Activation Loop Phosphorylation Controls Protein Kinase D-Dependent Activation of Nuclear Factor κB

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Abstract
Activation of the inducible transcription factor nuclear factor κB (NF-κB) occurs in cells exposed to oxidative stress, and the serine/threonine kinase protein kinase D (PKD) is critical for signal relay to NF-κB. We have recently delineated two coordinated events that control PKD activation in response to oxidative stress: phosphorylation at Tyr463 by the tyrosine kinase Abl, and phosphorylation at the activation loop Ser738/Ser742 by the protein kinase C (PKC) isoform PKCδ. The result is fully active PKD that controls NF-κB activation through the IκB kinase (IKK) complex. Here, we investigate the mechanism by which PKD controls IKK/NF-κB activation. Resveratrol, a potent antioxidant, blocks both PKD activation and NF-κB induction. In particular, resveratrol blocked PKD activation loop phosphorylation and activity, and this was caused by a specific inhibition of the Ser738/Ser742 kinase PKCδ. On the other hand, resveratrol did not affect Abl kinase activity and had no effect on Tyr463 phosphorylation. Moreover, we show that the mechanism by which resveratrol inhibits NF-κB is by blocking the translocation of PKD to the IKK complex, specifically by inhibiting Ser738/Ser742 phosphorylation. We therefore propose that rather than acting as an antioxidant, resveratrol specifically blocks oxidative stress-dependent NF-κB activation by interfering with PKD phosphorylation and association with the IKK complex.