Regulation of neutrophil function by Rac GTPases.
Rac plays a central role in regulating neutrophil responses to inflammatory signals, including actin remodeling, chemotaxis, and superoxide production by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Rac-GTP is a component of the membrane-assembled NADPH oxidase complex, and new evidence suggests that Rac-GTP interacts directly with the oxidase flavocytochrome, in addition to binding to the regulatory p67 subunit, to regulate electron transfer both independently and cooperatively from NADPH to molecular oxygen. Other new studies suggest that Rac-GTP plays a dual role in NADPH oxidase activation, and can initiate signaling pathways leading to translocation of cytosolic oxidase subunits in addition to functioning in the assembled enzyme complex. Rac activation in response to neutrophil chemoattractants may be regulated in large part by a newly identified guanine nucleotide exchange factor, P-Rex1, which is activated by either phosphatidylinositols or Gbetagamma subunits. Multiple Rac GTPase activating proteins are present in neutrophils and may also modulate levels of Rac-GTP. The importance of Rac in a broad range of neutrophil functions is shown by the variety of defects seen in neutrophils from Rac2 knockout mice and from a patient with recurrent infections and a dominant-negative mutation in Rac2.
Dinauer
Mary C
MC
Department of Pediatrics, Herman B. Wells Center for Pediatric Research, James Whitcomb Riley Hospitals for Children, Indiana University School of Medicine, Indianapolis 46202, USA. mdinauer@iupui.edu
D000818:Animals; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism / Q000502:physiology; D006801:Humans; D019255:NADPH Oxidases / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D009504:Neutrophils / Q000201:enzymology* / Q000502:physiology; D011485:Protein Binding; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000097766:RAC2 GTP-Binding Protein
D020662:Guanine Nucleotide Exchange Factors; D019255:NADPH Oxidases; D020744:rac GTP-Binding Proteins; D000097766:RAC2 GTP-Binding Protein; C453280:PREX1 protein, human