The overall aim of this grant renewal is to learn more about a recently discovered pathway by which exogenous fibronectin binds specifically, saturably, and reversibly to surfaces of substrate-attached cultured fibroblasts and is subsequently incorporated irreversibly into the extracelluar matrix. The following questions will be addressed: 1. What features of fibronectin are required for binding to cell surfaces and transfer to the extracellular matrix? Do proteins which are homologous to fibronectin, such as tissue plasminogen activator and blood coagulation Factor XII, also bind to the fibronectin matrix assembly receptor? 2. How is the pathway for exogenous fibronectin related to the pathway by which endogenous fibronectin (i.e., fibronectin synthesized by cultured fibroblasts) enters the extracellular matrix? 3. What cell surface molecules are responsible for binding of fibronectin and its transfer to the extracellular matrix? 4. Exactly what happens during transfer of fibronectin to the extracellular matrix? 5. Can evidence for similar pathways be found in tissues? 6. What factors modulate the activities of the pathways? What are the mechanisms of modulation? 7. Do proteolytic fragments of fibronectin which interact with the fibronectin matrix assembly receptor have effects on cell growth and morphology that are not shared by the intact molecule? A variety of complementary biochemical, cell biological, immunochemical, radioisotopic, and molecular biological techniques will be used. The investigations may give considerable insight into how cells control the elaboration of extracellular matrices during embryogenesis, wound healing, inflammation, and neoplastic transformation.
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