The long term goal of the proposed research is to understand how signal transduction cascades initiated by extracellular matrix-integrin interactions regulate cell adhesion, cell motility, cell growth and differentiation. Our goal is 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 this proposal. The proposed studies focus specifically on the role of focal adhesion kinase in mediating signals from the extracellular matrix through the beta-integrin receptors. The three aims emphasize the identification and characterization of molecules that directly interact with FAK and link both upstream and downstream signaling components; defining the role of FAK and interacting partners in mediating signals that regulate cell motility and growth; and finally studying how cells utilize a potentially novel mechanism to regulate adhesion signaling during development.
The specific aims are: 1. Using our base of knowledge about the structural organization of the domains of FAK, we will seek to define new structural and functional linkages mediated by C-terminal protein interaction motifs; 2. determine the functional role of FAK in the organization of focal complexes and focal adhesions and determine how FAK contributes to the regulation of cell migration in response to growth factors and cell matrix molecules; and 3. explore the possible in vivo regulation of adhesion signaling by the cell1tissue type-specific expression of the C-terminal domain of FAK, FRNK ( FAK-related NonKinase) and examine the consequences of knocking out FRNK on the course and extent of normal development of the mouse.
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