycosylation

45

1

N-linked (GlcNAc...) Potential

Glycosylation

106

1

N-linked (GlcNAc...) Potential

Glycosylation

149

1

N-linked (GlcNAc...) Potential

Glycosylation

202

1

N-linked (GlcNAc...) Potential

Glycosylation

399

1

N-linked (GlcNAc...) Potential

Glycosylation

405

1

N-linked (GlcNAc...) Potential

Glycosylation

607

1

N-linked (GlcNAc...) Potential

Glycosylation

635

1

N-linked (GlcNAc...) Potential

Glycosylation

785

1

N-linked (GlcNAc...) Potential

Glycosylation

879

1

N-linked (GlcNAc...) Potential

Glycosylation

930

1

N-linked (GlcNAc...) Potential

Natural variations

Alternative sequence

755

1

S → STWWKEPLNIVSFLFCFAS in isoform 2.

Natural variant

143

1

R → Q

Natural variant

156

1

S → L

Natural variant

168

1

E → D

Natural variant

238

1

L → S: dbSNP rs34349517.

Natural variant

316

1

I → M: dbSNP rs35225896.

Natural variant

320

1

A → V: dbSNP rs35776110.

Natural variant

375

1

N → S: dbSNP rs33917957.

Natural variant

773

1

P → L in gastric cancer.

Natural variant

970

1

R → C: dbSNP rs34589476.

Natural variant

991

1

P → S in gastric cancer; prolonged tyrosine phosphorylation in response to HGF/SF; transforming activity in athymic nude mice.

Natural variant

992

1

T → I Low transforming activity in athymic nude mice.

Natural variant

1092

1

V → I in HPRC; constitutive autophosphorylation.

Natural variant

1094

1

H → L in HPRC; constitutive autophosphorylation; causes malignant transformation in cell lines.

Natural variant

1094

1

H → R in HPRC; causes malignant transformation in cell lines.

Natural variant

1094

1

H → Y in HPRC; constitutive autophosphorylation; causes malignant transformation in cell lines.

Natural variant

1106

1

H → D in HPRC; constitutive autophosphorylation; causes malignant transformation in cell lines.

Natural variant

1131

1

M → T in HPRC; germline mutation.

Natural variant

1173

1

T → I in HCC.

Natural variant

1188

1

V → L in HPRC; germline mutation.

Natural variant

1195

1

L → V in HPRC; somatic mutation.

Natural variant

1220

1

V → I in HPRC; germline mutation.

Natural variant

1228

1

D → H in HPRC; somatic mutation.

Natural variant

1228

1

D → N in HPRC; germline mutation.

Natural variant

1230

1

Y → C in HPRC; germline mutation.

Natural variant

1230

1

Y → D in HPRC; constitutive autophosphorylation; causes malignant transformation in cell lines.

Natural variant

1230

1

Y → H in HPRC; somatic mutation.

Natural variant

1244

1

K → R in HCC.

Natural variant

1250

1

M → I in HCC.

Natural variant

1250

1

M → T in HPRC; somatic mutation.

Experimental info

Sequence conflict

1191

1

G → A in AAA59591. Ref.2

Sequence conflict

1272

1

V → L in AAC60383. Ref.3

Sequence conflict

1272

1

V → L Ref.4

Secondary structure

1

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