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Originally published In Press as doi:10.1074/jbc.M102001200 on May 17, 2001

J. Biol. Chem., Vol. 276, Issue 31, 29079-29090, August 3, 2001
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Constitutive Association of c-N-Ras with c-Raf-1 and Protein Kinase Cepsilon in Latent Signaling Modules*

Mark HamiltonDagger , Jinhui Liao, Martha K. Cathcart, and Alan Wolfman§

From the Department of Cell Biology, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195

Phorbol ester stimulation of the MAPK cascade is believed to be mediated through the protein kinase C (PKC)-dependent activation of Raf-1. Although several studies suggest that phorbol ester stimulation of MAPK is insensitive to dominant-negative Ras, a requirement for Ras in Raf-1 activation by PKC has been suggested recently. We now demonstrate that in normal, quiescent mouse fibroblasts, endogenous c-N-Ras is constitutively associated with both c-Raf-1 and PKCepsilon in a biochemically silent, but latent, signaling module. Chemical inhibition of novel PKCs blocks phorbol 12-myristate 13-acetate (PMA)-mediated activation of MAPKs. Down-regulation of PKCepsilon protein levels by antisense oligodeoxyribonucleotides blocks MAPK activation in response to PMA stimulation, demonstrating that PKCepsilon activity is required for MAPK activation by PMA. c-Raf-1 activity in immunoprecipitated c-N-Ras·c-Raf-1·PKCepsilon complexes is stimulated by PMA and is inhibited by GF109203X, thereby linking c-Raf-1 activation in this complex to PKC activation. These observations suggest that in quiescent cells Ras is organized into ordered, inactive signaling modules. Furthermore, the regulation of the MAPK cascade by both Ras and PKC is intimately linked, converging at the plasma membrane through their association with c-Raf-1.

* This work was supported by American Heart Association Grant 96001110 (to A. W.) and National Institutes of Health Grant GM62644 (to A. W.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Current address: Lilly Research Laboratories, DC 1543, Lilly Corporate Center, Indianapolis, IN 46285. Tel.: 317-433-6836; Fax: 317-276-9159; E-mail: hamilton_mark@lilly.com.

§ To whom correspondence should be addressed: Dept. Cell Biology, NC10, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland OH 44195. Tel.: 216-444-1228; Fax: 216-444-9404; E-mail: wolfmaa@ccf.org.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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