Induction of Apoptosis by Protein Kinase Cδ Is Independent of Its Kinase Activity

Abstract

Protein kinase C, a multigene family of phospholipiddependent and diacylglycerol-activated Ser/Thr protein kinases, is a key component in many signal transduction pathways. The kinase activity was thought to be essential for a plethora of biological processes attributed to these enzymes. Here we show that at least one protein kinase C function, the induction of apoptosis by protein kinase C␦, is independent of the kinase activity. Stimulation of green fluorescent protein-protein kinase C␦ fusion protein with phorbol ester or diacylglycerol led to its redistribution within seconds after the stimulus. Membrane blebbing, an early hallmark of apoptosis, was visible as early as 20 min after stimulation, and nuclear condensation was visible after 3-5 h. Apoptosis could be inhibited by expression of Bcl-2 but not by specific protein kinase C inhibitors. In addition, a kinase-negative mutant of protein kinase C␦ also induced apoptosis to the same extent as the wild type enzyme. Apoptosis was confined to the protein kinase C␦-overexpressing cells. Stimulation of overexpressed protein kinase C⑀ did not result in increased apoptosis. Our results indicate that distinct protein kinase C isozymes induce apoptosis in vascular smooth muscle cells. More importantly, they show that some protein kinase C effector functions are independent of the catalytic activity.

Selective activation of protein kinase C-δ and -ɛ by 6,11,12,14-tetrahydroxy-abieta-5,8,11,13-tetraene-7-one (coleon U)

“…Herein, it is believed that translocation of a specific PKC isoform to a cellular compartment is the major determinant of its specificity and function [28]. Indeed, similarly to results from mammalian cells [28,29], we found that in the absence of activators both nPKC- and - were detection of PKC- mitochondrial localisation [33]. Another work also showed that although induction of apoptosis via activation of PKC- and - increased cytochrome c release and accumulation of ROS, no PKC- and - were detected in mitochondria [8].…”

Kinase activity-independent anchoring function of protein kinase C-δ. Focus on “Protein kinase C-δ regulates the subcellular localization of Shc in H2O2-treated cardiomyocytes”

“…Thus, the study by Guo and colleagues clearly demonstrates that neither the phosphorylation nor catalytic activation of PKC␦ is required for the H 2 O 2 -induced physical interaction of PKC␦ with Shc or the subsequent translocation of the complex in neonatal cardiomyocytes (9). Consistent with the study by Guo and colleagues, studies in rat aortic smooth muscle cells have provided evidence that PKC␦ exhibits kinase-independent functions (8).…”

Variable expression of protein kinase Cε in human melanoma cells regulates sensitivity to TRAIL-induced apoptosis

“…PKC activates the MAPK ERK1/2 pathway by stimulating the Raf-Ras-MAPK kinase pathway in different cell types (26,27). In this study, we showed that the protective effect of activation of PKC is at least in part associated with activation of ERK1/2 induced by TRAIL (23).…”