The long term goal of this research is to understand the mechanisms by which cell adhesion to extracellular matrix regulate cell cycle progression. Dr. Guan and his colleagues have recently found that integrin signaling through FAK plays a major role in cell cycle regulation in cell adhesion. Their analyses using an inducible expression system suggested a critical role for focal adhesion localization of FAK and its associated signaling molecules, and identified Erks and cyclin D1 as important mediators of cell cycle regulation by the integrin-FAK signaling pathways. Studies from his laboratory and others have also suggested that FAK can interact with multiple intracellular signaling molecules to trigger several downstream signaling pathways. In addition, they have identified a novel cellular protein that can associate with both FAK and its related kinase Pyk2 and may function as an inhibitor of the FAK family kinases in intracellular signaling. In this proposal, the investigators plan to dissect the molecular mechanisms underlying cell cycle regulation by integrin-FAK signaling pathways.
In Aim 1, they will first analyze the relative contributions of FAK/Src vs FAK/PI3K complexes in cell cycle regulation by FAK. They will then examine the roles of signaling molecules downstream from the FAK/Src and FAK/PI3K complexes including p130cas, Grb2 and Akt. Lastly, they will determine the role of focal adhesion localization of the FAK signaling complexes.
In Aim 2, the group will examine FAK regulation of cyclin D1 at transcription level by analyzing transactivation of cyclin D1 promoter reporter by FAK signaling pathways as well as the effect of inducible expression of FAK and its mutants on endogenous cyclin D1. They will also investigate regulation of cyclin D1 protein synthesis and degradation and the potential role of eIF-4E, 4E-BPs and cyclin D1 phosphorylation as mediators of cyclin D1 regulation by FAK signaling pathways. Finally, they will determine whether overexpression of cyclin D1 can rescue cell cycle inhibition caused by disruption of FAK signaling. In the last Aim, they will identify the binding sites for both FAK and FAP200. They will then investigate the potential mechanism by which FAP200 may function as an inhibitor of FAK to regulate cell cycle progression, and the alternative possibility that FAP200 may serve as a novel FAK substrate which plays a role in cell cycle regulation by FAK. The investigators hope that these studies will provide new insights into the mechanisms by which cell adhesion to extracellular matrix regulate cell cycle progression.
Showing the most recent 10 out of 40 publications
