Protein kinase D mediates a stress-induced NF-kappaB activation and survival pathway.
The activation of the transcription factor NF-kappaB is critical for a number of physiological responses. Here, we provide evidence for a signaling pathway that mediates NF-kappaB 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-kappaB in response to oxidative stress. PKD activates NF-kappaB through the IKK complex and more specifically, IKKbeta, leading to I(kappa)B(alpha) 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-kappaB.
Storz
Peter
P
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
Toker
Alex
A
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology*; D017931:DNA Primers; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism
D017931:DNA Primers; D016328:NF-kappa B; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D019000:Phosphotyrosine; C089212:protein kinase D; D011493:Protein Kinase C