3-Phosphoinositide-dependent protein kinase-1-mediated IkappaB kinase beta (IkkB) phosphorylation activates NF-kappaB signaling.
The IkappaB kinase (IKK)/NF-kappaB and phosphatidylinositol 3-OH-kinase/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt pathways regulate various cellular functions, especially cell survival. These two pathways are often activated in many tumors and are thought to be associated with tumor progression. However, the cross-talk between them remains unclear. Here we show that PDK1 can activate IKK/NF-kappaB signaling in addition to Akt signaling to promote cell survival. Screening kinases that could modulate NF-kappaB activity revealed that expression of an upstream Akt kinase PDK1 up-regulates NF-kappaB transcriptional activity. We found that PDK1 directly phosphorylates IKKbeta at the Ser(181) residue in the activation loop, leading to NF-kappaB nuclear translocation and NF-kappaB-dependent anti-apoptotic gene expression. IKKalpha is not required for PDK1-mediated NF-kappaB activation because NF-kappaB activation was observed in IKKalpha(-/-) mouse embryonic fibroblast (MEF) cells as in wild type MEF cells. Akt, which was previously reported to activate IKKalpha, did not participate in the PDK1-dependent IKKbeta or NF-kappaB activation. The siRNA-mediated PDK1 gene silencing attenuated NF-kappaB activity and increased TRAIL-mediated cytotoxicity. Moreover, expression of constitutively active IKKbeta overcame the PDK1 siRNA-mediated susceptibility to TRAIL. These results indicate that PDK1 is a critical regulator of cell survival by modulating the IKK/NF-kappaB pathway in addition to the Akt pathway.
Tanaka
Hiroshi
H
Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.
Fujita
Naoya
N
Tsuruo
Takashi
T
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002470:Cell Survival; D024202:Electrophoretic Mobility Shift Assay; D020868:Gene Silencing; D006801:Humans; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D007163:Immunosorbent Techniques; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014162:Transfection
D016328:NF-kappa B; D034741:RNA, Small Interfering; D012694:Serine; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase