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Molecular and Cellular Biology, February 2007, p. 899-911, Vol. 27, No. 3
0270-7306/07/$08.00+0     doi:10.1128/MCB.00756-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Abr and Bcr, Two Homologous Rac GTPase-Activating Proteins, Control Multiple Cellular Functions of Murine Macrophages ^,

Young Jin Cho,^1, Jess M. Cunnick,^1,, Sun-Ju Yi,¹ Vesa Kaartinen,² John Groffen,¹ and Nora Heisterkamp^1*

Section of Molecular Carcinogenesis, Division of Hematology/Oncology,¹ Developmental Biology Program, Departments of Pathology and Surgery, Childrens Hospital Los Angeles, Saban Research Institute, and Keck School of Medicine, University of Southern California, Los Angeles, California²

Received 1 May 2006/ Returned for modification 24 June 2006/ Accepted 30 October 2006

Small GTPases of the Rho family are key regulators of phagocytic leukocyte function. Abr and Bcr are homologous, multidomain proteins. Their C-terminal domain has GTPase-activating protein (GAP) activity that, in vitro, is specific for Rac and Cdc42. To address the in vivo relevance of these entire proteins, of which little is known, the current study examined the effect of the genetic ablation of Abr and Bcr in murine macrophages. The concomitant loss of Abr and Bcr induced multiple alterations of macrophage cellular behavior known to be under the control of Rac. Macrophages lacking both Abr and Bcr exhibited an atypical, elongated morphology that was reproduced by the ectopic expression of GAP domain mutant Abr and Bcr in a macrophage cell line and of constitutively active Rac in primary macrophages. A robust increase in colony-stimulating factor 1 (CSF-1)-directed motility was observed in macrophages deficient for both proteins and, in response to CSF-1 stimulation, Abr and Bcr transiently translocated to the plasma membrane. Phagocytosis of opsonized particles was also increased in macrophages lacking both proteins and correlated with sustained Rac activation. Bcr and Abr GAP mutant proteins localized around phagosomes and induced distinct phagocytic cup formation. These results identify Abr and Bcr as the only GAPs to date that specifically negatively regulate Rac function in vivo in primary macrophages.

Published ahead of print on 20 November 2006.

Supplemental material for this article may be found at http://mcb.asm.org/.

Y.J.C. and J.M.C. contributed equally to this work.

Present address: College of Science and Technology, Fairmont State University, 1201 Locust Ave., Fairmont, WV 26554.

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