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J. Biol. Chem., Vol. 276, Issue 19, 15929-15938, May 11, 2001
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From the The Rho GTPase, Rac2, is expressed
only in hematopoietic cell lineages, suggesting a specific cellular
function in these cells. Genetic targeting studies in mice showed that
Rac2 is an essential regulator of neutrophil chemotaxis, L-selectin
capture and rolling, and superoxide production. Recently, a dominant
negative mutation of Rac2, D57N, has been reported to be
associated with a human phagocytic immunodeficiency. To
understand further the cellular phenotypes associated with this D57N
Rac2 mutant we examined its biochemical characteristics and functional
effects when expressed in primary murine bone marrow cells. When
compared with wild type (WT) Rac2, D57N Rac2 displayed ~10% GTP
binding ability resulting from a markedly enhanced rate of GTP
dissociation and did not respond to the guanine nucleotide exchange
factors. These results suggest that D57N Rac2 may act in a dominant
negative fashion in cells by sequestering endogenous guanine nucleotide
exchange factors. When expressed in hematopoietic cells, D57N Rac2
reduced endogenous activities of not only Rac2, but also Rac1 and
decreased cell expansion in vitro in the presence of growth
factors due to increased cell apoptosis. Unexpectedly, D57N expression
had no effect on proliferation. In contrast, expansion of cells
transduced with WT Rac2 and a dominant active mutant, Q61L, was
associated with significantly increased proliferation. Transplantation
of transduced bone marrow cells into lethally irradiated recipients showed that the percentage of D57N-containing peripheral blood cells
decreased markedly from 40% at 1 month to <5% by 3 months postinjection. Neutrophils derived in vitro from the
transduced progenitor cells containing D57N demonstrated markedly
impaired migration and O
Biochemical and Biological Characterization of a Human Rac2
GTPase Mutant Associated with Phagocytic Immunodeficiency*
§,§,§,§
Howard Hughes Medical Institute and the
§ Herman B Wells Center for Pediatric Research, Department
of Pediatrics, Indiana University School of Medicine, Indianapolis,
Indiana 46202, and the ¶ Department of Biochemistry, University of
Tennessee at Memphis, Memphis, Tennessee 38163
*
This work was supported in part by National Institutes of
Health Grant GM60523 (to Y. Z.).The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Howard Hughes
Medical Institute, 1044 West Walnut St., Rm. 402, Indianapolis, IN
46202-5225. Tel.: 317-274-8960; Fax: 317-274-8679; E-mail: dwilliam@iupui.edu.
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