Oxidative Stress Induces Protein Kinase C-mediated Activation Loop Phosphorylation and Nuclear Redistribution of Protein Kinase D

Abstract

Oxidative stress has been implicated in aging and in a wide range of diseases affecting the nervous, respiratory, cardiovascular, and gastrointestinal systems in humans (1, 2). Exposure of cells to reactive oxygen species (ROS) 1 at high concentrations or for extended periods damages cellular DNA, widely hypothesized to either induce cell death via apoptosis/necrosis (3) or facilitate progression toward malignant transformation (4). In contrast, cell exposure to ROS for brief times and/or at limited concentrations induces signals that trigger diverse biological responses including proliferation, migration, or survival (1, 2). Recent studies (5-9) have also identified several mechanisms whereby stimuli or stresses including exposure to growth factors or ultraviolet light can induce ROS production within a variety of cell types. Consequently, the elucidation of cellular signal transduction pathways whereby ROS act as second messengers to mediate proliferation, differentiation, or transformation has recently become an area of intense investigation.Target molecules that mediate the initial sensing and subsequent propagation of ROS-induced signals include cellular protein-tyrosine phosphatases (10) and PTEN (11), a bifunctional tyrosine phosphatase/phosphatidylinositol 3-phosphate phosphatase. Reversible inhibition of these signal-regulating enzymes by ROS induces acute or aberrantly persistent increases in signal transmission through protein tyrosine phosphorylation and 3-phosphorylated inositol lipids, respectively. By modifying redox-sensitive functional domains, intracellular ROS also directly alter the activities of a wide range of other signal transduction proteins, including proximal receivers and transmitters of external signals, i.e. receptor and nonreceptor tyrosine kinases (12, 13) and monomeric and heterotrimeric G proteins (14, 15), and more distal elements including transcription factors and their regulatory serine-threonine protein kinases including ASK1, BMK1, and PKC (16).PKC, an enzyme family of at least 10 distinct isoforms with unique tissue distributions and dynamic subcellular localization, induces both short term alterations in cellular activities and long term effects such as differentiation, proliferation, and apoptosis (17). Multiple signal transduction pathways can be mobilized to mediate PKC activation during oxidative stress, including stimulation of phospholipase C␥ via enhanced tyrosine phosphoryla-

Protein Kinase D Specifically Mediates Apoptosis Signal-regulating Kinase 1-JNK Signaling Induced by H2O2 but Not Tumor Necrosis Factor

“…3A). The pattern of PKD translocation in EC is similar to that was observed in Swiss 3T3 cells in response to H 2 O 2 (26). In contrast, TNF did not induce these translocations of PKD (Fig.…”

Protein Kinase D Induces Transcription through Direct Phosphorylation of the cAMP-response Element-binding Protein

“…In this study, we found that pervanadate resulted in phosphorylation of CREB. Previous studies by others showed that oxidative stress induced by H 2 O 2 activates PKD via a PKC-and Src-dependent pathway and results in the nuclear transport of PKD (78,79). Moreover, as H 2 O 2 can induce phosphorylation of CREB in several cell lines (34), this may suggest a possible role of PKD as a CREB kinase in response to oxidative stress.…”

Regulation of H2O2-induced necrosis by PKC and AMP-activated kinase signaling in primary cultured hepatocytes

“…However, in contrast to JNK, Akt is believed to play a protective role against ROS-induced apoptosis, and pharmacological or genetic inhibition of Akt has been shown to sensitize cells to H 2 O 2 -induced apoptosis (17,32). The activation of PKC has also been shown to occur in response to treatment with H 2 O 2 or chemicals that generate ROS, such as menadione, to cells (13,18,57). In some cases, PKC activation plays a protective role (33): in RALA255 cells (a hepatocyte cell line), PKC inhibitors were found to sensitize cells to ROS-induced apoptosis (58).…”