Protein kinase D mediates a stress-induced NF-κB activation and survival pathway

The activation of the transcription factor NF-κB is critical for a number of physiological responses. Here, we provide evidence for a signaling pathway that mediates NF-κB activation in response to oxidative stress. We show that tyrosine phosphorylation of protein kinase D (PKD) at Y463 in the Pleckstrin Homology (PH) domain is mediated by the Src and Abl tyrosine kinase signaling pathway, and that this is both necessary and sufficient to activate NF-κB in response to oxidative stress. PKD activates NF-κB through the IKK complex and more specifically, IKKβ, leading to IκBα degradation. We also present evidence that this pathway is required for increased cellular survival in response to oxidative stress. We propose a model in which protection from oxidative stress-induced cell death requires the tyrosine phosphorylation of PKD leading to the activation of the transcription factor NF-κB.