MECHANISMS OF SIGNAL TRANSDUCTION
Epidermal Growth Factor Receptor-dependent Akt Activation by Oxidative Stress Enhances Cell Survival*

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The serine/threonine kinase Akt (also known as protein kinase B) is activated in response to various stimuli by a mechanism involving phosphoinositide 3-kinase (PI3-K). Akt provides a survival signal that protects cells from apoptosis induced by growth factor withdrawal, but its function in other forms of stress is less clear. Here we investigated the role of PI3-K/Akt during the cellular response to oxidant injury. H2O2treatment elevated Akt activity in multiple cell types in a time- (5–30 min) and dose (400 μM-2 mm)-dependent manner. Expression of a dominant negative mutant of p85 (regulatory component of PI3-K) and treatment with inhibitors of PI3-K (wortmannin and LY294002) prevented H2O2-induced Akt activation. Akt activation by H2O2 also depended on epidermal growth factor receptor (EGFR) signaling; H2O2 treatment led to EGFR phosphorylation, and inhibition of EGFR activation prevented Akt activation by H2O2. As H2O2 causes apoptosis of HeLa cells, we investigated whether alterations of PI3-K/Akt signaling would affect this response. Wortmannin and LY294002 treatment significantly enhanced H2O2-induced apoptosis, whereas expression of exogenous myristoylated Akt (an activated form) inhibited cell death. Constitutive expression of v-Akt likewise enhanced survival of H2O2-treated NIH3T3 cells. These results suggest that H2O2activates Akt via an EGFR/PI3-K-dependent pathway and that elevated Akt activity confers protection against oxidative stress-induced apoptosis.

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To whom correspondence and reprint requests should be addressed: Cell Stress and Aging Section, Laboratory of Biological Chemistry, NIA,National Institutes of Health, Box 12, 5600 Nathan Shock Dr., Baltimore, MD 21224-6825. Tel.: 410-558-8446; Fax: 410-558-8386; E-mail: [email protected].