PKCdelta survival signaling in cells containing an activated p21Ras protein requires PDK1.
Protein kinase C delta (PKCdelta) modulates cell survival and apoptosis in diverse cellular systems. We recently reported that PKCdelta functions as a critical anti-apoptotic signal transducer in cells containing activated p21(Ras) and results in the activation of AKT, thereby promoting cell survival. How PKCdelta is regulated by p21(Ras), however, remains incompletely understood. In this study, we show that PKCdelta, as a transducer of anti-apoptotic signals, is activated by phosphotidylinositol 3' kinase/phosphoinositide-dependent kinase 1 (PI(3)K-PDK1) to deliver the survival signal to Akt in the environment of activated p21(Ras). PDK1 is upregulated in cells containing an activated p21Ras. Knock-down of PDK1, PKCdelta, or AKT forces cells containing activated p21(Ras) to undergo apoptosis. PDK1 regulates PKCdelta activity, and constitutive expression of PDK1 increases PKCdelta activity in different cell types. Conversely, expression of a kinase-dead (dominant-negative) PDK1 significantly suppresses PKCdelta activity. p21(Ras)-mediated survival signaling is therefore regulated by via a PI(3)K-AKT pathway, which is dependent upon both PDK1 and PKCdelta, and PDK1 activates and regulates PKCdelta to determine the fate of cells containing a mutated, activated p21(Ras).
Xia
Shuhua
S
Cancer Research Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Chen
Zhihong
Z
Forman
Lora W
LW
Faller
Douglas V
DV
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D017209:Apoptosis; D041702:BALB 3T3 Cells / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor / Q000378:metabolism; D002470:Cell Survival; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D011905:Genes, ras; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology; D051745:Protein Kinase C-delta / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction
D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D064413:3-Phosphoinositide-Dependent Protein Kinases; C494918:AKT1 protein, human; C514862:Akt1 protein, mouse; C578562:PDPK1 protein, human; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051745:Protein Kinase C-delta; C501009:HRAS protein, human; D015689:Oncogene Protein p21(ras); D016283:Proto-Oncogene Proteins p21(ras)