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

Protein kinase D (PKD) participates in activation of the transcription factor NFB (nuclear factor 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 NFB 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 (protein kinase C ), a kinase that is activated by Src in response to oxidative stress. We also show that other PKCs, including PKC and PKC , do not participate in PKD activation or NFB 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 SrcPKC pathway. Once active, the signal is relayed to the activation of NFB in oxidative stress responses.