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Molecular and Cellular Biology, January 2007, p. 312-323, Vol. 27, No. 1
0270-7306/07/$08.00+0     doi:10.1128/MCB.00985-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Rac Effector p67phox Regulates Phagocyte NADPH Oxidase by Stimulating Vav1 Guanine Nucleotide Exchange Activity{triangledown} ,{dagger}

Wenyu Ming,1 Shijun Li,1,{ddagger} Daniel D. Billadeau,2 Lawrence A. Quilliam,3 and Mary C. Dinauer1,4*

Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, 1044 West Walnut Street, R4 451A, Indianapolis, Indiana 46202,1 Division of Developmental Oncology Research, Department of Immunology, Mayo Clinic, 13-11C Guggenheim, 200 First Street Southwest, Rochester, Minnesota 55905,2 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, and Walther Cancer Institute, 635 Barnhill Drive, MS-4053, Indianapolis, Indiana 46202,3 Departments of Microbiology and Immunology and Medical and Molecular Genetics, Indiana University School of Medicine, 1044 West Walnut Street, R4 402C, Indianapolis, Indiana 462024

Received 2 June 2006/ Returned for modification 10 July 2006/ Accepted 9 October 2006

The phagocyte NADPH oxidase catalyzes the reduction of molecular oxygen to superoxide and is essential for microbial defense. Electron transport through the oxidase flavocytochrome is activated by the Rac effector p67phox. Previous studies suggest that Vav1 regulates NADPH oxidase activity elicited by the chemoattractant formyl-Met-Leu-Phe (fMLP). We show that Vav1 associates with p67phox and Rac2, but not Rac1, in fMLP-stimulated human neutrophils, correlating with superoxide production. The interaction of p67phox with Vav1 is direct and activates nucleotide exchange on Rac, which enhances the interaction between p67phox and Vav1. This provides new molecular insights into regulation of the neutrophil NADPH oxidase, suggesting that chemoattractant-stimulated superoxide production can be amplified by a positive feedback loop in which p67phox targets Vav1-mediated Rac activation.

* Corresponding author. Mailing address: Cancer Research Institute, 1044 W. Walnut Street, R4 402C, Indianapolis, IN 46202. Phone: (317) 274-8645. Fax: (317) 274-8679. E-mail: mdinauer{at}iupui.edu.

{triangledown} Published ahead of print on 23 October 2006.

{dagger} Supplemental material for this article is available at http://mcb.asm.org/.

{ddagger} Present address: Department of Urology, Stanford University Medical Center, 300 Pasteur Dr., Stanford, CA 94305.

Molecular and Cellular Biology, January 2007, p. 312-323, Vol. 27, No. 1
0270-7306/07/$08.00+0     doi:10.1128/MCB.00985-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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