PKCδ survival signaling in cells containing an activated p21 Ras protein requires PDK1

Abstract

Protein kinase C δ (PKCδ) modulates cell survival and apoptosis in diverse cellular systems. We recently reported that PKCδ 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 PKCδ is regulated by p21 Ras, however, remains incompletely understood. In this study, we show that PKCδ, as a transducer of anti-apoptotic signals, is activated by phosphotidylinositol 3′ kinase/phosphoinositide-dependent kinase 1 (PI 3K–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, PKCδ, or AKT forces cells containing activated p21 Ras to undergo apoptosis. PDK1 regulates PKCδ activity, and constitutive expression of PDK1 increases PKCδ activity in different cell types. Conversely, expression of a kinase-dead (dominant-negative) PDK1 significantly suppresses PKCδ activity. p21 Ras-mediated survival signaling is therefore regulated by via a PI 3K–AKT pathway, which is dependent upon both PDK1 and PKCδ, and PDK1 activates and regulates PKCδ to determine the fate of cells containing a mutated, activated p21 Ras.