The overall goal of this proposal is to understand the role of focal adhesion kinase (FAK) signaling with respect to the processes of tumorigenesis. Work from a number of labs has identified FAK as a component of both integrin and growth factor receptor signaling pathways. In many advanced and metastatic tumors, FAK is overexpressed and highly tyrosine phosphorylated. However, our knowledge is very limited with regard to how FAK contributes to the processes of cell transformation and tumor progression in vivo. We will test the overall hypothesis that elevated FAK expression and activity provides a selective advantage promoting solid tumor growth through the enhancement of anchorage-independent cell survival, through the regulation of metalloproteinase expression, and through the release of angiogenic factors in vivo. In particular, we will test the hypothesis that these events are mediated in part through elevated Rac activity, JNK/SAP kinase signaling, and through the alteration of gene expression events.
Aim -1 of this proposal will test the functional significance of elevated FAK expression in human adenocarcinoma cells in vitro and in vivo using FAK antisense mRNA.
Aim -2 will evaluate the role of elevated FAK tyrosine phosphorylation in the regulation of mammary carcinoma cell growth/survival in vitro and in vivo using dominant-negative FRNK expression.
Aim -3 will determine the molecular connections of Src-FAK signaling promoting cell invasion in vitro as well as enhanced tumor growth and angiogenesis in vivo through comparisons of Src-transformed FAK-null and FAK-reconstituted cells. In all of these studies, we will implement an innovative strategy of rescuing the loss or absence of FAK function through the adenoviral-mediated overexpression of epitope-tagged FAK and mutants of FAK. These studies will elucidate the functional differences of FAK as an adaptor protein compared to a role for FAK as signaling kinase. Achievement of these goals will yield new information on the role of FAK signaling and will aid in the development of therapeutic strategies to control the growth and spread of tumor cells. ? ?
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