Molecular bases of cell adhesion: The goal of this project is to understand how the membrane receptor for fibronectin mediates the complex process of cell adhesion. In this context, we will critically analyze four fundamental aspects of receptor behavior using a combination of biochemical, immunochemcial and biophysical approaches. (1) We will examine the cell surface display of fibronectin receptor in relation to receptor function. We will determine whether monovalent or polyvalent ligands induce receptor down regulation. We will ascertain if protein kinases regulate receptor display. We will test whether down regulation of fibronectin receptor actually alters fibronectin dependent cell adhesion. (2) Since the clustering of fibronectin receptor seems to be essential to the formation of cell adhesion sites, we will study the role of fibronectin receptor microaggregation (clustering) in receptor function. We will determine if monovalent or polyvalent ligands can induce receptor clustering. We will evaluate whether protein kinases regulate receptor clustering. We will determine whether the ability to cluster is innate to the fibronectin receptor, or if accessory proteins are involved. (3) We have previously demonstrated that both cAMP dependent protein kinase (cAdPK) and protein kinase C regulate fibronectin mediated cell adhesion. As a vital further step in understanding kinase regulation, we will attempt to identify critical kinase substrates in the cell adhesion pathway; we will prepare antibodies against these phosphoproteins and use the antibodies to explore the roles of these phosphoproteins in adhesion. (4) Little is know about transmembrane signaling mechanisms involving fibronectin receptor or related """"""""integrin"""""""" type receptors. We have obtained preliminary evidence that G proteins may be involved in the fibronectin mediated adhesion pathway; we will critically analyze this possibility, and attempt to test whether G protein directly or indirectly impinge on the adhesion process.
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