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Molecular and Cellular Biology, May 2004, p. 4384-4394, Vol. 24, No. 10
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.10.4384-4394.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Sequential Activation of Phosphatidylinositol 3-Kinase, ßPix, Rac1, and Nox1 in Growth Factor-Induced Production of H2O2

Hye Sun Park,1 Seung Hye Lee,2 Dongeun Park,2 Jun Sung Lee,3 Sung Ho Ryu,3 Won Jae Lee,1 Sue Goo Rhee,4 and Yun Soo Bae1*

Center for Cell Signaling Research, Division of Molecular Life Sciences, Ewha Womans University, Seoul 120-750,1 School of Biological Sciences, Seoul National University, Seoul 151-742, Korea,2 Division of Molecular and Life Science, Postech,3 Laboratory of Cell Signaling, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland4

Received 2 July 2003/ Returned for modification 2 December 2003/ Accepted 11 February 2004

The generation of reactive oxygen species (ROS) in cells stimulated with growth factors requires the activation of phosphatidylinositol 3-kinase (PI3K) and the Rac protein. We report here that the COOH-terminal region of Nox1, a protein related to gp91phox (Nox2) of phagocytic cells, is constitutively associated with ßPix, a guanine nucleotide exchange factor for Rac. Both growth factor-induced ROS production and Rac1 activation were completely blocked in cells depleted of ßPix by RNA interference. Rac1 was also shown to bind to the COOH-terminal region of Nox1 in a growth factor-dependent manner. Moreover, the depletion of Nox1 by RNA interference inhibited growth factor-induced ROS generation. These results suggest that ROS production in growth factor-stimulated cells is mediated by the sequential activation of PI3K, ßPix, and Rac1, which then binds to Nox1 to stimulate its NADPH oxidase activity.

* Corresponding author. Mailing address: Center for Cell Signaling Research, Division of Molecular Life Sciences, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemoon-Gu, Seoul 120-750, Korea. Phone: 82-2-3277-2729. Fax: 82-2-3277-3760. E-mail: baeys{at}ewha.ac.kr.

Molecular and Cellular Biology, May 2004, p. 4384-4394, Vol. 24, No. 10
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.10.4384-4394.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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