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1
* Department of Neurology, Ernest Gallo Clinic and Research Center, University of California San Francisco, San Francisco, California 94110-3518, USA; and
Center for Experimental Therapeutics and Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160, USA
1Correspondence: M.G.K., Center for Experimental Therapeutics and Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6160, USA. E-mail: marcelo{at}spirit.gcrc.upenn.edu
Protein kinase C (PKC), a family of related serine-threonine kinases, is a key player in the cellular responses mediated by the second messenger diacylglycerol (DAG) and the phorbol ester tumor promoters. The traditional view of PKCs as DAG/phospholipid-regulated proteins has expanded in the last few years by three seminal discoveries. First, PKC activity and maturation is controlled by autophosphorylation and transphosphorylation mechanisms, which includes phosphorylation of PKC isozymes by phosphoinositide-dependent protein kinases (PDKs) and tyrosine kinases. Second, PKC activity and localization are regulated by direct interaction with different types of interacting proteins. Protein–protein interactions are now recognized as important mechanisms that target individual PKCs to different intracellular compartments and confer selectivity by associating individual isozymes with specific substrates. Last, the discovery of novel phorbol ester receptors lacking kinase activity allows us to speculate that some of the biological responses elicited by phorbol esters or by activation of receptors coupled to elevation in DAG levels could be mediated by PKC-independent pathways.—Ron, D., Kazanietz, M. G. New insights into the regulation of protein kinase C and novel phorbol ester receptors.
Key Words: PKC • signal transduction • phorbol ester • chimaerin • anchoring proteins
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F. C. Gomez-Merino, C. A. Brearley, M. Ornatowska, M. E. F. Abdel-Haliem, M.-I. Zanor, and B. Mueller-Roeber AtDGK2, a Novel Diacylglycerol Kinase from Arabidopsis thaliana, Phosphorylates 1-Stearoyl-2-arachidonoyl-sn-glycerol and 1,2-Dioleoyl-sn-glycerol and Exhibits Cold-inducible Gene Expression J. Biol. Chem., February 27, 2004; 279(9): 8230 - 8241. [Abstract] [Full Text] [PDF]
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 S. Perrini, A. Natalicchio, L. Laviola, G. Belsanti, C. Montrone, A. Cignarelli, V. Minielli, M. Grano, G. De Pergola, R. Giorgino, et al. Dehydroepiandrosterone Stimulates Glucose Uptake in Human and Murine Adipocytes by Inducing GLUT1 and GLUT4 Translocation to the Plasma Membrane Diabetes, January 1, 2004; 53(1): 41 - 52. [Abstract] [Full Text] [PDF]
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J. H. Tinsley, N. R. Teasdale, and S. Y. Yuan Involvement of PKC{delta} and PKD in pulmonary microvascular endothelial cell hyperpermeability Am J Physiol Cell Physiol, January 1, 2004; 286(1): C105 - C111. [Abstract] [Full Text] [PDF]
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B. Ananthanarayanan, R. V. Stahelin, M. A. Digman, and W. Cho Activation Mechanisms of Conventional Protein Kinase C Isoforms Are Determined by the Ligand Affinity and Conformational Flexibility of Their C1 Domains J. Biol. Chem., November 21, 2003; 278(47): 46886 - 46894. [Abstract] [Full Text] [PDF]
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M. Marcet-Palacios, K. Graham, C. Cass, A. D. Befus, I. Mayers, and M. W. Radomski Nitric Oxide and Cyclic GMP Increase the Expression of Matrix Metalloproteinase-9 in Vascular Smooth Muscle J. Pharmacol. Exp. Ther., October 1, 2003; 307(1): 429 - 436. [Abstract] [Full Text] [PDF]
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 A R Giniatullin and R A Giniatullin Dual Action of Hydrogen Peroxide on Synaptic Transmission at the Frog Neuromuscular Junction J. Physiol., October 1, 2003; 552(1): 283 - 293. [Abstract] [Full Text] [PDF]
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J. A. Tapia, L. J. Garcia-Marin, and R. T. Jensen Cholecystokinin-stimulated Protein Kinase C-{delta} Kinase Activation, Tyrosine Phosphorylation, and Translocation Are Mediated by Src Tyrosine Kinases in Pancreatic Acinar Cells J. Biol. Chem., September 12, 2003; 278(37): 35220 - 35230. [Abstract] [Full Text] [PDF]
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Y. Tanaka, M. V. Gavrielides, Y. Mitsuuchi, T. Fujii, and M. G. Kazanietz Protein Kinase C Promotes Apoptosis in LNCaP Prostate Cancer Cells through Activation of p38 MAPK and Inhibition of the Akt Survival Pathway J. Biol. Chem., September 5, 2003; 278(36): 33753 - 33762. [Abstract] [Full Text] [PDF]
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T. Murakami, F. Sakane, S.-i. Imai, K. Houkin, and H. Kanoh Identification and Characterization of Two Splice Variants of Human Diacylglycerol Kinase {eta} J. Biol. Chem., September 5, 2003; 278(36): 34364 - 34372. [Abstract] [Full Text] [PDF]
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 E. Mazzoni, A. Adam, E. Bal de Kier Joffe, and J. A. Aguirre-Ghiso Immortalized Mammary Epithelial Cells Overexpressing Protein Kinase C {gamma} Acquire a Malignant Phenotype and Become Tumorigenic in Vivo Mol. Cancer Res., August 1, 2003; 1(10): 776 - 787. [Abstract] [Full Text] [PDF]
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G. Li, Y.-J. Kim, C. Mantel, and H. E. Broxmeyer P-Selectin Enhances Generation of CD14+CD16+ Dendritic-Like Cells and Inhibits Macrophage Maturation from Human Peripheral Blood Monocytes J. Immunol., July 15, 2003; 171(2): 669 - 677. [Abstract] [Full Text] [PDF]
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J. Cao, P. Burn, and Y. Shi Properties of the Mouse Intestinal Acyl-CoA:Monoacylglycerol Acyltransferase, MGAT2 J. Biol. Chem., July 3, 2003; 278(28): 25657 - 25663. [Abstract] [Full Text] [PDF]
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 J. R. Stewart, M. C. Artime, and C. A. O'Brian Resveratrol: A Candidate Nutritional Substance for Prostate Cancer Prevention J. Nutr., July 1, 2003; 133(7): 2440S - 2443. [Abstract] [Full Text] [PDF]
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L. H. Abdullah, J. T. Bundy, C. Ehre, and C. W. Davis Mucin secretion and PKC isoforms in SPOC1 goblet cells: differential activation by purinergic agonist and PMA Am J Physiol Lung Cell Mol Physiol, July 1, 2003; 285(1): L149 - L160. [Abstract] [Full Text] [PDF]
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 D. Thomas, W. Zhang, K. Wu, A.-B. Wimmer, B. Gut, G. Wendt-Nordahl, S. Kathofer, V. A.W. Kreye, H. A. Katus, W. Schoels, et al. Regulation of HERG potassium channel activation by protein kinase C independent of direct phosphorylation of the channel protein Cardiovasc Res, July 1, 2003; 59(1): 14 - 26. [Abstract] [Full Text] [PDF]
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E. N. Brown and J. J. Galligan Muscarinic receptors couple to modulation of nicotinic ACh receptor desensitization in myenteric neurons Am J Physiol Gastrointest Liver Physiol, June 9, 2003; 285(1): G37 - G44. [Abstract] [Full Text] [PDF]
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K. Chida, T. Hara, T. Hirai, C. Konishi, K. Nakamura, K. Nakao, A. Aiba, M. Katsuki, and T. Kuroki Disruption of Protein Kinase C{eta} Results in Impairment of Wound Healing and Enhancement of Tumor Formation in Mouse Skin Carcinogenesis Cancer Res., May 15, 2003; 63(10): 2404 - 2408. [Abstract] [Full Text] [PDF]
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P. L. Menna, G. Skilton, F. C. Leskow, D. F. Alonso, D. E. Gomez, and M. G. Kazanietz Inhibition of Aggressiveness of Metastatic Mouse Mammary Carcinoma Cells by the {beta}2-Chimaerin GAP Domain Cancer Res., May 1, 2003; 63(9): 2284 - 2291. [Abstract] [Full Text] [PDF]
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J. Cao, J. Lockwood, P. Burn, and Y. Shi Cloning and Functional Characterization of a Mouse Intestinal Acyl-CoA:Monoacylglycerol Acyltransferase, MGAT2 J. Biol. Chem., April 11, 2003; 278(16): 13860 - 13866. [Abstract] [Full Text] [PDF]
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N. Engedal and H. K. Blomhoff Combined Action of ERK and NFkappa B Mediates the Protective Effect of Phorbol Ester on Fas-induced Apoptosis in Jurkat Cells J. Biol. Chem., March 21, 2003; 278(13): 10934 - 10941. [Abstract] [Full Text] [PDF]
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S. R. Bolsover, J. C. Gomez-Fernandez, and S. Corbalan-Garcia Role of the Ca2+/Phosphatidylserine Binding Region of the C2 Domain in the Translocation of Protein Kinase Calpha to the Plasma Membrane J. Biol. Chem., March 14, 2003; 278(12): 10282 - 10290. [Abstract] [Full Text] [PDF]
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A. Siflinger-Birnboim and A. Johnson Protein kinase C modulates pulmonary endothelial permeability: a paradigm for acute lung injury Am J Physiol Lung Cell Mol Physiol, March 1, 2003; 284(3): L435 - L451. [Abstract] [Full Text] [PDF]
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C. Kast, M. Wang, and M. Whiteway The ERK/MAPK Pathway Regulates the Activity of the Human Tissue Factor Pathway Inhibitor-2 Promoter J. Biol. Chem., February 21, 2003; 278(9): 6787 - 6794. [Abstract] [Full Text] [PDF]
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A. V. Babwah, L. B. Dale, and S. S. G. Ferguson Protein Kinase C Isoform-specific Differences in the Spatial-Temporal Regulation and Decoding of Metabotropic Glutamate Receptor1a-stimulated Second Messenger Responses J. Biol. Chem., February 7, 2003; 278(7): 5419 - 5426. [Abstract] [Full Text] [PDF]
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F. Chu, N. E. Ward, and C. A. O'Brian PKC isozyme S-cysteinylation by cystine stimulates the pro-apoptotic isozyme PKC{delta} and inactivates the oncogenic isozyme PKC{varepsilon} Carcinogenesis, February 1, 2003; 24(2): 317 - 325. [Abstract] [Full Text] [PDF]
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 M. Guo, M. H. Wu, F. Korompai, and S. Y. Yuan Upregulation of PKC genes and isozymes in cardiovascular tissues during early stages of experimental diabetes Physiol Genomics, January 15, 2003; 12(2): 139 - 146. [Abstract] [Full Text] [PDF]
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M. Nanjundan and F. Possmayer Pulmonary phosphatidic acid phosphatase and lipid phosphate phosphohydrolase Am J Physiol Lung Cell Mol Physiol, January 1, 2003; 284(1): L1 - L23. [Abstract] [Full Text] [PDF]
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V. Novotny-Diermayr, T. Zhang, L. Gu, and X. Cao Protein Kinase C delta Associates with the Interleukin-6 Receptor Subunit Glycoprotein (gp) 130 via Stat3 and Enhances Stat3-gp130 Interaction J. Biol. Chem., December 13, 2002; 277(51): 49134 - 49142. [Abstract] [Full Text] [PDF]
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 T. L. Anthony, J. D. Lindsey, and R. N. Weinreb Latanoprost's Effects on TIMP-1 and TIMP-2 Expression in Human Ciliary Muscle Cells Invest. Ophthalmol. Vis. Sci., December 1, 2002; 43(12): 3705 - 3711. [Abstract] [Full Text] [PDF]
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 R. L. Darley, L. Pearn, N. Omidvar, M. Sweeney, J. Fisher, S. Phillips, T. Hoy, and A. K. Burnett Protein kinase C mediates mutant N-Ras-induced developmental abnormalities in normal human erythroid cells Blood, December 1, 2002; 100(12): 4185 - 4192. [Abstract] [Full Text] [PDF]
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P. Luppi, C. Haluszczak, D. Betters, C. A. H. Richard, M. Trucco, and J. A. DeLoia Monocytes are progressively activated in the circulation of pregnant women J. Leukoc. Biol., November 1, 2002; 72(5): 874 - 884. [Abstract] [Full Text] [PDF]
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F. Sakane, S.-i. Imai, K. Yamada, T. Murakami, S. Tsushima, and H. Kanoh Alternative Splicing of the Human Diacylglycerol Kinase delta Gene Generates Two Isoforms Differing in Their Expression Patterns and in Regulatory Functions J. Biol. Chem., November 1, 2002; 277(45): 43519 - 43526. [Abstract] [Full Text] [PDF]
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 J. C. Lenz, H. P. Reusch, N. Albrecht, G. Schultz, and M. Schaefer Ca2+-controlled competitive diacylglycerol binding of protein kinase C isoenzymes in living cells J. Cell Biol., October 28, 2002; 159(2): 291 - 302. [Abstract] [Full Text] [PDF]
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