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A more recent version of this article appeared on August 1, 2004
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Submitted on November 25, 2003
Revised on May 3, 2004
Accepted on May 4, 2004
Department of Microbiology and Immunology and the Biophysics Research Division, University of Michigan Medical School, Ann Arbor, Michigan 48109-0620
Monitoring Editor: Frank Solomon
The small G-proteins Cdc42, Rac1,and Rac2 regulate the rearrangements of actin and membrane necessary for Fc
receptor-mediated phagocytosis by macrophages. Activated, GTP-bound Cdc42, Rac1 and Rac2 bind to the p21-binding domain (PBD) of PAK1, and this interaction provided a basis for microscopic methods to localize activation of these G-proteins inside cells. FRET-based stoichiometry of fluorescent chimeras of actin, PBD, Cdc42, Rac1, and Rac2 was used to quantify G-protein activation relative to actin movements during phagocytosis of IgG-opsonized erythrocytes. The activation dynamics of endogenous G-proteins, localized using YFP-labeled PBD, was restricted to phagocytic cups, with a prominent spike of activation over an actin-poor region at the base of the cup. Refinements of FRET stoichiometry allowed calculation of the fractions of activated GTPases in forming phagosomes. Cdc42 activation was restricted to the leading margin of the cell, whereas Rac1 was active throughout the phagocytic cup. During phagosome closure, activation of Rac1 and Rac2 increased uniformly and transiently in the actin-poor region of phagosomal membrane. These distinct roles for Cdc42, Rac1 and Rac2 in the component activities of phagocytosis indicate mechanisms by which their differential regulation coordinates rearrangements of actin and membranes.
*Corresponding author.
Joel A. Swanson, E-mail: jswan{at}umich.edu
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