Journal Article

Met, metastasis, motility and more

Gherardi, Ermanno, Birchmeier, Carmen, Vande Woude, George F., Birchmeier, Walter

2003

Overview

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 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Amino acids / Animals / Binding Sites / Biochemistry / Biomedical and Life Sciences / Cancer / Cancer Research / Cell Biology / Cell Line / Cell Movement / Cell Size / Developmental Biology / Embryonic growth stage / Enzymes / Growth factors / Hepatocyte Growth Factor - chemistry / Hepatocyte Growth Factor - genetics / Hepatocyte Growth Factor - metabolism / Intracellular Signaling Peptides and Proteins / Kinases / Life Sciences / Ligands / Medical research / Met protein / Metastasis / Models, Molecular / Morphogenesis / Motility / Mutation / Neoplasm Metastasis / Neoplasms - genetics / Neoplasms - metabolism / Neoplasms - pathology / Phosphoproteins - metabolism / Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Protein Tyrosine Phosphatases - metabolism / Proteins / Proto-Oncogene Proteins c-met - chemistry / Proto-Oncogene Proteins c-met - genetics / Proto-Oncogene Proteins c-met - metabolism / review-article / Signal Transduction - physiology / Stem Cells