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Rac2D57N, a dominant inhibitory Rac2 mutant that inhibits p38 kinase signaling and prevents surface ruffling in bone-marrow-derived macrophages

Abell, Amy N., DeCathelineau, Aimee M., Weed, Scott A., Ambruso, Daniel R., Riches, David W., Johnson, Gary L.·2004·Journal of Cell Science
DOI 10.1242/jcs.00853
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Abstract

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 Rac2D57N in leukocytes, Rac2D57N was expressed in primary murine bone-marrow-derived macrophages (cells that we show express approximately equal amounts of Rac1 and Rac2). Rac2D57N expression in macrophages inhibited membrane ruffling. Rac2D57N expression inhibited the formation of macropinosomes, demonstrating a functional effect of the loss of surface membrane dynamics. Surprisingly, Rac2D57N induced an elongated, spread morphology but did not affect microtubule networks. Rac2D57N also inhibited lipopolysaccharide-stimulated p38 kinase activation. Examination of guanine nucleotide binding to recombinant Rac2D57N revealed reduced dissociation of GDP and association of GTP. Coimmunoprecipitation studies of Rac2D57N with RhoGDIα and Tiam1 demonstrated increased binding of Rac2D57N to these upstream regulators of Rac signaling relative to the wild type. Enhanced binding of Rac2D57N to its upstream regulators would inhibit Rac-dependent effects on actin cytoskeletal dynamics and p38 kinase signaling.

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Cited by

Metadata

Authors
Abell, A. N., DeCathelineau, A. M., Weed, S. A., Ambruso, D. R., Riches, D. W., & Johnson, G. L.
Affiliations
  • Department of Pharmacology, University of Colorado Health Sciences Center, 4200 East Ninth Ave, Denver, CO 80262, USA
  • Program in Experimental Pathology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA
  • Department of Craniofacial Biology, University of Colorado Health Sciences Center, 4200 East Ninth Ave, Denver, CO 80262, USA
  • Bonfils Blood Center and the Department of Pediatrics, University of Colorado School of Medicine, Denver, CO 80230, USA
Venue
Journal of Cell Science
Publisher
The Company of Biologists
Published
2004-01-15
Volume
117
Issue
2
Pages
243-255
ISSN
  • 1477-9137
  • 0021-9533
DOI
10.1242/jcs.00853
Cited by
15
References
2
Language
en

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