. Angiogenesis is a feature of many diseases, including diabetic retinopathy, rheumatoid arthritis, atherogenesis, and the growth and metastasis of solid tumors. The prototypes of the fibroblast growth factor (FGF) family are among the angiogenic growth factors that act directly on vascular cells to induce proliferation and cell migration. The long-term goal of this application is to elucidate the signaling pathway initiated by FGF-1 in the hope to ultimately reveal new strategies for anti-angiogenic therapy. This research, which is being supported by the current grant, has focused on cortactin, a FGF signaling molecule and a substrate of Src tyrosine kinase. The results of the research demonstrate that (i) cortactin is a filamentous actin (F-actin) cross-linker and can be down-regulated by Src; (ii) tyrosine phosphorylation of cortactin is implicated in the migration of endothelial cells; (iii) Src and cortactin are required for FGF-1 mediated shape change and cell migration, and (iv) tyrosine phosphorylation deregulates cortactin dimerization. These results indicate that cortactin is an important signaling molecule that transmits the FGF signals to the cytoskeleton and is involved in a discrete pathway for shape change and cell migration. The objective of this application is to investigate the mechanism by which cortactin acts within cells. Dr. Zhan hypothesizes that (i) the F-actin cross-linking activity of cortactin is important for cell migration, shape change and endothelial cell differentiation (tube formation); (ii) while the cortactin signal pathway is distinct from that for the mitogenic response, it is integrated with other early signaling events of FGF-1; and (iii) translocation of cortactin into the leading edge of cells induced by FGF-1 is important for cell migration. To test these hypotheses, Dr. Zhan will study the mechanism for cortactin dimerization and F-actin cross-linking. He will then examine the functional role of the activity of cortactin in FGF-1-mediated cell shape change, cell motility and endothelial cell differentiation. In addition, he will examine the role of the early FGF-1 signaling molecules in the tyrosine phosphorylation of cortactin. Finally, he will dissect the mechanism for the redistribution of cortactin within cells in response to FGF-1 and explore possible intracellular molecules that target cortactin into the leading edge of cells. It is anticipated that the results from these studies will delineate the signal pathways that lead to cell migration and mitogenesis.
