Oxidative Stress Induces Protein Kinase D Activation in Intact Cells

Protein kinase D (PKD) is a protein serine kinase that is directly stimulated in vitro by phorbol esters and diacylglycerol in the presence of phospholipids, and activated by phorbol esters, neuropeptides, and platelet-derived growth factor via protein kinase C (PKC) in intact cells. Recently, oxidative stress was shown to activate transfected PKC isoforms via tyrosine phosphorylation, but PKD activation was not demonstrated. Here, we report that oxidative stress initiated by addition of H2O2 (0.15–10 mm) to quiescent Swiss 3T3 fibroblasts activates PKD in a dose- and time- dependent manner, as measured by autophosphorylation and phosphorylation of an exogenous substrate, syntide-2. Oxidative stress also activated transfected PKD in COS-7 cells but not a kinase-deficient mutant PKD form or a PKD mutant with critical activating serine residues 744 and 748 mutated to alanines. Genistein, or the specific Src inhibitors PP-1 and PP-2 (1–10 μm) inhibited H2O2-mediated PKD activation by 45%, indicating that Src contributes to this signaling pathway. PKD activation by H2O2 was also selectively potentiated by cotransfection of PKD together with an active form of Src (v-Src) in COS-7 cells, as compared with PDB-mediated activation. The specific phospholipase C inhibitor, U73122 partly blocked H2O2-mediated but not PDB-mediated PKD activation. In contrast, PKC inhibitors blocked H2O2 or PDB-mediated PKD activation essentially completely, suggesting that whereas Src mediates part of its effects via phospholipase C activation, PKC acts more proximally as an upstream activator of PKD. Together, these studies reveal that oxidative stress activates PKD by initiating distinct Src-dependent and -independent pathways involving PKC.

• Publication year

  2000

• Venue

  Journal of Biological Chemistry

• Publication date

  2000-06-02

• Fields of study

  Biology, Medicine, Chemistry, Environmental Science

• Identifiers
  DOI 10.1074/JBC.M908959199PMID 10748111
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Activation of protein kinase D by signaling through the alpha subunit of the heterotrimeric G protein G(q).

  2000cited by this paper
• Lysophosphatidic acid rapidly induces protein kinase D activation through a pertussis toxin-sensitive pathway.

  2000cited by this paper
• Regulation of gene expression by reactive oxygen.

  1999cited by this paper
• The Pleckstrin Homology Domain of Protein Kinase D Interacts Preferentially with the η Isoform of Protein Kinase C*

  1999cited by this paper
• Protein kinase D in small cell lung cancer cells: rapid activation through protein kinase C.

  1999cited by this paper
• Signal transduction by reactive oxygen species in non‐phagocytic cells

  1999cited by this paper
• Activating SRC mutation in a subset of advanced human colon cancers

  1999cited by this paper
• Redox regulation of cellular signalling.

  1999cited by this paper
• Phosphorylation‐dependent protein kinase Dactivation

  1999cited by this paper
• Characterization of Serine 916 as an in VivoAutophosphorylation Site for Protein Kinase D/Protein Kinase Cμ*

  1999cited by this paper
• Association of Protein Kinase Cμ with Type II Phosphatidylinositol 4-Kinase and Type I Phosphatidylinositol-4-phosphate 5-Kinase*

  1998cited by this paper
• Involvement of Tyrosine Phosphorylation and Protein Kinase C in the Activation of Phospholipase D by H2O2 in Swiss 3T3 Fibroblasts*

  1998cited by this paper
• The extended protein kinase C superfamily.

  1998cited by this paper
• Oxygen radicals and signaling.

  1998cited by this paper
• p38 Mitogen-activated Protein Kinase Is a Critical Component of the Redox-sensitive Signaling Pathways Activated by Angiotensin II

  1998cited by this paper
• Identification of in Vivo Phosphorylation Sites Required for Protein Kinase D Activation*

  1998cited by this paper
• Mediators of inflammation: production and implication in inflammatory bowel disease.

  1998cited by this paper
• Rapid activation of the novel serine/threonine protein kinase, protein kinase D by phorbol esters, angiotensin II and PDGF‐BB in vascular smooth muscle cells

  1998cited by this paper
• Activation of protein kinase C by tyrosine phosphorylation in response to H2O2.

  1997cited by this paper
• Oxidative stress activates extracellular signal-regulated kinases through Src and Ras in cultured cardiac myocytes of neonatal rats.

  1997cited by this paper
• Bombesin, Vasopressin, Endothelin, Bradykinin, and Platelet-derived Growth Factor Rapidly Activate Protein Kinase D through a Protein Kinase C-dependent Signal Transduction Pathway*

  1997cited by this paper
• Epidermal Growth Factor (EGF)-induced Generation of Hydrogen Peroxide

  1997cited by this paper
• Phospholipase D: enzymology, mechanisms of regulation, and function.

  1997cited by this paper
• The neuropeptide substance P activates transcription factor NF-kappa B and kappa B-dependent gene expression in human astrocytoma cells.

  1997cited by this paper
• Phorbol ester, but not ischemic preconditioning, activates protein kinase D in the rat heart.

  1997cited by this paper
• Bryostatin 1 Induces Biphasic Activation of Protein Kinase D in Intact Cells*

  1997cited by this paper
• Dissociation of tyrosine phosphorylation and activation of phosphoinositide phospholipase C induced by the protein kinase C inhibitor Ro-31-8220 in Swiss 3T3 cells treated with platelet-derived growth factor.

  1997cited by this paper
• Activation of Mitogen-activated Protein Kinase by HO

  1996cited by this paper
• Induction of c-jun protooncogene expression by hydrogen peroxide through hydroxyl radical generation and p60SRC tyrosine kinase activation.

  1996cited by this paper
• Discovery of a Novel, Potent, and Src Family-selective Tyrosine Kinase Inhibitor

  1996cited by this paper
• Protein kinase D (PKD) activation in intact cells through a protein kinase C‐dependent signal transduction pathway.

  1996cited by this paper
• Sublethal levels of oxidant stress stimulate multiple serine/threonine kinases and suppress protein phosphatases in Jurkat T cells.

  1995cited by this paper
• Tyrosine phosphorylation of protein kinase C-delta in response to the activation of the high-affinity receptor for immunoglobulin E modifies its substrate recognition.

  1995cited by this paper
• Requirement for Generation of H2O2 for Platelet-Derived Growth Factor Signal Transduction

  1995cited by this paper
• Participation of Reactive Oxygen Species in the Lysophosphatidic Acid-stimulated Mitogen-activated Protein Kinase Kinase Activation Pathway (*)

  1995cited by this paper
• Oxidant-induced activation of protein kinase C in UC11MG cells.

  1995cited by this paper
• Activation of phospholipase C gamma in Schizosaccharomyces pombe by coexpression of receptor or nonreceptor tyrosine kinases

  1995cited by this paper
• Hydrogen peroxide-and fetal bovine serum-induced DNA synthesis in vascular smooth muscle cells: positive and negative regulation by protein kinase C isoforms.

  1995cited by this paper
• Phosphoinositide-specific phospholipase C and mitogenic signaling.

  1995cited by this paper
• Selective activation of protein kinase C isoforms by v-Src.

  1995cited by this paper
• Protein kinase C and lipid signaling for sustained cellular responses

  1995cited by this paper
• Expression and Characterization of PKD, a Phorbol Ester and Diacylglycerol-stimulated Serine Protein Kinase (*)

  1995cited by this paper
• Oxidant-Induced Activation of Protein Kinase C in Uc11mg Cells

  1995cited by this paper
• Tyrosine phosphorylation and stimulation of protein kinase Cδ from porcine spleen by src in vitro

  1994cited by this paper
• PKCu is a novel, atypical member of the protein kinase C family.

  1994cited by this paper
• Activation of the mitogen-activated protein kinase signaling pathway in neutrophils. Role of oxidants.

  1994cited by this paper
• X-irradiation, phorbol esters, and H2O2 stimulate mitogen-activated protein kinase activity in NIH-3T3 cells through the formation of reactive oxygen intermediates.

  1994cited by this paper
• Molecular cloning and characterization of protein kinase D: a target for diacylglycerol and phorbol esters with a distinctive catalytic domain.

  1994cited by this paper
• ZAP-70 tyrosine kinase, CD45, and T cell receptor involvement in UV- and H2O2-induced T cell signal transduction.

  1994cited by this paper
• Protein kinase C--a question of specificity.

  1994cited by this paper
• Tyrosine phosphorylation and stimulation of protein kinase C delta from porcine spleen by src in vitro. Dependence on the activated state of protein kinase C delta.

  1994cited by this paper
• Calmodulin-dependent protein kinase II mediates inactivation of MPF and CSF upon fertilization of Xenopus eggs

  1993cited by this paper
• Purification and characterization of Ca2+/calmodulin-dependent protein kinase V from rat cerebrum.

  1993cited by this paper
• In vitro tyrosine phosphorylation of PLC-gamma 1 and PLC-gamma 2 by src-family protein tyrosine kinases.

  1993cited by this paper
• Activation of the zeta isozyme of protein kinase C by phosphatidylinositol 3,4,5-trisphosphate.

  1993cited by this paper
• U73122 inhibits Ca2+ oscillations in response to cholecystokinin and carbachol but not to JMV-180 in rat pancreatic acinar cells.

  1992cited by this paper
• Expression of four protein kinase C isoforms in rat fibroblasts. Differential alterations in ras-, src-, and fos-transformed cells.

  1992cited by this paper
• v-Src activates both protein kinase C-dependent and independent signaling pathways in murine fibroblasts.

  1991cited by this paper
• The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C.

  1991cited by this paper
• Nonmutagenic mechanisms in carcinogenesis: role of protein kinase C in signal transduction and growth control.

  1991cited by this paper
• The insulinomimetic agents H2O2 and vanadate stimulate protein tyrosine phosphorylation in intact cells.

  1990cited by this paper
• Oxygen free radicals and iron in relation to biology and medicine: some problems and concepts.

  1986cited by this paper
• Overexpressed pp60c-src can induce focus formation without complete transformation of NIH 3T3 cells

  1985cited by this paper

• Pyocyanin Isolated from Pseudomonas aeruginosa: Characterization, Biological Activity and Its Role in Cancer and Neurodegenerative Diseases

  2022cites this paper
• Identification of Hub Prognosis-Associated Oxidative Stress Genes in Pancreatic Cancer Using Integrated Bioinformatics Analysis

  2020cites this paper
• UbK is Involved in the Resistance of Bacillus Subtilis to Oxidative Stress

  2020cites this paper
• Protein Kinase D was involved in vascular remodeling in spontaneously hypertensive rats

  2019cites this paper
• Retracted: Upregulated microRNA‐31 inhibits oxidative stress‐induced neuronal injury through the JAK/STAT3 pathway by binding to PKD1 in mice with ischemic stroke

  2019cites this paper
• CREB signals as PBMC-based biomarkers of cognitive dysfunction: A novel perspective of the brain-immune axis.

  2019cites this paper
• Function and Regulation of Protein Kinase D in Oxidative Stress: A Tale of Isoforms

  2018cites this paper
• Protein kinase D displays intrinsic Tyr autophosphorylation activity: insights into mechanism and regulation

  2018cites this paper
• The Activation Role of Protein Kinase D1 Important In Mitochondria and Oxidative Stress in Association with Pancreatic Cancer

  2018cites this paper
• The iPSC proteomic compendium

  2018cites this paper
• Redox Biology of Respiratory Viral Infections

  2018cites this paper
• Hydrogen peroxide modifies both activity and isoforms of acetylcholinesterase in human neuroblastoma SH-SY5Y cells

  2017cites this paper
• Aldosterone‐induced protein kinase signalling and the control of electrolyte balance

  2017cites this paper
• Protein kinase D inhibitor CRT0066101 suppresses bladder cancer growth in vitro and xenografts via blockade of the cell cycle at G2/M

  2017cites this paper
• Mitochondrial and Oxidative Stress-Mediated Activation of Protein Kinase D1 and Its Importance in Pancreatic Cancer

  2017cites this paper
• Differential regulation of PKD isoforms in oxidative stress conditions through phosphorylation of a conserved Tyr in the P+1 loop

  2017cites this paper
• Protein kinase D1 (PKD1) phosphorylation on Ser203 by type I p21-activated kinase (PAK) regulates PKD1 localization

  2017cites this paper
• Modulation of Hallmarks of Brain Aging by Environmental Enrichment

  2016cites this paper
• Protein Kinase D Enzymes as Regulators of EMT and Cancer Cell Invasion

  2016cites this paper
• Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease.

  2015cites this paper
• Elucidation of the Roles of the Src Kinases in Pancreatic Acinar Cell Signaling

  2015cites this paper
• Mitochondrial homeostasis: the interplay between mitophagy and mitochondrial biogenesis.

  2014cites this paper
• Organic silicon protects human neuroblastoma SH-SY5Y cells against hydrogen peroxide effects

  2014cites this paper
• Structural Insight Into Protein Kinase D Small Molecule Inhibition

  2014cites this paper
• Modulation of T Cell Metabolism and Function through Calcium Signaling

  2013cites this paper
• Intrazelluläre Signaltransduktionsmechanismen pankreatischer Sternzellen nach G-Protein gekoppelter Stimulation

  2013cites this paper
• A role for phospholipase D in angiotensin II-induced protein kinase D activation in adrenal glomerulosa cell models.

  2013cites this paper
• Hope and Fear for Interferon: The Receptor-Centric Outlook on the Future of Interferon Therapy

  2013cites this paper
• Crosstalk between apoptosis, necrosis and autophagy.

  2013cites this paper
• Strategies developed by the marine bacterium Pseudomonas fluorescens BA3SM1 to resist metals: A proteome analysis.

  2013cites this paper
• Distinctive roles of PLD signaling elicited by oxidative stress in synaptic endings from adult and aged rats.

  2012cites this paper
• Nanog Increases Focal Adhesion Kinase (FAK) Promoter Activity and Expression and Directly Binds to FAK Protein to Be Phosphorylated*

  2012cites this paper
• Oxidative Stress and Liver Injury

  2011cites this paper
• Protein Kinase D Orchestrates the Activation of DRAK2 in Response to TCR-Induced Ca2+ Influx and Mitochondrial Reactive Oxygen Generation

  2011cites this paper
• TARGETING PROTEIN KINASE D BY NOVEL SMALL MOLECULE INHIBITORS AND RNA INTERFERENCE IN PROSTATE CANCER

  2011cites this paper
• PKD is a kinase of Vps34 that mediates ROS-induced autophagy downstream of DAPk

  2011cites this paper
• Design, Synthesis, and Biological Evaluation of PKD Inhibitors

  2011cites this paper
• Protein kinase D signaling: multiple biological functions in health and disease.

  2011cites this paper
• The regulation of NOX4 expression by insulin and its role in the modulation of TGF-ß-induced apoptosis in murine hepatocytes

  2011cites this paper
• Redox Signaling and Cardiac Sarcomeres*

  2011cites this paper
• TNF-α potentiates lysophosphatidic acid-induced COX-2 expression via PKD in human colonic myofibroblasts.

  2011cites this paper
• Generation Influx and Mitochondrial Reactive Oxygen 2+ DRAK2 in Response to TCR-Induced Ca Protein Kinase D Orchestrates the Activation of

  2011cites this paper
• New insights into redox-modulated cell signaling.

  2011cites this paper
• Protein kinase D as a potential new target for cancer therapy.

  2010cites this paper
• Targeting tissue oxidative damage by means of cell signaling modulators: the antioxidant concept revisited.

  2010cites this paper
• Regulation and Function of Protein Kinase D Signaling

  2010cites this paper
• Role of protein kinase D signaling in pancreatic cancer.

  2010cites this paper
• PKC–PKD Interplay in Cancer

  2010cites this paper
• ULTRAVIOLET B IRRADIATION AND ACTIVATION OF PROTEIN KINASE D IN PRIMARY MOUSE EPIDERMAL KERATINOCYTES

  2010cites this paper
• Protein Kinase D1 Mediates Stimulation of DNA Synthesis and Proliferation in Intestinal Epithelial IEC-18 Cells and in Mouse Intestinal Crypts*

  2010cites this paper
• Ligand-Stimulated Downregulation of the Alpha Interferon Receptor: Role of Protein Kinase D2

  2010cites this paper
• Mitochondrial diacylglycerol initiates protein-kinase-D1-mediated ROS signaling

  2009cites this paper
• A protein kinase Cdelta-dependent protein kinase D pathway modulates ERK1/2 and JNK1/2 phosphorylation and Bim-associated apoptosis by asbestos.

  2009cites this paper
• Myoglobin Induces Vascular Cell Adhesion Molecule-1 Expression through c-Src Kinase-Activator Protein-1/Nuclear Factor-ĸB Pathways

  2009cites this paper
• Loss of cell–cell contacts induces NF‐κB via RhoA‐mediated activation of protein kinase D1

  2009cites this paper
• Protein kinase D mediates synergistic expression of COX-2 induced by TNF-{alpha} and bradykinin in human colonic myofibroblasts.

  2009cites this paper
• Protein kinase D3 (PKD3) contributes to prostate cancer cell growth and survival through a PKCepsilon/PKD3 pathway downstream of Akt and ERK 1/2.

  2008cites this paper
• Sequential Protein Kinase C (PKC)-dependent and PKC-independent Protein Kinase D Catalytic Activation via Gq-coupled Receptors

  2008cites this paper
• Vascular endothelial growth factor induces heat shock protein (HSP) 27 serine 82 phosphorylation and endothelial tubulogenesis via protein kinase D and independent of p38 kinase.

  2008cites this paper
• Protein Kinase D Regulates Trafficking of Dendritic Membrane Proteins in Developing Neurons

  2008cites this paper
• PKD, PKD2, and p38 MAPK mediate Hsp27 serine‐82 phosphorylation induced by neurotensin in pancreatic cancer PANC‐1 cells

  2008cites this paper
• A kalcineurin szerepe az in vitro porcdifferenciáció szabályozásában és a humán mononukleáris sejtek jelátviteli folyamataiban

  2007cites this paper
• DAP kinase regulates JNK signaling by binding and activating protein kinase D under oxidative stress

  2007cites this paper
• Protein Kinase D Induces Transcription through Direct Phosphorylation of the cAMP-response Element-binding Protein*

  2007cites this paper
• A Novel Tyrosine Phosphorylation Site in Protein Kinase D Contributes to Oxidative Stress-mediated Activation*

  2007cites this paper
• Mechanisms of hypotonic inhibition of the sodium, proton exchanger type 1 (NHE1) in a biliary epithelial cell line (Mz‐Cha‐1)

  2007cites this paper
• Type II PtdInsP kinases: location, regulation and function.

  2007cites this paper
• Oxyl radicals, redox-sensitive signalling cascades and antioxidants.

  2007cites this paper
• CCK causes PKD1 activation in pancreatic acini by signaling through PKC-delta and PKC-independent pathways.

  2007cites this paper
• Vanadate-induced activation of cytosolic phospholipase A2alpha in L929 cells: Roles of tyrosine kinase, protein kinase C, and extracellular signal-regulated kinase.

  2007cites this paper
• Identification of a novel phosphorylation site in c-jun directly targeted in vitro by protein kinase D.

  2007cites this paper
• Regulation of Cell Cycle Progression and Cellular Survival in Primary Rat Hepatocytes

  2007cites this paper
• Cell signaling in oxidative stress-induced liver injury.

  2007cites this paper
• Protein kinase D1: a protein of emerging translational interest.

  2007cites this paper
• Use of metabolic pathway flux information in anticancer drug design.

  2007cites this paper
• Sulfated polymannuroguluronate, a novel anti‐acquired immune deficiency syndrome drug candidate, blocks neuroinflammatory signalling by targeting the transactivator of transcription (Tat) protein

  2006cites this paper
• Protein kinase D protects against oxidative stress-induced intestinal epithelial cell injury via Rho/ROK/PKC-delta pathway activation.

  2006influential citation
• Hydrogen peroxide-induced arachidonic acid release in L929 cells; roles of Src, protein kinase C and cytosolic phospholipase A2alpha.

  2006cites this paper
• Activation of protein kinase D3 by signaling through Rac and the alpha subunits of the heterotrimeric G proteins G12 and G13.

  2006cites this paper
• Regulation of type II PIP kinase by PKD phosphorylation.

  2006cites this paper
• The activation loop phosphorylation of protein kinase D is an early marker of neuronal DNA damage

  2006cites this paper
• Glycolysis inhibition for anticancer treatment

  2006cites this paper
• Requirement of Protein Kinase D Tyrosine Phosphorylation for VEGF-A165-induced Angiogenesis through Its Interaction and Regulation of Phospholipase Cγ Phosphorylation*

  2006cites this paper
• EGF blocks NADPH oxidase activation by TGF‐β in fetal rat hepatocytes, impairing oxidative stress, and cell death

  2006cites this paper
• Protein kinase D protects against oxidative stress-induced intestinal epithelial cell injury via Rho/ROK/PKC-δ pathway activation

  2006influential citation
• Characterization of a Novel Protein Kinase D

  2006cites this paper
• Hydrogen peroxide-induced arachidonic acid release in L929 cells; roles of Src, protein kinase C and cytosolic phospholipase A2α

  2006cites this paper
• CHAPTER 4 – Metabolic Networks in Cancer Cells

  2006cites this paper
• Protein kinase D3 activation and phosphorylation by signaling through G alpha q.

  2005cites this paper
• Phosphorylation of histone deacetylase 7 by protein kinase D mediates T cell receptor–induced Nur77 expression and apoptosis

  2005cites this paper
• Hydrogen peroxide inhibits formation of cartilage in chicken micromass cultures and decreases the activity of calcineurin: implication of ERK1/2 and Sox9 pathways.

  2005cites this paper
• A Phosphorylation State-specific Antibody Recognizes Hsp27, a Novel Substrate of Protein Kinase D*

  2005cites this paper
• Protein Kinase D Specifically Mediates Apoptosis Signal-regulating Kinase 1-JNK Signaling Induced by H2O2 but Not Tumor Necrosis Factor*

  2005cites this paper
• Protein Kinase D Signaling*

  2005cites this paper
• Dual Phospholipase C/Diacylglycerol Requirement for Protein Kinase D1 Activation in Lymphocytes*

  2005cites this paper
• Protein Kinase C-Independent Effects of Protein Kinase D3 in Glucose Transport in L6 Myotubes

  2005cites this paper
• Protein kinase D3 activation and phosphorylation by signaling through Gαq

  2005cites this paper
• G protein-coupled receptor-mediated phosphorylation of the activation loop of protein kinase D: dependence on plasma membrane translocation and protein kinase Cepsilon.

  2004cites this paper
• Hepatocyte Resistance to Oxidative Stress Is Dependent on Protein Kinase C-mediated Down-regulation of c-Jun/AP-1*

  2004cites this paper
• Lipid Raft Disruption Triggers Protein Kinase C and Src-dependent Protein Kinase D Activation and Kidins220 Phosphorylation in Neuronal Cells*

  2004cites this paper