The long-term goal of these studies is to understand how the spatial and temporal activation of protein tyrosine kinases, FAK and Src, regulates the formation, organization and turnover of cellular adhesions and how this dynamic process links to the downstream activation of key signaling pathways. Integrin signaling controls a wide variety of intracellular events, including cell adhesion, migration, cytoskeletal organization, growth, and survival. Key mediators in integrin signaling are the non-receptor protein tyrosine kinases, Focal Adhesion Kinase (FAK) and Src. Data from our laboratory, as well as data from many others, have shown that FAK and Src play an important role in providing signals that contribute to the organization and turnover of cellular adhesions. Indeed, it is now clear that at the molecular level, cell adhesions are functionally heterogeneous and very dynamic. Thus, """"""""integrin signaling"""""""" is likely comprised of many functionally distinct signaling compartments, differentially regulated in """"""""space and time"""""""". Work during the past granting period has focused on the identification of FAK/Src binding proteins, characterization of the nature of the adhesion complex and identification of downstream signaling pathways linked to FAK. Drawing on the knowledge gained in the past five years, we now focus on understanding the spatial and temporal dynamics of integrin signaling and the role of FAK and Src in this process. We propose three aims. First, we will explore the role of FAK in controlling the dynamics of early focal complex formation and turnover. Second, we will determine the biochemical linkages between integrins, FAK and the small GTPase Rac and Arfl. Finally, we will use imaging approaches to identify the spatial and temporal signals produced in response to integrin engagement, as well as determine spatial and temporal formation of protein-protein complexes. These studies should provide information on events that are critical to directional (polarized) cell migration, cell-cell organization and cell polarity in normal and cancer cells.
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