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J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/09/955/12 $2.00
Volume 186, Number 6, September 15, 1997 955-966

Rho is Required for the Initiation of Calcium Signaling and Phagocytosis by Fcgamma Receptors in Macrophages

By David J. Hackam,*Dagger Ori D. Rotstein,Dagger Alan Schreiber,§ Wei-jian Zhang,*Dagger and Sergio Grinstein*

From the * Division of Cell Biology, Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada; Dagger  Department of Surgery,  The Toronto Hospital, Toronto, Ontario, M5G 2C4, Canada; and § Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4283

Phagocytosis of bacteria by macrophages and neutrophils is an essential component of host defense against infection. The mechanism whereby the interaction of opsonized particles with Fcgamma receptors triggers the engulfment of opsonized particles remains incompletely understood, although activation of tyrosine kinases has been recognized as an early step. Recent studies in other systems have demonstrated that tyrosine kinases can in turn signal the activation of small GTPases of the ras superfamily. We therefore investigated the possible role of Rho in Fc receptor-mediated phagocytosis. To this end we microinjected J774 macrophages with C3 exotoxin from Clostridium botulinum, which ADP-ribosylates and inactivates Rho. C3 exotoxin induced the retraction of filopodia, the disappearance of focal complexes, and a global decrease in the F-actin content of J774 cells. In addition, these cells exhibited increased spreading and the formation of vacuolar structures. Importantly, inactivation of Rho resulted in the complete abrogation of phagocytosis. Inhibition of Fcgamma receptor-mediated phagocytosis by C3 exotoxin was confirmed in COS cells, which become phagocytic upon transfection of the Fcgamma RIIA receptor. Rho was found to be essential for the accumulation of phosphotyrosine and of F-actin around phagocytic cups and for Fcgamma receptor-mediated Ca2+ signaling. The clustering of receptors in response to opsonin, an essential step in Fcgamma -induced signaling, was the earliest event shown to be inhibited by C3 exotoxin. The effect of the toxin was specific, since clustering and internalization of transferrin receptors were unaffected by microinjection of C3. These data identify a role for small GTPases in Fcgamma receptor-mediated phagocytosis by leukocytes.


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