Molecular basis of cancer diathesis

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To develop new strategies to suppress carcinogenesis and to control cancer progression, it is critical to understand the fundamental roles and regulatory features of proto-oncogene and anti-oncogene products at the molecular level. In this study, we extensively analyzed the normal functions and regulation of the src family of proto-oncogene products (SFK) in order to understand the role played by SFK in cancer progression, and particularly in the acquisition of metastatic activity.1. Studies of epithelial cancer cells and mutant mice that lack Csk, a negative regulator of SFK, revealed that SFK plays critical roles in cell migration and in the regulation of the epithelial-like cell to mesencymal-like cell transition (EMT). It was also found that SFK is involved in the cell-cell adhesion required for the maintenance of cell polarity and for the regulation of cell proliferation through the control of cytoskeletal organization. Cortactin, an actin binding protein, and its associated molec … More ules were identified as potential targets of SFK in the epithelial-like cell to mesencymal-like cell transition. Furthermore, Csk acted as the critical regulator of these phenomena, suggesting that Csk could be used as a potential therapeutic target to control cancer progression and/or metastasis. 2. In the lipid raft fraction that provides a platform for SFK signaling, we identified a novel membrane phosphoprotein Cbp (Csk binding protein) as an initial target of SFK, and showed that it serves as a membrane scaffold protein for Csk. 3. To analyze the fundamental roles of SFK in animals, we identified SFK and Csk orthologues in C. elegans. Analysis of mutant worms revealed that SRC-1, an orthologue of Src, plays an essential role in controlling the migration of specific cell types during organogenesis. The Rac signaling pathway was identified as a downstream target of SRC-1. 4. Based on the structural information provided by the crystal structure of Csk, we proposed a molecular basis for SFK regulation by Csk. Less