Rac2 in reglation of cytoskeletal function

Indiana Univ-Purdue Univ At Indianapolis, Indianapolis IN

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Abstract

Rho GTPases are widely recognized as the critical integrators of signals from the cell surface that control cell morphology and motility in all eukaryotic cell types examined, including hematopoietic cells. The ultimate targets of these signals are alterations in the organization of the actin cytoskeleton. Signals from Rac, a rho family GTPase, result in actin polymerization at the cell periphery that is crucial for extension of the leading edge of crawling cells, for the phagocytosis of pathogens and for correct uptake and presentation of antigen by dendritic cells. The generation of a strain of mice deficient in the hematopoietic-specific GTPase Rac2 provides a unique animal model in which to study the role of signaling pathways utilizing this GTPase in their physiological context. Mice deficient in Rac2 exhibited multiple defects in neutrophil functions related to the actin cytoskeleton including chemotaxis, integrin- and selectin-mediated adhesion and phagocytosis. Underlying these defects appears to be a disturbance in actin dynamics at rest and in response to stimulus. We propose studies to determine the mechanisms by which Rac2 deficiency results in disturbed actin dynamics. We will characterize the phenotypes of Rac2 deficient macrophages, neutrophils and dendritic cells that relate to actin dynamics, and using retroviral transduction we will determine the requirement for Rac2-specific sequences for normal function in these cell types. The will determine the requirement for Rac2-specific sequences for normal function in these cell types. We will determine the mechanistic basis for disturbed actin dynamics in the absence of Rac2 by measuring the roles of de novo nucleation of actin filaments and barbed end uncapping, and the roles of components of signaling pathways that lie between Rac and components of the actin cytoskeleton. Studies described in this project will further understanding of the role of the cytoskeleton and the pathways that control it in innate and acquired immunity.