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J. Biol. Chem., Vol. 280, Issue 19, 19036-19044, May 13, 2005

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Protein Kinase D Specifically Mediates Apoptosis Signal-regulating Kinase 1-JNK Signaling Induced by H₂O₂ but Not Tumor Necrosis Factor^*

Wei Zhang, Shusen Zheng, Peter Storz¶, and Wang Min||

From the Interdepartmental Program in Vascular Biology and Transplantation, Boyer Center for Molecular Medicine, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510, Key Laboratory of Combined Multi-organ Transplantation of Ministry of Health China, The First Affiliated Hospital, Zhejiang University College of Medicine, 79 Qingchun Road, Hangzhou 310003, China, and ^¶Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215

Although both tumor necrosis factor (TNF) and H₂O₂ induce activation of c-Jun N-terminal kinase (JNK) kinase cascades, it is not known whether they utilize distinct intracellular signaling pathways. In this study, we first examined a variety of pharmacological inhibitors on TNF and H₂O₂-induced JNK activation. Gö6983 or staurosporine, which inhibits protein kinase C isoforms had no effects on TNF or H₂O₂-induced JNK activation. However, Gö6976 and calphostin, which can inhibit protein kinase C as well as protein kinase D (PKD), blocked H₂O₂- but not TNF-induced JNK activation, suggesting that PKD may be specifically involved in H₂O₂-induced JNK activation. Consistently, H₂O₂, but not TNF, induced phosphorylation of PKD and translocation of PKD from endothelial cell membrane to cytoplasm where it associates with the JNK upstream activator, apoptosis signal-regulating kinase 1 (ASK1). The association is mediated through the pleckstrin homology domain of PKD and the C-terminal domain of ASK1. Inhibition of PKD by Gö6976 or by small interfering RNA of PKD blocked H₂O₂-induced ASK1-JNK activation and endothelial cell apoptosis. Interestingly, H₂O₂ induced 14-3-3 binding to PKD via the phospho-Ser-205/208 and phospho-Ser-219/223 and H₂O₂-induced 14-3-3 binding of PKD was specifically blocked by Gö6976 but not by Gö6983. More significantly, the 14-3-3-binding defective forms of PKD failed to associate with ASK1 and to activate JNK signaling, highlighting the importance of 14-3-3 binding of PKD in H₂O₂-induced activation of ASK1-JNK cascade. Thus, our data have identified PKD as a critical mediator in H₂O₂- but not TNF-induced ASK1-JNK signaling.

Received for publication, December 30, 2004 , and in revised form, March 1, 2005.

^* This work was supported by grants from National Institutes of Health 1R01HL65978-01 and AHA 0151259T (to W. M.). 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.

^|| An AHA Established Investigator. To whom correspondence should be addressed: Interdepartmental Program in Vascular Biology and Transplantation, Dept. of Pathology, Yale University School of Medicine, BCMM 454, 295 Congress Ave., New Haven, CT 06510. Tel.: 203-785-6047; Fax: 203-737-2293; E-mail: wang.min{at}yale.edu.

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