Role of the hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition

• Published in: Cytokine & growth factor reviews 2002-02, Vol.13 (1), p.41-59
• Main Authors: Maulik, Gautam, Shrikhande, Amol, Kijima, Takashi, Ma, Patrick C., Morrison, Paul T., Salgia, Ravi
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antineoplastic Agents - pharmacology; c-Met; c-Met protein; Cell Division; Cell motility and migration; Cell Movement; Hepatocyte Growth Factor - metabolism; Hepatocyte growth factor receptors; Hepatocyte growth factor/scatter factor; Humans; Inhibitors; Ligands; Metastasis; Models, Biological; Molecular Sequence Data; Mutation; Neoplasms - metabolism; Neoplasms - therapy; Neovascularization, Pathologic; paxillin; Phylogeny; Protein Binding; Proto-Oncogene Proteins c-met - physiology; Reactive Oxygen Species; scatter factor; Sequence Homology, Amino Acid; Signal transduction; Tumor Cells, Cultured
• ISSN: 1359-6101
• DOI: 10.1016/S1359-6101(01)00029-6

Receptor tyrosine kinases have become important therapeutic targets for anti-neoplastic molecularly targeted therapies. c-Met is a receptor tyrosine kinase shown to be over-expressed and mutated in a variety of malignancies. Stimulation of c-Met via its ligand hepatocyte growth factor also known as scatter factor (HGF/SF), leads to a plethora of biological and biochemical effects in the cell. There has been considerable knowledge gained on the role of c-Met–HGF/SF axis in normal and malignant cells. This review summarizes the structure of c-Met and HGF/SF and their family members. Since there are known mutations of c-Met in solid tumors, particularly in papillary renal cell carcinoma, we have summarized the various mutations and over-expression of c-Met known thus far. Stimulation of c-Met can lead to scattering, angiogenesis, proliferation, enhanced cell motility, invasion, and eventual metastasis. The biological functions altered by c-Met are quite unique and described in detail. Along with biological functions, various signal transduction pathways, including the cytoskeleton are altered with the activation of c-Met–HGF/SF loop. We have recently shown the phosphorylation of focal adhesion proteins, such as paxillin and p125FAK in response to c-Met stimulation in lung cancer cells, and this is detailed here. Finally, c-Met when mutated or over-expressed in malignant cells serves as an important therapeutic target and the most recent data in terms of inhibition of c-Met and downstream signal transduction pathways is summarized.