The Roles And Mechanisms Of Focal Adhesion Kinase In The Regulation Of Angiogenesis

Focal Adhesion Kinase (FAK) is a cytoplasmic tyrosine kinase that mediates signal transduction of integrins and other cell surface receptors in a variety of cells, including endothelial cells (ECs). Phosphorylation of FAK and its interactions with other signaling molecules have been shown to trigger several signaling pathways in the regulation of cellular functions, including cell migration, cell cycle progression and cell survival. Consistent with its critical importance in the regulation of various cellular functions, deletion of the FAK gene in mice leads to death at embryonic day 8.5 (E8.5) due to defects in the axial mesodermal tissues including the cardiovascular system with incomplete development of both the blood vessels and the heart. Using a conditional mouse knock out approach, we and others have recently shown a role of FAK in vascular angiogenesis. Further studies with primary FAK deficient ECs showed that the essential function of FAK in the regulation of EC activities, including EC migration, proliferation and survival may contribute to the regulation of angiogenesis in vivo (Chapter 2). The availability of the floxed FAK mice and ECs isolated from these mice allowed us to further investigate the role of specific FAK downstream pathways in EC functions by rescuing the various phenotypes with FAK mutants lacking specific interactions with its target both in vitro and in vivo. In this dissertation, we revealed a novel function of FAK in the regulation of centrosomal functions in a Ser-732 phosphorylation-dependent manner in ECs during mitosis, which plays a role in the regulation of EC proliferation and tubulogenesis in vitro and tumor angiogenesis in vivo (Chapter 3)