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First published online December 15, 2003
doi: 10.1242/10.1242/jcs.00853

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Rac2^D57N, a dominant inhibitory Rac2 mutant that inhibits p38 kinase signaling and prevents surface ruffling in bone-marrow-derived macrophages

Amy N. Abell^1,*,, Aimee M. DeCathelineau⁴, Scott A. Weed², Daniel R. Ambruso³, David W. Riches⁴ and Gary L. Johnson^1,*,

¹ Department of Pharmacology, University of Colorado Health Sciences Center, 4200 East Ninth Ave, Denver, CO 80262, USA
² Department of Craniofacial Biology, University of Colorado Health Sciences Center, 4200 East Ninth Ave, Denver, CO 80262, USA
³ Bonfils Blood Center and the Department of Pediatrics, University of Colorado School of Medicine, Denver, CO 80230, USA
⁴ Program in Experimental Pathology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA

Authors for correspondence (e-mail: amy_abell{at}med.unc.edu; glj{at}med.unc.edu)

Accepted 4 September 2003

Rac2 is a Rho GTPase that is expressed in cells of hematopoietic origin, including neutrophils and macrophages. We recently described an immunodeficient patient with severe, recurrent bacterial infections that had a point mutation in one allele of the Rac2 gene, resulting in the substitution of aspartate 57 with asparagine. To ascertain further the effects of Rac2^D57N in leukocytes, Rac2^D57N was expressed in primary murine bone-marrow-derived macrophages (cells that we show express approximately equal amounts of Rac1 and Rac2). Rac2^D57N expression in macrophages inhibited membrane ruffling. Rac2^D57N expression inhibited the formation of macropinosomes, demonstrating a functional effect of the loss of surface membrane dynamics. Surprisingly, Rac2^D57N induced an elongated, spread morphology but did not affect microtubule networks. Rac2^D57N also inhibited lipopolysaccharide-stimulated p38 kinase activation. Examination of guanine nucleotide binding to recombinant Rac2^D57N revealed reduced dissociation of GDP and association of GTP. Coimmunoprecipitation studies of Rac2^D57N with RhoGDI and Tiam1 demonstrated increased binding of Rac2^D57N to these upstream regulators of Rac signaling relative to the wild type. Enhanced binding of Rac2^D57N to its upstream regulators would inhibit Rac-dependent effects on actin cytoskeletal dynamics and p38 kinase signaling.

Key words: Rac2, Bone-marrow-derived macrophage, p38 kinase, Actin, Human mutation

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