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J. Biol. Chem., Vol. 280, Issue 16, 16319-16324, April 22, 2005

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Implication of Phospholipase D2 in Oxidant-induced Phosphoinositide 3-Kinase Signaling via Pyk2 Activation in PC12 Cells^*

Yoshiko Banno, Kenji Ohguchi¶, Naoki Matsumoto||, Masahiro Koda, Masashi Ueda||, Akira Hara||, Ivan Dikic**, and Yoshinori Nozawa¶

From the Department of Cell Signaling, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan, ^¶Gifu International Institute of Biotechnology, Kakamigahara 504-0838, Japan, ^||Department of Biochemistry, Gifu Pharmaceutical University, Gifu 502-8585, Japan, and ^**Institute of Biochemistry II, University of Frankfurt, Frankfurt D-60590, Germany

The role of phospholipase D (PLD) activation in hydrogen peroxide (H₂O₂)-induced signal transduction and cellular responses is not completely understood. Here we present evidence that Ca²⁺-dependent tyrosine kinase, Pyk2, requires PLD activation to mediate survival pathways in rat pheochromocytoma PC12 cells under oxidative stress. The H₂O₂-induced phosphorylation of two Pyk2 sites (Tyr⁵⁸⁰, and Tyr⁸⁸¹) was suppressed by 1-butanol, an inhibitor of transphosphatidylation by PLD, and also by transfection of catalytically negative mouse PLD2K758R (PLD2KR). Furthermore, we found that PLD2 was associated with Pyk2 and Src, and that activation of PLD2 was required for H₂O₂-enhanced association of Src with Pyk2 leading to full activation of Pyk2. H₂O₂-induced phosphorylation of Akt and p70S6K was dependent on phosphatidylinositol 3-kinase (PI3K) activity and was abolished by 1-butanol but not t-butanol. Furthermore, the PI3K/Akt activation in response to H₂O₂ was reduced by transfection of either PLD2KR or the dominant negative Pyk2DN. This study is the first demonstration that PLD2 activation is implicated in Src-dependent phosphorylation of Pyk2 (Tyr⁵⁸⁰ and Tyr⁸⁸¹) by promoting the complex formation between Pyk2 and activated Src in PC12 cells exposed to H₂O₂, thereby resulting in activation of the survival signaling pathway PI3K/Akt/p70S6K.

Received for publication, September 22, 2004 , and in revised form, February 9, 2005.

^* This work was supported in part by Grants-in-aid for Scientific Research (B) 12470042 and (C) 12680633 from the Ministry of Education, Science, Sports, and Culture of Japan. 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.

To whom correspondence should be addressed: Dept. of Cell Signaling, Gifu University Graduate School of Medicine, Yanagido 1-1, Gifu 501-1194, Japan. Tel.: 81-58-230-6202; Fax: 81-58-230-6202; E-mail; banno{at}cc.gifu-u.ac.jp.

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