Focal Adhesion Kinase Signaling and Inflammation: Novel Functions in Intestinal Epithelial Cells and Macrophages

Focal adhesion kinase (FAK) is a multidomain non-receptor tyrosine kinase that has been shown to contribute significantly to inflammatory signaling pathways as well as tumor progression in cancer. Thus FAK represents a key therapeutic target for disease treatment. FAK is known to regulate a diverse set of cellular processes, including adhesion, migration, proliferation, and survival. This thesis expands upon these known functions of FAK by using two conditional FAK knockout mouse models to deplete FAK in two cell types in which FAK function has not been well characterized, intestinal epithelial cells and macrophages. First, with the generation of an intestinal epithelial cell-specific conditional FAK knockout mouse model, it was found that while FAK is required for epithelial cell survival, compensating mechanisms exist to regulate homeostasis in the absence of FAK. However FAK is absolutely required for intestinal epithelial cell proliferation and restitution following mucosal injury. Second, in order to study the role of FAK in regulating key macrophage functions, a myeloid-specific conditional FAK knockout mouse model was used. Using macrophages isolated from these mice, we identified unique 1 integrin-mediated pathways that regulate macrophage chemotaxis. Finally, as FAK was previously reported to play a role in phagocytosis, we investigated FAK-dependent signaling pathways regulating bacterial uptake by macrophages. To expand upon these findings, in vivo infections in myeloid-specific conditional FAK knockout mice were performed with the enteropathogen Yersinia pseudotuberculosis to examine the contribution of FAK expression in myeloid cells to the host inflammatory response following  bacterial infection. These data suggest that FAK expression in myeloid cells  contributes to the host response to infection by promoting bacterial survival. However, the exact mechanism by which FAK plays a role in this process is unclear. The related FAK family member Pyk2 has been shown to exhibit compensatory and non-redundant functions with regard to FAK. Thus, the study of Pyk2 function in these cell types will provide compelling avenues to expand upon the findings outlined in this thesis.

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