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Molecular and Cellular Biology, April 2004, p. 2614-2626, Vol. 24, No. 7
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.7.2614-2626.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Protein Kinase C{delta} Selectively Regulates Protein Kinase D-Dependent Activation of NF-{kappa}B in Oxidative Stress Signaling

Peter Storz, Heike Döppler, and Alex Toker*

Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215

Received 17 September 2003/ Returned for modification 27 October 2003/ Accepted 8 January 2004

Protein kinase D (PKD) participates in activation of the transcription factor NF-{kappa}B (nuclear factor {kappa}B) in cells exposed to oxidative stress, leading to increased cellular survival. We previously demonstrated that phosphorylation of PKD at Tyr463 in the PH (pleckstrin homology) domain is mediated by the Src-Abl pathway and that it is necessary for PKD activation and subsequent NF-{kappa}B induction. Here we show that activation of PKD in response to oxidative stress requires two sequential signaling events, i.e., phosphorylation of Tyr463 by Abl, which in turn promotes a second step, phosphorylation of the PKD activation loop (Ser738/Ser742). We show that this is mediated by PKC{delta} (protein kinase C{delta}), a kinase that is activated by Src in response to oxidative stress. We also show that other PKCs, including PKC{varepsilon} and PKC{zeta}, do not participate in PKD activation or NF-{kappa}B induction. We propose a model in which two coordinated signaling events are required for PKD activation. Tyrosine phosphorylation in the PH domain at Tyr463, mediated by the Src-Abl pathway, which in turn facilitates the phosphorylation of Ser738/Ser742 in the activation loop, mediated by the Src-PKC{delta} pathway. Once active, the signal is relayed to the activation of NF-{kappa}B in oxidative stress responses.

* Corresponding author. Mailing address: Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Ave., RN-237, Boston, MA 02215. Phone: (617) 667-8535. Fax: (617) 667-3616. E-mail: atoker{at}bidmc.harvard.edu.

Molecular and Cellular Biology, April 2004, p. 2614-2626, Vol. 24, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.7.2614-2626.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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