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Science 286 (5445): 1741-1744

Copyright © 1999 by the American Association for the Advancement of Science

Phosphorylation and Regulation of Raf by Akt (Protein Kinase B)

Sven Zimmermann, Karin Moelling *

Activation of the protein kinase Raf can lead to opposing cellular responses such as proliferation, growth arrest, apoptosis, or differentiation. Akt (protein kinase B), a member of a different signaling pathway that also regulates these responses, interacted with Raf and phosphorylated this protein at a highly conserved serine residue in its regulatory domain in vivo. This phosphorylation of Raf by Akt inhibited activation of the Raf-MEK-ERK signaling pathway and shifted the cellular response in a human breast cancer cell line from cell cycle arrest to proliferation. These observations provide a molecular basis for cross talk between two signaling pathways at the level of Raf and Akt.

Institute of Medical Virology, University of Zurich, Gloriastrasse 30/32, CH-8028 Zurich, Switzerland.
*   To whom correspondence should be addressed. E-mail: moelling{at}

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Glucocorticoid Conditioning of Myeloid Progenitors Enhances TLR4 Signaling via Negative Regulation of the Phosphatidylinositol 3-Kinase-Akt Pathway.
T. Y. Zhang and R. A. Daynes (2007)
J. Immunol. 178, 2517-2526
   Abstract »    Full Text »    PDF »
MEK-ERK-mediated Phosphorylation of Mdm2 at Ser-166 in Hepatocytes: Mdm2 IS ACTIVATED IN RESPONSE TO INHIBITED Akt SIGNALING.
M. Malmlof, E. Roudier, J. Hogberg, and U. Stenius (2007)
J. Biol. Chem. 282, 2288-2296
   Abstract »    Full Text »    PDF »
Activation of Akt Predicts Poor Outcome in Neuroblastoma.
D. Opel, C. Poremba, T. Simon, K.-M. Debatin, and S. Fulda (2007)
Cancer Res. 67, 735-745
   Abstract »    Full Text »    PDF »
Differential Regulation of B-Raf Isoforms by Phosphorylation and Autoinhibitory Mechanisms.
I. Hmitou, S. Druillennec, A. Valluet, C. Peyssonnaux, and A. Eychene (2007)
Mol. Cell. Biol. 27, 31-43
   Abstract »    Full Text »    PDF »
A Splice Variant of CD99 Increases Motility and MMP-9 Expression of Human Breast Cancer Cells through the AKT-, ERK-, and JNK-dependent AP-1 Activation Signaling Pathways.
H.-J. Byun, I.-K. Hong, E. Kim, Y.-J. Jin, D.-I. Jeoung, J.-H. Hahn, Y.-M. Kim, S. H. Park, and H. Lee (2006)
J. Biol. Chem. 281, 34833-34847
   Abstract »    Full Text »    PDF »
Induction of Krox-24 by Endogenous Cannabinoid Type 1 Receptors in Neuro2A Cells Is Mediated by the MEK-ERK MAPK Pathway and Is Suppressed by the Phosphatidylinositol 3-Kinase Pathway.
E. S. Graham, N. Ball, E. L. Scotter, P. Narayan, M. Dragunow, and M. Glass (2006)
J. Biol. Chem. 281, 29085-29095
   Abstract »    Full Text »    PDF »
Differential Roles of Phosphoinositide-Dependent Protein Kinase-1 and Akt1 Expression and Phosphorylation in Breast Cancer Cell Resistance to Paclitaxel, Doxorubicin, and Gemcitabine.
K. Liang, Y. Lu, X. Li, X. Zeng, R. I. Glazer, G. B. Mills, and Z. Fan (2006)
Mol. Pharmacol. 70, 1045-1052
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Akt Down-Regulates ERK1/2 Nuclear Localization and Angiotensin II-induced Cell Proliferation through PEA-15.
M. Gervais, C. Dugourd, L. Muller, C. Ardidie, B. Canton, L. Loviconi, P. Corvol, H. Chneiweiss, and C. Monnot (2006)
Mol. Biol. Cell 17, 3940-3951
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Scaffolding Protein Grb2-associated Binder 1 Sustains Epidermal Growth Factor-induced Mitogenic and Survival Signaling by Multiple Positive Feedback Loops.
A. Kiyatkin, E. Aksamitiene, N. I. Markevich, N. M. Borisov, J. B. Hoek, and B. N. Kholodenko (2006)
J. Biol. Chem. 281, 19925-19938
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Atrogin-1/MAFbx and MuRF1 Are Downregulated in Aging-Related Loss of Skeletal Muscle.
E. Edstrom, M. Altun, M. Hagglund, and B. Ulfhake (2006)
J Gerontol A Biol Sci Med Sci 61, 663-674
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Macrophage-Colony-Stimulating Factor-Induced Proliferation and Lipopolysaccharide-Dependent Activation of Macrophages Requires Raf-1 Phosphorylation to Induce Mitogen Kinase Phosphatase-1 Expression..
E. Sanchez-Tillo, M. Comalada, C. Farrera, A. F. Valledor, J. Lloberas, and A. Celada (2006)
J. Immunol. 176, 6594-6602
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IGF-I and insulin receptor signal transduction in trout muscle cells.
J. Castillo, I. Ammendrup-Johnsen, M. Codina, I. Navarro, and J. Gutierrez (2006)
Am J Physiol Regulatory Integrative Comp Physiol 290, R1683-R1690
   Abstract »    Full Text »    PDF »
Akt Signaling and Growth of the Heart.
K. Walsh (2006)
Circulation 113, 2032-2034
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Akt1 Is Required for Physiological Cardiac Growth.
B. DeBosch, I. Treskov, T. S. Lupu, C. Weinheimer, A. Kovacs, M. Courtois, and A. J. Muslin (2006)
Circulation 113, 2097-2104
   Abstract »    Full Text »    PDF »
Melittin Inhibits Vascular Smooth Muscle Cell Proliferation through Induction of Apoptosis via Suppression of Nuclear Factor-{kappa}B and Akt Activation and Enhancement of Apoptotic Protein Expression.
D. J. Son, S. J. Ha, H. S. Song, Y. Lim, Y. P. Yun, J. W. Lee, D. C. Moon, Y. H. Park, B. S. Park, M. J. Song, et al. (2006)
J. Pharmacol. Exp. Ther. 317, 627-634
   Abstract »    Full Text »    PDF »
Varicella-zoster virus influences the activities of components and targets of the ERK signalling pathway..
M. Rahaus, N. Desloges, and M. H. Wolff (2006)
J. Gen. Virol. 87, 749-758
   Abstract »    Full Text »    PDF »
Genetic alterations in signaling pathways in melanoma..
F. G. Haluska, H. Tsao, H. Wu, F. S. Haluska, A. Lazar, and V. Goel (2006)
Clin. Cancer Res. 12, 2301s-2307s
   Abstract »    Full Text »    PDF »

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