Focal Adhesion Kinase (FAK) Family Members Regulate Monocyte Survival at Homeostasis and Macrophage-mediated Control of Breast Tumor Progression

Monocytes and macrophages are innate immune effector cells that perform a diverse set of activities essential for the maintenance of tissue homeostasis and the process of disease resolution. Hallmarks of these cells include substantial functional plasticity and the capacity to migrate. These attributes are strongly influenced by extra-cellular stimuli, and the ability to properly integrate environmental signals is critical for monocytes and macrophages to perform their effector functions. The FAK family of kinases consists of two closely related non-receptor protein tyrosine kinases, FAK and Pyk2, which function as important regulators of integrin-mediated signaling. My thesis research has focused on establishing the expression and function of FAK kinases in monocyte and macrophage populations. In this thesis, we demonstrate that FAK is not abundantly expressed in monocytes, but is highly expressed in macrophages. In contrast, Pyk2 could be detected in both monocytes and macrophages; however, Pyk2 protein expression is significantly upregulated in Ly6C-neg monocytes and macrophages compared with less differentiated monocyte subsets. We go on to show that the regulated expression of FAK kinases in monocyte and macrophage populations also has functional implications. Our data strongly suggest that Pyk2 limits the accumulation of Ly6C-neg monocytes at homeostasis by promoting apoptosis in these cells. We also show that FAK activity in macrophages restricts the outgrowth of breast carcinomas in a murine model of cancer. The studies presented here reveal novel functions for FAK kinases in monocytes and macrophages, and contribute to a more comprehensive understanding of the molecular signaling that regulates the activities of these cells during steady-state and pathogenic conditions.