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* Herman B Wells Center for Pediatric Research and Departments of Pediatrics (Hematology/Oncology), Microbiology/Immunology, and Medical and Molecular Genetics,
Biochemistry and Molecular Biology, and
Walther Oncology Center and Walther Cancer Institute,
James Whitcomb Riley Hospital for Children, Indiana University Medical School, Indianapolis, IN 46202
The hemopoietic-specific Rho family GTPase Rac2 shares 92% amino
acid identity with ubiquitously expressed Rac1. Neutrophils from
rac2-/- mice have multiple defects,
including chemoattractant-stimulated NADPH oxidase activity and
chemotaxis, which may result from an overall reduction in cellular Rac
or mechanisms that discriminate Rac1 and Rac2. We show that murine
neutrophils have similar amounts of Rac1 and Rac2, unlike human
neutrophils, which express predominantly Rac2. An affinity
precipitation assay for Rac-GTP showed that although FMLP-induced
activation of both isoforms in wild-type neutrophils, 
4-fold more
Rac2-GTP was detected than Rac1-GTP. Wild-type and Rac2-deficient
neutrophils have similar levels of total Rac1. FMLP-induced Rac1-GTP in
rac2-/- neutrophils was 3-fold greater
than in wild-type cells, which have similar levels of total Rac1, yet
FMLP-stimulated F-actin, chemotaxis, and superoxide production are
markedly impaired in rac2-/- neutrophils.
Heterozygous rac2+/- neutrophils, which had
intermediate levels of total and FMLP-induced activated Rac2, exhibited
intermediate functional responses to FMLP, suggesting that Rac2 was
rate limiting for these functions. Thus, phenotypic defects in
FMLP-stimulated Rac2-deficient neutrophils appear to reflect distinct
activation and signaling profiles of Rac 1 and Rac2, rather than a
reduction in the total cellular level of Rac.
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