Protein kinase Cdelta selectively regulates protein kinase D-dependent activation of NF-kappaB in oxidative stress signaling.
Protein kinase D (PKD) participates in activation of the transcription factor NF-kappaB (nuclear factor kappaB) 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-kappaB 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 PKCdelta (protein kinase Cdelta), a kinase that is activated by Src in response to oxidative stress. We also show that other PKCs, including PKCepsilon and PKCzeta, do not participate in PKD activation or NF-kappaB 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-PKCdelta pathway. Once active, the signal is relayed to the activation of NF-kappaB in oxidative stress responses.
Storz
Peter
P
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Döppler
Heike
H
Toker
Alex
A
D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D051745:Protein Kinase C-delta; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D016328:NF-kappa B; D017382:Reactive Oxygen Species; C089212:protein kinase D; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta