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Mol. Cell. Biol. 18 (2): 790-798

Copyright © 1998 by the American Society for Microbiology. All rights reserved.

Mol Cell Biol, February 1998, p. 790-798, Vol. 18, No. 2
Copyright © 1998, American Society for Microbiology. All rights reserved.

Activation of the Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Pathway by Conventional, Novel, and Atypical Protein Kinase C Isotypes

Dorothee C. Schönwasser,1 Richard M. Marais,2 Christopher J. Marshall,2 and Peter J. Parker1,*

Imperial Cancer Research Fund, London WC2A 3PX,1 and C.R.C. Center for Cell and Molecular Biology, Chester Beatty Laboratories, Institute of Cancer Research, London SW3 6JB,2 United Kingdom

Received 24 December 1996/Returned for modification 17 March 1997/Accepted 28 October 1997

Phorbol ester treatment of quiescent Swiss 3T3 cells leads to cell proliferation, a response thought to be mediated by protein kinase C (PKC), the major cellular receptor for this class of agents. We demonstrate here that this proliferation is dependent on the activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) cascade. It is shown that dominant-negative PKC-alpha inhibits stimulation of the ERK/MAPK pathway by phorbol esters in Cos-7 cells, demonstrating a role for PKC in this activation. To assess the potential specificity of PKC isotypes mediating this process, constitutively active mutants of six PKC isotypes (alpha , beta 1, delta , varepsilon , eta , and zeta ) were employed. Transient transfection of these PKC mutants into Cos-7 cells showed that members of all three groups of PKC (conventional, novel, and atypical) are able to activate p42 MAPK as well as its immediate upstream activator, the MAPK/ERK kinase MEK-1. At the level of Raf, the kinase that phosphorylates MEK-1, the activation cascade diverges; while conventional and novel PKCs (isotypes alpha  and eta ) are potent activators of c-Raf1, atypical PKC-zeta cannot increase c-Raf1 activity, stimulating MEK by an independent mechanism. Stimulation of c-Raf1 by PKC-alpha and PKC-eta was abrogated for RafCAAX, which is a membrane-localized, partially active form of c-Raf1. We further established that activation of Raf is independent of phosphorylation at serine residues 259 and 499. In addition to activation, we describe a novel Raf desensitization induced by PKC-alpha , which acts to prevent further Raf stimulation by growth factors. The results thus demonstrate a necessary role for PKC and p42 MAPK activation in 12-O-tetradecanoylphorbol-13-acetate induced mitogenesis and provide evidence for multiple PKC controls acting on this MAPK cascade.

* Corresponding author. Mailing address: Imperial Cancer Research Fund, P.O. Box 123, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom. Phone: 171-269 3388. Fax: 171-269 3092. E-mail: parkerp{at}

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Inhibitors of Protein Kinase C (PKC) Prevent Activated Transcription: ROLE OF EVENTS DOWNSTREAM OF NF-{kappa}B DNA BINDING.
M. C. Catley, L. M. Cambridge, Y. Nasuhara, K. Ito, J. E. Chivers, A. Beaton, N. S. Holden, M. W. Bergmann, P. J. Barnes, and R. Newton (2004)
J. Biol. Chem. 279, 18457-18466
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Leukocyte-specific protein 1 targets the ERK/MAP kinase scaffold protein KSR and MEK1 and ERK2 to the actin cytoskeleton.
R. E. Harrison, B. A. Sikorski, and J. Jongstra (2004)
J. Cell Sci. 117, 2151-2157
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Involvement of the ERK Signaling Cascade in Protein Kinase C-mediated Cell Cycle Arrest in Intestinal Epithelial Cells.
J. A. Clark, A. R. Black, O. V. Leontieva, M. R. Frey, M. A. Pysz, L. Kunneva, A. Woloszynska-Read, D. Roy, and J. D. Black (2004)
J. Biol. Chem. 279, 9233-9247
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c-Kit-Mediated Overlapping and Unique Functional and Biochemical Outcomes via Diverse Signaling Pathways.
L. Hong, V. Munugalavadla, and R. Kapur (2004)
Mol. Cell. Biol. 24, 1401-1410
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Exercise-Induced Protein Kinase C Isoform-Specific Activation in Human Skeletal Muscle.
S. Perrini, J. Henriksson, J. R. Zierath, and U. Widegren (2004)
Diabetes 53, 21-24
   Abstract »    Full Text »    PDF »
Protein Kinase C Promotes Apoptosis in LNCaP Prostate Cancer Cells through Activation of p38 MAPK and Inhibition of the Akt Survival Pathway.
Y. Tanaka, M. V. Gavrielides, Y. Mitsuuchi, T. Fujii, and M. G. Kazanietz (2003)
J. Biol. Chem. 278, 33753-33762
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Fibroblast Growth Factor Receptor-1 Is Essential for In Vitro Cardiomyocyte Development.
P. Dell'Era, R. Ronca, L. Coco, S. Nicoli, M. Metra, and M. Presta (2003)
Circ. Res. 93, 414-420
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Protein kinase C{beta}1, a major regulator of TCR-CD28-activated signal transduction leading to IL-2 gene transcription and secretion.
U. E. Dreikhausen, K. Gorf, K. Resch, and M. Szamel (2003)
Int. Immunol. 15, 1089-1098
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PKC{zeta} participates in activation of inflammatory response induced by enteropathogenic E. coli.
S. D. Savkovic, A. Koutsouris, and G. Hecht (2003)
Am J Physiol Cell Physiol 285, C512-C521
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Regulation of ERK1 and ERK2 by Glucose and Peptide Hormones in Pancreatic {beta} Cells.
D. Arnette, T. B. Gibson, M. C. Lawrence, B. January, S. Khoo, K. McGlynn, C. A. Vanderbilt, and M. H. Cobb (2003)
J. Biol. Chem. 278, 32517-32525
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Loss of Protein Kinase C{alpha} Expression May Enhance the Tumorigenic Potential of Gli1 in Basal Cell Carcinoma.
G. W. Neill, L. R Ghali, J. L. Green, M. S. Ikram, M. P. Philpott, and A. G. Quinn (2003)
Cancer Res. 63, 4692-4697
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MAPK-dependent Degradation of G Protein-coupled Receptor Kinase 2.
A. Elorza, P. Penela, S. Sarnago, and F. Mayor Jr. (2003)
J. Biol. Chem. 278, 29164-29173
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Novel PKC{eta} Is Required To Activate Replicative Functions of the Major Nonstructural Protein NS1 of Minute Virus of Mice.
S. Lachmann, J. Rommeleare, and J. P. F. Nuesch (2003)
J. Virol. 77, 8048-8060
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Regulation of hyaluronan secretion into rabbit synovial joints in vivo by protein kinase C.
C L Anggiansah, D Scott, A Poli, P J Coleman, E Badrick, R M Mason, and J R Levick (2003)
J. Physiol. 550, 631-640
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c-Jun NH2-Terminal Kinase-Mediated Signaling Is Essential for Pseudomonas aeruginosa ExoS-Induced Apoptosis.
J. Jia, M. Alaoui-El-Azher, M. Chow, T. C. Chambers, H. Baker, and S. Jin (2003)
Infect. Immun. 71, 3361-3370
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Cocaine Produces Cardiac Hypertrophy by Protein Kinase C Dependent Mechanisms.
R. J. Henning and Y. Li (2003)
Journal of Cardiovascular Pharmacology and Therapeutics 8, 149-160
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Neurotensin Stimulates Protein Kinase C-dependent Mitogenic Signaling in Human Pancreatic Carcinoma Cell Line PANC-1.
S. Guha, J. A. Lunn, C. Santiskulvong, and E. Rozengurt (2003)
Cancer Res. 63, 2379-2387
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Activation of Raf-1 Signaling by Protein Kinase C through a Mechanism Involving Raf Kinase Inhibitory Protein.
K. C. Corbit, N. Trakul, E. M. Eves, B. Diaz, M. Marshall, and M. R. Rosner (2003)
J. Biol. Chem. 278, 13061-13068
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Mesenchymal Chondrosarcoma: Molecular Characterization by a Proteomic Approach, with Morphogenic and Therapeutic Implications.
R. E. Brown and J. L. Boyle (2003)
Ann. Clin. Lab. Sci. 33, 131-141
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Intestinal epithelial responses to enteric pathogens: effects on the tight junction barrier, ion transport, and inflammation.
J Berkes, V K Viswanathan, S D Savkovic, and G Hecht (2003)
Gut 52, 439-451
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pp90RSK- and protein kinase C-dependent pathway regulates p42/44MAPK-induced LDL receptor transcription in HepG2 cells.
G. S. Kapoor, C. Golden, B. Atkins, and K. D. Mehta (2003)
J. Lipid Res. 44, 584-593
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