University of Virginia Health System

Protein Kinases in Cell Adhesion;The long term goal of our research is to understand how signal transduction cascades initiated by growth factors and extracellular matrix-integrin interactions regulate cell adhesion, cell motility, cell growth and differentiation. We seek to understand how such signaling pathways are organized (wired) in normal cells and to ultimately define the cellular alterations (both genetic and environmental) that lead to abnormal adhesion signaling in cancer cells. Studies over the past five years have identified two major classes of signaling molecules that participate in and regulate adhesion signaling, protein tyrosine kinases and members of the family of small GTPases. How these two classes of regulatory proteins function to organize the complex signaling required for cell adhesion and movement is a central theme of our laboratory. One area of intense study is the role of focal adhesion kinase (FAK) in mediating signals from the extracellular matrix through the beta-integrin receptors. We are focusing on the identification and characterization of molecules that directly interact with FAK and link FAK with both upstream and downstream signaling components. We are seeking to define the role of FAK and interacting partners in mediating signals that regulate cell motility and growth. Finally we are studying how cells utilize a potentially novel mechanism to regulate adhesion signaling during development. A second area of emphasis in the laboratory is to understand how individual tyrosine kinase substrates contribute to tyrosine kinase directed signaling. Studies of "cortactin", a tyrosine phosphorylated actin binding protein, point to a role for cortactin in the control of membrane ruffling and cell motility. Future studies will focus on the role of the cytoskeleton and associated regulatory proteins in orchestrating compartmentalized signaling in response to growth factor and adhesion signals during normal developmental processes and in cancer cells.