The many hats of protein kinase Cδ: one enzyme with many functions.

A large number of protein substrates are phosphorylated by each protein kinase under physiological and pathological conditions. However, it remains a challenge to determine which of these phosphorylated substrates of a given kinase is critical for each cellular response. Genetics enabled the generation of separation-of-function mutations that selectively cause a loss of one molecular event without affecting others, thus providing some tools to assess the importance of that one event for the measured physiological response. However, the genetic approach is laborious and not adaptable to all systems. Furthermore, pharmacological tools of the catalytic site are not optimal due to their non-selective nature. In the present brief review, we discuss some of the challenges in drug development that will regulate the multifunctional protein kinase Cδ (PKCδ).

[1]  I. G. Fantus,et al.  FFA-induced hepatic insulin resistance in vivo is mediated by PKCδ, NADPH oxidase, and oxidative stress. , 2014, American journal of physiology. Endocrinology and metabolism.

[2]  J. Campos,et al.  Acute Inhibition of Excessive Mitochondrial Fission After Myocardial Infarction Prevents Long‐term Cardiac Dysfunction , 2013, Journal of the American Heart Association.

[3]  Julio C. B. Ferreira,et al.  Glyceraldehyde-3-phosphate Dehydrogenase (GAPDH) Phosphorylation by Protein Kinase Cδ (PKCδ) Inhibits Mitochondria Elimination by Lysosomal-like Structures following Ischemia and Reoxygenation-induced Injury* , 2013, The Journal of Biological Chemistry.

[4]  K. Das,et al.  Protein kinase C, an elusive therapeutic target? , 2012, Nature Reviews Drug Discovery.

[5]  Jeewon Kim,et al.  PKCδ activation mediates angiogenesis via NADPH oxidase activity in PC‐3 prostate cancer cells , 2011, The Prostate.

[6]  P. Wender,et al.  Translating Nature's Library: The Bryostatins and Function-Oriented Synthesis. , 2011, Israel journal of chemistry.

[7]  R. Sobel,et al.  Aberrant mitochondrial fission in neurons induced by protein kinase Cδ under oxidative stress conditions in vivo , 2011, Molecular biology of the cell.

[8]  C. Deutschman,et al.  Protection against sepsis‐induced lung injury by selective inhibition of protein kinase C‐δ (δ‐PKC) , 2011, Journal of leukocyte biology.

[9]  A. Basu,et al.  Two Faces of Protein Kinase Cδ: The Contrasting Roles of PKCδ in Cell Survival and Cell Death , 2010, TheScientificWorldJournal.

[10]  D. Mochly‐Rosen,et al.  Highly Specific Modulators of Protein Kinase C Localization: Applications to Heart Failure. , 2010, Drug discovery today. Disease mechanisms.

[11]  M. Denning,et al.  Loss of protein kinase C delta gene expression in human squamous cell carcinomas: a laser capture microdissection study. , 2010, The American journal of pathology.

[12]  L. Aiello,et al.  Activation of PKC-δ and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy , 2009, Nature Medicine.

[13]  D. Mochly‐Rosen,et al.  The PKCδ -Abl complex communicates ER stress to the mitochondria – an essential step in subsequent apoptosis , 2008, Journal of Cell Science.

[14]  C. Granger,et al.  Intracoronary KAI-9803 as an Adjunct to Primary Percutaneous Coronary Intervention for Acute ST-Segment Elevation Myocardial Infarction , 2008, Circulation.

[15]  R. Sobel,et al.  Sustained pharmacological inhibition of deltaPKC protects against hypertensive encephalopathy through prevention of blood-brain barrier breakdown in rats. , 2007, The Journal of clinical investigation.

[16]  D. Mochly‐Rosen,et al.  deltaPKC participates in the endoplasmic reticulum stress-induced response in cultured cardiac myocytes and ischemic heart. , 2007, Journal of molecular and cellular cardiology.

[17]  M. Rezaee,et al.  Impaired perfusion after myocardial infarction is due to reperfusion-induced deltaPKC-mediated myocardial damage. , 2007, Cardiovascular research.

[18]  D. Mochly‐Rosen,et al.  Reperfusion-Induced Translocation of &dgr;PKC to Cardiac Mitochondria Prevents Pyruvate Dehydrogenase Reactivation , 2005, Circulation research.

[19]  L. Wodicka,et al.  A small molecule–kinase interaction map for clinical kinase inhibitors , 2005, Nature Biotechnology.

[20]  S. Steinberg.  Distinctive activation mechanisms and functions for protein kinase Cdelta. , 2004, The Biochemical journal.

[21]  D. Mochly‐Rosen,et al.  Protein kinase Cdelta activation induces apoptosis in response to cardiac ischemia and reperfusion damage: a mechanism involving BAD and the mitochondria. , 2004, The Journal of biological chemistry.

[22]  D. Mochly‐Rosen,et al.  Suppression of Graft Coronary Artery Disease by a Brief Treatment With a Selective &egr;PKC Activator and a &dgr;PKC Inhibitor in Murine Cardiac Allografts , 2004 .

[23]  G. Steinberg,et al.  Protein Kinase C δ Mediates Cerebral Reperfusion Injury In Vivo , 2004, The Journal of Neuroscience.

[24]  Qingbo Xu,et al.  Loss of PKC-δ alters cardiac metabolism , 2004 .

[25]  P. Yock,et al.  Inhibition of &dgr;-Protein Kinase C Protects Against Reperfusion Injury of the Ischemic Heart In Vivo , 2003, Circulation.

[26]  D. Mochly‐Rosen,et al.  Opposing effects of δ- and ζ-protein kinase C isozymes on cardiac fibroblast proliferation: use of isozyme-selective inhibitors , 2003 .

[27]  T. Rando,et al.  Sequential activation of individual PKC isozymes in integrin-mediated muscle cell spreading: a role for MARCKS in an integrin signaling pathway. , 2002, Journal of cell science.

[28]  U. Kikkawa,et al.  Establishment of a binding assay for protein kinase C isozymes using synthetic C1 peptides and development of new medicinal leads with protein kinase C isozyme and C1 domain selectivity. , 2002, Pharmacology & therapeutics.

[29]  Qingbo Xu,et al.  Exacerbated vein graft arteriosclerosis in protein kinase Cδ–null mice , 2001 .

[30]  G. Dorn,et al.  Opposing cardioprotective actions and parallel hypertrophic effects of δPKC and ɛPKC , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[31]  D. Wheeler,et al.  Relation of the induction of epidermal ornithine decarboxylase and hyperplasia to the different skin tumor–promotion susceptibilities of protein kinase Cα, ‐δ and ‐ϵ transgenic mice , 2001 .

[32]  E. Kremmer,et al.  beta2-chimaerin is a novel target for diacylglycerol: binding properties and changes in subcellular localization mediated by ligand binding to its C1 domain. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[33]  S. Schwarze,et al.  In vivo protein transduction: delivery of a biologically active protein into the mouse. , 1999, Science.

[34]  Shengfang Jin,et al.  Inactivation of DNA-Dependent Protein Kinase by Protein Kinase Cδ: Implications for Apoptosis , 1998, Molecular and Cellular Biology.

[35]  D. Mochly‐Rosen,et al.  Peptide modulators of protein–protein interactions in intracellular signaling , 1998, Nature Biotechnology.

[36]  D. Fabbro,et al.  Phosphorylation Specificities of Protein Kinase C Isozymes for Bovine Cardiac Troponin I and Troponin T and Sites within These Proteins and Regulation of Myofilament Properties* , 1996, The Journal of Biological Chemistry.

[37]  G. Milne,et al.  Residues in the Second Cysteine-rich Region of Protein Kinase C δ Relevant to Phorbol Ester Binding as Revealed by Site-directed Mutagenesis (*) , 1995, The Journal of Biological Chemistry.

[38]  F. Marks,et al.  Rottlerin, a novel protein kinase inhibitor. , 1994, Biochemical and biophysical research communications.

[39]  M. Disatnik,et al.  Localization of protein kinase C isozymes in cardiac myocytes. , 1994, Experimental cell research.

[40]  Y. Nishizuka,et al.  Isolation and characterization of delta-subspecies of protein kinase C from rat brain. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[41]  Y. Nishizuka,et al.  The structure, expression, and properties of additional members of the protein kinase C family. , 1988, The Journal of biological chemistry.

[42]  D. Mochly‐Rosen,et al.  Use of a novel method to find substrates of protein kinase C delta identifies M2 pyruvate kinase. , 2007, The international journal of biochemistry & cell biology.

[43]  P. Cohen,et al.  Specificity and mechanism of action of some commonly used protein kinase inhibitors. , 2000, The Biochemical journal.