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Met, metastasis, motility and more

Key Points

  • The Met receptor tyrosine kinase binds to, and is activated by, its specific ligand, the growth and motility factor HGF/SF (hepatocyte growth factor/scatter factor).

  • HGF/SF shares its overall domain structure with proteinases of the plasminogen family; the domain structure of Met is unique and its extracellular sequence is related to semaphorins and the semaphorin receptors (plexins).

  • Met activation results in tyrosine phosphorylation of the receptor at a unique bidentate docking site in the carboxy-terminal end of Met, which recruits signalling molecules such as the scaffolding adaptor Gab1 (growth-factor-receptor-bound protein 2 (Grb2)-associated binder 1). Gab1 mediates most of the complex cellular responses to Met activation.

  • The juxtamembrane domain of Met contains an additional docking site that, when phosphorylated, recruits Cbl, a ubiquitin ligase, which results in Met ubiquitylation, endocytosis and degradation.

  • Met activation can induce proliferation, dissociation of epithelial cells (scattering) and motility. Furthermore, signals from Met elicit a complex morphogenic response — the formation of branched tubules from epithelial cells grown in a collagen matrix.

  • During development, Met and HGF/SF are essential for the growth and survival of epithelial cell types and for migration of muscle progenitors. In adult physiology, Met activity prevents tissue damage and enhances liver regeneration.

  • Met is activated in human cancer by several molecular mechanisms, for example: mutations that alter the sequence and activity of the kinase domain; by overexpression; or by simultaneous expression of receptor and ligand, which results in the autocrine stimulation of cancer cells.

  • Met and HGF/SF are important targets for cancer therapy and many efforts are directed towards the identification of inhibitors that are active in vivo.

Abstract

Hepatocyte growth factor/scatter factor and its receptor, the tyrosine kinase Met, arose late in evolution and are unique to vertebrates. In spite of this, Met uses molecules such as Gab1 — homologues of which are present in Caenorhabditis elegans and Drosophila melanogaster — for downstream signalling. Pivotal roles for Met in development and cancer have been established: Met controls cell migration and growth in embryogenesis; it also controls growth, invasion and metastasis in cancer cells; and activating Met mutations predispose to human cancer.

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Figure 1: Hepatocyte growth factor/scatter factor.
Figure 2: The Met receptor tyrosine kinase.
Figure 3: Substrate-binding sites of Met and the Tpr–Met oncoprotein.
Figure 4: Recruitment of Gab1 and Shp2 to Met and the plasma membrane.
Figure 5: Met-induced scattering and invasion.
Figure 6: Met signalling.
Figure 7: Met and cell migration in vivo.
Figure 8: MET mutations identified in human tumours.

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Acknowledgements

We would like to thank K. Grossmann, H. Wende, H. Brohmann and G. Schütz for the preparation of figures and M. Rosario for helpful discussions. We also thank B. Knudsen, C. Gao, C. Graveel, M. Gustafson, N. Shinomiya, Q. Xie, and Y. Zhang for assistance with Table 1. Finally, we are grateful to M. Reed, R. Hahn, D. Nadziejka, V. Long and S. Olbrich for assistance with the manuscript.

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Correspondence to George F. Vande Woude.

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DATABASES

Interpro

K1–K4

integrin α

LocusLink

ERK/MAPK

Swiss-Prot

C3G

coagulation factor X

coagulation factor XI

coagulation factor XII

Crk

EGF

Gab1

Grb2

HGF

MET

plasminogen

Rac1

Ras

Ron

Shp2

tPA

uPA

FURTHER INFORMATION

HGF/SF, Met and cancer today

Glossary

IMMUNOGLOBULIN DOMAIN

A protein domain of 90 amino acids consisting of two β-sheets. There are at least 5 distinct structural sets of the domain (V, C1, C2, I and E) that differ in the number, length and position of the strands that compose the two β-sheets.

KRINGLE DOMAIN

A protein domain of 80 amino acids characterized by limited secondary-structure elements and defined by three conserved disulphide bonds.

SERINE PROTEINASES

Endopeptidases that contain serine, histidine and aspartate in the catalytic site and include the complex, multidomain enzymes of the complement, blood-clotting and fibrinolytic systems. They are synthesized as inactive, single-chain zymogens and converted into active enzymes by site-specific proteolysis.

HEPARAN-SULPHATE PROTEOGLYCAN

A protein that is bound to a complex polysaccharide (heparan-sulphate glycosaminoglycan) that is present at the cell surface or in the extracellular matrix. When bound to ligand, it can have a key signalling role.

TYROSINE KINASE DOMAIN

A protein domain with the ability to catalyse the transfer of the γ-phosphate group of ATP to tyrosine residues on protein substrates. Several growth-factor receptors have tyrosine-kinase activity, which triggers a cascade of protein–protein interactions as a result of ligand-induced kinase activation.

SEMA DOMAIN

A protein domain of 450 amino acids identified in the semaphorin axon guidance proteins. Plexins (cell adhesion and semaphorin receptors) and the Met and Ron receptors also contain the sema domain or a variant of it. The sema domain of the Met receptor and of semaphorins adopts a β-propeller fold.

SH3 DOMAIN

(Src-homology-domain 3). A protein sequence of about 50 amino acids that recognizes and binds sequences rich in proline.

SH2 DOMAIN

(Src-homology-2 domain). A protein motif that recognizes and binds tyrosine-phosphorylated sequences, and thereby has a key role in relaying cascades of signal transduction.

PLECKSTRIN-HOMOLOGY (PH) DOMAIN

A sequence of 100 amino acids that is present in many signalling molecules and binds to lipid products of phosphatidylinositol 3-kinase. Pleckstrin is a protein of unknown function that was originally identified in platelets and is a principal substrate of protein kinase C.

E3 UBIQUITIN PROTEIN LIGASE

The third enzyme in a series — the first two are designated E1 and E2 — that is responsible for ubiquitylation of target proteins. E3 enzymes provide platforms for binding E2 enzymes and specific substrates, thereby coordinating ubiquitylation of the selected substrates.

EPITHELIAL–MESENCHYMAL TRANSITION

The transformation of an epithelial cell into a mesenchymal cell with migratory and invasive properties.

ETS/AP1 TRANSCRIPTION FACTOR

A bipartite transcription-regulatory element.

PLACENTAL TROPHOBLAST

The inner trophoblastic layer of cells that gives rise to the syncytiotrophoblast, which faces the maternal circulation and constitutes a layer through which all substances must pass from the mother to the fetus.

DERMOMYOTOME

Epithelial-cell layer in the dorsolateral region of the somite that faces the ectoderm and further differentiates into the most dorsal dermatome, which later differentiates into dermis and myotome — future skeletal muscles.

SOMITE

A mesodermal ball of cells adjacent to the neural tube that will differentiate into the muscle, vertebrae and dermis.

NEURAL CREST CELLS

A group of embryonic cells that separate from the embryonic neural plate and migrate, giving rise to the spinal and autonomic ganglia, peripheral glia, chromaffin cells, melanocytes and some haematopoietic cells.

NUDE MICE

Mice that have a mutation causing both hairlessness and defective formation of the thymus, which results in a lack of mature T cells.

OSTEOSARCOMA

A malignant tumour of the bone. It usually develops during the period of rapid growth during adolescence.

CARCINOMA

A malignant tumour of epithelial origin.

GLIOBLASTOMA MULTIFORME

A poorly differentiated, rapidly growing brain tumour that occurs most often in adults.

GELDANAMYCIN

A low-molecular-weight compound that binds to heat-shock protein 90 (Hsp90), a highly conserved cytosolic protein in eukaryotic and prokaryotic cells that functions as a chaperone. Geldanamycin inhibits Hsp90 function, which causes the proteasomal degradation of proteins that require the chaperone for maturation or stability. Geldanamycin therefore destabilizes proteins, such as Met, ErbB2, Bcr–Abl, or Akt/PKB, and can suppress tumour formation in animal models.

NUCLEAR IMAGING

The generation and analysis of diagnostic images showing the interaction of a radioactive compound with particular organs or tissues.

RADIOIMMUNOSCINTIGRAPHY

The use of radiolabelled antibodies or antibody derivatives for nuclear imaging.

CRE/LOXP

A site-specific recombination system derived from the Escherichia coli bacteriophage P1. Two short DNA sequences (loxP sites) are engineered to flank the target DNA. Activation of the Cre recombinase enzyme catalyses recombination between the loxP sites, which leads to the excision of the intervening sequence.

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Birchmeier, C., Birchmeier, W., Gherardi, E. et al. Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4, 915–925 (2003). https://doi.org/10.1038/nrm1261

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