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J. Biol. Chem., Vol. 278, Issue 23, 20828-20834, June 6, 2003

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Protein Kinase B Activation by Reactive Oxygen Species Is Independent of Tyrosine Kinase Receptor Phosphorylation and Requires Src Activity^*

Franca Esposito  , Giuseppa Chirico , Nicola Montesano Gesualdi , Inmaculada Posadas ¶, Rosario Ammendola  ||, Tommaso Russo , Giuseppe Cirino ¶ and Filiberto Cimino 

From the Dipartimento di Biochimica e Biotecnologie Mediche, Universitá di Napoli Federico II, Via Pansini 5 and ^¶Dipartimento di Farmacologia Sperimentale, Universitá Federico II, Via Domenico Montesano 49, Naples 80131, Italy

Reactive oxygen species (ROS) participate as second messengers in the mitogenic signal transduction. Most of the experimental data supporting the role of ROS as signaling molecules have been obtained by using H₂O₂. Exposure of cells to H₂O₂ rapidly increases tyrosine phosphorylation of tyrosine kinase receptors (TKRs) in the absence of growth factor binding, thus inducing the activation of downstream signaling cascades, like that of protein kinase B (AKT). Another molecule able to induce an increase of intracellular ROS levels is diethylmaleate (DEM), which acts by depleting the ROS scavenger reduced glutathione (GSH). A comparison of the effects exerted by H₂O₂ and DEM shows that the latter induces redox modifications milder than those generated by H₂O₂. We also demonstrated that DEM-induced redox modifications are not accompanied by platelet-derived growth factor-receptor (PDGF-R) and epidermal growth factor-receptor Tyr phosphorylation, although they are able to activate ERKs and AKT, with kinetics different from those observed following H₂O₂ treatment. The activation of these two pathways is not blocked by AG1296, a selective inhibitor of PDGF-R Tyr kinase, thus confirming that the effects of DEM are not mediated by the TKR phosphorylation. On the contrary, PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazole[3,4-d]pyrimidine), an inhibitor of Src kinase, completely prevents DEM- and H₂O₂-induced AKT activation but has no effect on the pathway of ERKs. Finally, nitration of Tyr residues in PDGF-R is observed in DEM-treated cells, thus suggesting that ROS-induced modifications different from Tyr phosphorylation can occur at the growth factor-receptor level and can be involved in the regulation of signaling pathways.

Received for publication, November 20, 2002 , and in revised form, March 10, 2003.

This manuscript is dedicated to the memory of Eraldo Antonini, eminent biochemist, prematurely deceased twenty years ago, on March 19th, 1983.

^* This work was supported by grants from the Italian National Research Council PF Biotecnologie and PSt/74 Determinanti di salute e invecchiamento della popolazione and from Ministero dell'Universitá e della Ricerca Scientifica e Tecnologica (Prin 2000 and Prin 2002 and Piano Biomedicina-Progetto 1, Cluster 04). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| Present address: Dipartimento di Biologia Cellulare e dello Sviluppo, Sez. Biochimica, Universitá degli Studi di Palermo, Via del Vespro 127, Palermo 90128, Italy.

To whom correspondence should be addressed. Tel.: 39-81-746-3145; Fax: 39-81-746-4359 or 39-81-746-3650; E-mail: espositof{at}dbbm.unina.it.

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