FAK and Pyk2 Regulate the Intracellular Signaling Networks Required for Integrin-medicated Migration and Phagocytes by Macrophages

As an essential component of the immune system, macrophages are capable of a diverse range of functions including integrin-mediated adhesion to and extravasation from blood vessels, chemotaxis, phagocytosis and the release of cytokines. The FAK family of kinases consists of two closely related protein tyrosine kinases, FAK and Pyk2, which function as important regulators of integrin-mediated signaling. The generation of myeloid-specific conditional FAK knockout mice has allowed us to examine the complex interplay between FAK, Pyk2 and other downstream effectors involved in integrin signaling in primary macrophages. In this thesis, I demonstrate that macrophages derived from these mice display significant motility defects in vitro and that the loss of FAK in vivo results in reduced levels of inflammatory monocyte infiltration to sites of inflammation. These data indicate that by disrupting FAK in monocyte/macrophages, such that the ability of these cells to migrate is inhibited, the macrophage-specific host response to inflammation can be altered. These results have significant consequences when considered within the context of chronic inflammatory diseases and cancer. Importantly, we establish that the invasive capacity of tumor cells co-cultured with FAK -/- macrophages is reduced and provide preliminary in vivo evidence indicating that tumor outgrowth may be delayed in myeloid-specific conditional FAK knockout mice. Further investigation of the signaling pathways controlling macrophage motility reveals that migration is regulated by two distinct pathways: one dependent on the expression of FAK and Pyk2, and the other pathway dependent on the linkage between ii 4-integrin and the adapter protein paxillin. I have also examined the host signaling networks involved in the integrin-mediated phagocytosis of the enteropathogen Yersinia pseudotuberculosis, demonstrating that simultaneous expression of the two Yersinia adhesins, invasin and YadA, stimulates two independent pathways in which FAK and Pyk2 perform distinct, non-redundant functions required for bacterial internalization. In summary, the studies presented here shed light on the molecular signaling involved in macrophage motility and phagocytosis, and contribute to a more comprehensive understanding of the regulation of the actin cytoskeleton in cells of the myeloid lineage.

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