Role of the hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition.
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.
Maulik
Gautam
G
Department of Medicine, Division of Adult Oncology, Lowe Center for Thoracic Oncology, Binney Street, Boston, MA 02115, USA.
Shrikhande
Amol
A
Kijima
Takashi
T
Ma
Patrick C
PC
Morrison
Paul T
PT
Salgia
Ravi
R
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division; D002465:Cell Movement; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism* / Q000628:therapy*; D009389:Neovascularization, Pathologic; D010802:Phylogeny; D011485:Protein Binding; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D017382:Reactive Oxygen Species; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D008024:Ligands; D017382:Reactive Oxygen Species; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met