Integrins are involved in the regulation of multiple aspects of tumor cell biology such as proliferation, apoptosis, invasion, motility and tumor angiogenesis. However, the precise mechanism by which integrins trigger these biological processes in cancer is not well defined. One potential hypothesis is that these responses might relate to integrin- mediated signal transduction. Focal adhesion kinase (FAK) and Src-family kinases have been demonstrated to be involved in integrin-mediated signaling. To directly address the function of Src-family kinases, Hck, Fgr and Lyn in integrin signaling, we have generated triple mutant mice that are deficient for all three of these kinases. Primary macrophages derived from mutant mice show impaired tyrosine phosphorylation following integrin ligation indicating that three kinases are involved in integrin signal transduction. To further investigate the roles of Hck, Fgr and Lyn in integrin signaling in tumor cells, we will generate tumorigenic cell lines from the triple mutant mice, then characterize the integrin-related signaling events in these cells compared to wild type cells. The current proposal provides the best model system to study the functional importance of Src-family kinases in integrin signaling of tumor cells.
