Studies on cyclic adenosine 3',5'-monophosphate-mediated inhibition of PI3 kinase-dependent cell signaling

Abstract

Activation of the phosphatidylinositol-3 kinase (PI3K) pathway plays an important role in mitogenic response of cell on variable stimuli. Akt and PDK contain a pleckstrin homology domain. Binding of PI3K products to the pleckstrin homology domain results in translocation of PKB/Akt and PDK to the plasma membrane where PKB/Akt is activated by phosphorylation by upsteam kinases including the PDK1. In many cells, the effect of cAMP is to diminish cell growth and promote differentiation, and in certain conditions cAMP is antagonistic to the effect of growth factors. Here, I showed that cAMP has inhibitory effects on PI3K pathway. cAMP inhibits PKB/Akt activity, PI3K lipid kinase activity, and PDK membrane localization but not PDK kinase activity. Theses data implicate that cAMP inhibits PKB/Akt though inhibiting PDK membrane localization by downregulating PI3K lipid kinase activity.