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MBC in Press, published online ahead of print October 26, 2005
Mol. Biol. Cell 10.1091/mbc.E05-06-0570

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Submitted on June 28, 2005
Revised on October 11, 2005
Accepted on October 14, 2005

Rac1 Leads to Phosphorylation-dependent Increase in Stability of the p66shc Adaptor Protein: Role in Rac1-induced Oxidative Stress

Firdous A. Khanday,* Tohru Yamamori,* Ilwola Mattagajasingh,* Zhe Zhang,{dagger} Artem Bugayenko,{ddagger} Asma Naqvi,* Lakshmi Santhanam,{ddagger} Nusrat Nabi,* Kenji Kasuno,* Billy W. Day,{dagger} and Kaikobad Irani*

*Cardiovascular Institute, University of Pittsburgh Medical Center and {dagger}Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15213; {ddagger}Johns Hopkins University School of Medicine, Baltimore, MD 21205

Monitoring Editor: Gerard Evan

The rac1 GTPase and the p66shc adaptor protein regulate intracellular levels of reactive oxygen species (ROS). We examined the relationship between rac1 and p66shc. Expression of constitutively active rac1 (rac1V12) increased phosphorylation, reduced ubiquitination, and increased stability of p66shc protein. Rac1V12-induced phosphorylation and up-regulation of p66shc was suppressed by inhibiting p38MAPK, and dependent on serine 54 and threonine 386 in p66shc. Phosphorylation of recombinant p66shc by p38MAPK in vitro was also partly dependent on serine 54 and threonine 386. Reconstitution of p66shc in p66shc-null fibroblasts increased intracellular ROS generated by rac1V12 which was significantly dependent on the integrity of residues 54 and 386. Overexpression of p66shc increased rac1V12-inducd apoptosis, an effect that was also partly dependent on serine 54 and threonine 386. Finally, RNAi-mediated down-regulation of endogenous p66shc suppressed rac1V12-induced cell death. These findings identify p66shc as a mediator of rac1-induced oxidative stress. In addition, they suggest that serine 54 and threonine 386 are novel phosphorylatable residues in p66shc that govern rac1-induced increase in its expression, through a decrease in its ubiquitination and degradation, and thereby mediate rac1-stimulated cellular oxidative stress and death.

Address correspondence to: Kaikobad Irani (iranik{at}upmc.edu)




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