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(The FASEB Journal. 1999;13:1658-1676.)
© 1999 FASEB

New insights into the regulation of protein kinase C and novel phorbol ester receptors

DORIT RON*1 and MARCELO G. KAZANIETZ{dagger}1

* Department of Neurology, Ernest Gallo Clinic and Research Center, University of California San Francisco, San Francisco, California 94110-3518, USA; and
{dagger} 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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S. Osmanagic-Myers and G. Wiche
Plectin-RACK1 (Receptor for Activated C Kinase 1) Scaffolding: A NOVEL MECHANISM TO REGULATE PROTEIN KINASE C ACTIVITY
J. Biol. Chem., April 30, 2004; 279(18): 18701 - 18710.
[Abstract] [Full Text] [PDF]


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CarcinogenesisHome page
F. Chu, L. H. Chen, and C. A. O'Brian
Cellular protein kinase C isozyme regulation by exogenously delivered physiological disulfides--implications of oxidative protein kinase C regulation to cancer prevention
Carcinogenesis, April 1, 2004; 25(4): 585 - 596.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Cell Physiol.Home page
P. Robin, I. Boulven, C. Bole-Feysot, Z. Tanfin, and D. Leiber
Contribution of PKC-dependent and -independent processes in temporal ERK regulation by ET-1, PDGF, and EGF in rat myometrial cells
Am J Physiol Cell Physiol, April 1, 2004; 286(4): C798 - C806.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
L. Davidson, A. J. Pawson, R. L. de Maturana, S. H. Freestone, P. Barran, R. P. Millar, and S. Maudsley
Gonadotropin-releasing Hormone-induced Activation of Diacylglycerol Kinase-{zeta} and Its Association with Active c-Src
J. Biol. Chem., March 19, 2004; 279(12): 11906 - 11916.
[Abstract] [Full Text] [PDF]


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J. Cell Sci.Home page
M. S. Zastrow, S. Vlcek, and K. L. Wilson
Proteins that bind A-type lamins: integrating isolated clues
J. Cell Sci., March 1, 2004; 117(7): 979 - 987.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Renal Physiol.Home page
A. V. Cybulsky, T. Takano, J. Papillon, A. Khadir, K. Bijian, and L. Le Berre
The actin cytoskeleton facilitates complement-mediated activation of cytosolic phospholipase A2
Am J Physiol Renal Physiol, March 1, 2004; 286(3): F466 - F476.
[Abstract] [Full Text]


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J. Biol. Chem.Home page
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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DiabetesHome page
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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Am. J. Physiol. Cell Physiol.Home page
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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J. Biol. Chem.Home page
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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J. Pharmacol. Exp. Ther.Home page
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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J. Physiol.Home page
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. Biol. Chem.Home page
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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J. Biol. Chem.Home page
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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J. Biol. Chem.Home page
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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Mol Cancer ResHome page
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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J. Immunol.Home page
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. Biol. Chem.Home page
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. Nutr.Home page
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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Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
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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Cardiovasc ResHome page
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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Am. J. Physiol. Gastrointest. Liver Physiol.Home page
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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Cancer Res.Home page
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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Cancer Res.Home page
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. Biol. Chem.Home page
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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J. Biol. Chem.Home page
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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J. Biol. Chem.Home page
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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Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
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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J. Biol. Chem.Home page
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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J. Biol. Chem.Home page
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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CarcinogenesisHome page
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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Physiol. GenomicsHome page
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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Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
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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J. Biol. Chem.Home page
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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IOVSHome page
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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BloodHome page
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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J. Leukoc. Biol.Home page
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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J. Biol. Chem.Home page
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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JCBHome page
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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