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MBC in Press, published online ahead of print May 7, 2008
Mol. Biol. Cell 10.1091/mbc.E08-02-0138

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Submitted on February 11, 2008
Revised on April 1, 2008
Accepted on April 30, 2008

The Involvement of the Tyrosine Kinase c-Src in the Regulation of Reactive Oxygen Species (ROS) Generation Mediated by NADPH oxidase-1 (Nox1)

Davide Gianni,* Ben Bohl,* Sara A. Courtneidge,{dagger} and Gary M. Bokoch*

*Departments of Immunology and Cell Biology, The Scripps Research Institute, La Jolla, CA 92037; {dagger}The Burnham Institute for Medical Research, La Jolla, CA 92037

Monitoring Editor: Jonathan Chernoff

NADPH oxidase (Nox) family enzymes are one of the main sources of cellular reactive oxygen species (ROS), which have been shown to function as second messenger molecules. To date 7 members of this family have been reported, including Nox1–5 and Duox1 and 2. With the exception of Nox2, the regulation of the Nox enzymes is still poorly understood. Nox1 is highly expressed in the colon, and requires two cytosolic regulators, NoxO1 and NoxA1, as well as the binding of Rac1 GTPase, for its activity.

In this study, we investigate the role of the tyrosine kinase c-Src in the regulation of ROS formation by Nox1. We show that c-Src induces Nox1-mediated ROS generation in the HT29 human colon carcinoma cell line through a Rac-dependent mechanism. Treatment of HT29 cells with the Src inhibitor PP2, expression of a kinase-inactive form of c-Src, and c-Src depletion by siRNA reduce both ROS generation and the levels of active Rac1. This is associated with decreased Src-mediated phosphorylation and activation of the Rac1-GEF Vav2. Consistent with this, Vav2 siRNA that specifically reduces endogenous Vav2 protein is able to dramatically decrease Nox1-dependent ROS generation and completely abolish c-Src-induced Nox1 activity. Taken together, these results establish c-Src as an important regulator of Nox1 activity, and may provide insight into the mechanisms of tumor formation in colon cancers.

Address correspondence to: Gary M. Bokoch (Bokoch{at}scripps.edu)






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