Negative regulation of phosphatidylinositol 3-kinase and Akt signalling pathway by PKC.
Although substantial studies have begun to explore the regulation of phosphatidylinositol 3-kinase/Akt cascade by different signalling pathways, whether protein kinase C (PKC) activity plays a crucial role remains as yet unclear. In this study, we found that in A549 and HEK293 cells non-selective PKC inhibitors Ro 31-8220 and bisindolylmaleimide VIII, and PKCbeta inhibitor LY 379196, caused Akt/PKB phosphorylation at Ser 473 and increased the upstream activator, integrin-linked kinase (ILK) activity. The increased Akt phosphorylation was blocked by phosphatidylinositol 3-kinase inhibitor wortmannin and the newly identified PIP(3)-dependent kinases (PDK) inhibitor SB 203580. In contrast to the Akt stimulation caused by PKC inhibitors, PMA attenuated Akt/PKB phosphorylation. We also found that this stimulating effect on Akt phosphorylation by PKC inhibitors was not the result of phosphatase inhibition, since treatment with PP2A, PP2B and tyrosine phosphatase inhibitors (okadaic acid, FK506 and sodium orthovanadate, respectively) had no effect. We conclude that phosphatidylinositol 3-kinase/Akt signalling pathway is regulated by PKC in a negative manner.
Wen
Hui C
HC
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Huang
Wan C
WC
Ali
Adnan
A
Woodgett
James R
JR
Lin
Wan W
WW
D000730:Androstadienes / Q000494:pharmacology; D002460:Cell Line; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D008698:Mesylates / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010749:Phosphoprotein Phosphatases / Q000502:physiology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011758:Pyrroles / Q000494:pharmacology; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D000077191:Wortmannin; D000099200:Scaffold Protein ILK
D000730:Androstadienes; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D008698:Mesylates; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010749:Phosphoprotein Phosphatases; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011758:Pyrroles; D012694:Serine; D000077191:Wortmannin; D000099200:Scaffold Protein ILK; C434605:5,21 - 12,17-dimetheneo-18H-dibenzo(i,o)pyrrolo(3,4-1)(1,8)diazacyclohexandecine-18,10(19H)dione,8((dimethylamino)methyl)-6,7,8,9,10,11-hexahydro,monomethanesulfonate; C494918:AKT1 protein, human; C064758:Ro 31-8220; C064755:Ro 31-7549