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The MET Receptor Family

  • Chapter
Receptor Tyrosine Kinases: Family and Subfamilies

Abstract

The MET gene encodes a tyrosine kinase receptor and its ligand is hepatocyte growth factor/scatter factor (HGF/SF). MET is expressed in many tissues, organs, and types of cells, but is generally expressed in cells of epithelial origin. HGF/SF, on the other hand, is produced in stromal cells of mesenchymal origin. The MET receptor is synthesized as a 185 kDa single-chain precursor, which is proteolytically cleaved to yield a highly glycosylated extracellular α-subunit and a transmembrane β-subunit. The two subunits are linked by disulfide bonds to form the mature receptor. Paracrine activation of the MET receptor by HGF/SF activates multiple signaling pathways, including RAS/MAPK, PI3K/AKT, SRC, and STAT3, leading to pleiotropic cellular responses such as mitogenesis, motogenesis, and morphogenesis. The HGF/SF–MET pathway is essential for embryonic development, organ regeneration, and wound healing during adulthood. Disruption of HGF/SF–MET signaling has been implicated in several human diseases including autism, diabetes, and most types of human cancer. In tumor cells, aberrant activation of MET signaling occurs through amplification, mutation, and/or overexpression. Ligand-dependent activation promotes tumor progression by facilitating cell proliferation, migration, invasion, survival, and angiogenesis. The prevalence of the HGF/SF–MET pathway in human cancers has led to great interest in the pathway as a cancer drug target. Small-molecule inhibitors or biologics such as monoclonal antibodies directed against MET or HGF/SF impede tumor growth in cells expressing activated MET. Promising results have been reported from clinical trials with compounds targeting HGF/SF–MET signaling. Treatment using HGF/SF–MET antagonists on select patient subpopulations that have aberrant MET activity may improve therapeutic efficacy.

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Acknowledgments

We thank Kay Koo for administrative support and David Nadziejka for editing the manuscript. This work was supported by the Jay and Betty Van Andel Foundation.

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Authors and Affiliations

  1. Laboratory of Molecular Oncology, Van Andel Research Institute, 333 Bostwick NE, Grand Rapids, MI, 49503, USA

    ChongFeng Gao & George F. Vande Woude Ph.D.

Authors
  1. ChongFeng Gao
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  2. George F. Vande Woude Ph.D.
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Corresponding author

Correspondence to George F. Vande Woude Ph.D. .

Editor information

Editors and Affiliations

  1. School of Medicine and Public Health Department of Human Oncology, University of Wisconsin, Madison, Wisconsin, USA

    Deric L. Wheeler

  2. Department of Biological Regulation, Rehovot, Israel

    Yosef Yarden

Receptor at glance: comparison between MET and RON

Receptor at glance: comparison between MET and RON

 

MET

RON

Other names

HGFR

MST1R; CD136; MSPR; PTK8

Chromosome location

7q31.2

3q21.31

Gene size (bp)

126,193

16,872

Intron/exon

20/21

19/20

mRNA size (5′, ORF, 3′)

6,695

4,785

Amino acids

1,390

1,400

Molecular weight

190

185

Subunit (α-chain/β chain)(kDa)

145/45

150/35

Posttranslational modifications

Proteolytic processing; phosphorylation; ubiquitination

Proteolytic processing; phosphorylation; ubiquitination

Domains

SEMA; CR; IPT; JM; kinase domain; docking site

SEMA; CR; IPT; JM; kinase domain; docking site

Phosphorylation sites

Tyr1234/1235 in kinase domain

Tyr1349/1356 in docking site

Tyr1238/1239 in kinase domain

Tyr1353/1360 in docking site

Pathways activated

PI3K/AKT2; RAS/MAPK; SRC; STAT3; PLCγ−PKC; Crk

PI3K/AKT2; RAS/MAPK; SRC; STAT3; PLCγ−PKC; Crk; NO

Tissues expressed

Mainly in epithelial cells; also found in endothelial cells, neurons, hepatocytes, hematopoietic cells, and melanocytes

Macrophages; epithelial and keratinocyte cells

Distribution in epithelial cells

Basal lateral membrane

Apical membrane

Transcriptional factor binds to promoter

AP1; SP1; Est1; Pax3; P53; HIF1α

NF-κB; Est-1 and estrogen receptor

Ligand for the receptor

HGF/SF

HGFL/MSP

Cell type that produces ligand

Mesenchymal cells

Hepatocyte

Interaction between ligand and receptor

Paracrine

Endocrine

Induction of cellular responses

Proliferation; scatting; migration/invasion; surviving; branching morphogenesis; angiogenesis

Proliferation; scatting; migration/invasion; surviving; branching morphogenesis; angiogenesis

Knockout mouse phenotype

Early embryonic lethality (e13.5)

Early embryonic lethality (e7.5)

Ligand knock out phenotype

Early embryonic lethality (e16.5)

No gross phenotype; fertile

Human diseases

Cancer; autism; diabetes;

Inflammation; cancer

Point mutation in cancers

Papillary renal carcinomas; HCC; lung cancer; brain tumors

Papillary renal carcinomas

Overexpression and aberrant activation

Most types of human cancer

Breast, lung, prostate, gastric, pancreatic, renal, bladder, ovarian, gastrointestinal, and colon cancers

  1. The information about RON was obtained from the review by Wagh et al. [18].

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Gao, C., Vande Woude, G.F. (2015). The MET Receptor Family. In: Wheeler, D., Yarden, Y. (eds) Receptor Tyrosine Kinases: Family and Subfamilies. Springer, Cham. https://doi.org/10.1007/978-3-319-11888-8_8

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