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Science 286 (5445): 1738-1741

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

Differentiation Stage-Specific Inhibition of the Raf-MEK-ERK Pathway by Akt

Christian Rommel, 1 Brian A. Clarke, 1 Sven Zimmermann, 2 Lorna Nuñez, 1 Roni Rossman, 1 Kristina Reid, 1 Karin Moelling, 2 George D. Yancopoulos, 1* David J. Glass 1*

Extracellular signals often result in simultaneous activation of both the Raf-MEK-ERK and PI3K-Akt pathways (where ERK is extracellular-regulated kinase, MEK is mitogen-activated protein kinase or ERK kinase, and PI3K is phosphatidylinositol 3-kinase). However, these two signaling pathways were shown to exert opposing effects on muscle cell hypertrophy. Furthermore, the PI3K-Akt pathway was shown to inhibit the Raf-MEK-ERK pathway; this cross-regulation depended on the differentiation state of the cell: Akt activation inhibited the Raf-MEK-ERK pathway in differentiated myotubes, but not in their myoblast precursors. The stage-specific inhibitory action of Akt correlated with its stage-specific ability to form a complex with Raf, suggesting the existence of differentially expressed mediators of an inhibitory Akt-Raf complex.

1 Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
2 Institute of Medical Virology, University of Zürich, CH-8028, Zürich, Switzerland.
*   To whom correspondence should be addressed. E-mail:{at}

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A3 Adenosine Receptor Activation Inhibits Cell Proliferation via Phosphatidylinositol 3-Kinase/Akt-dependent Inhibition of the Extracellular Signal-regulated Kinase 1/2 Phosphorylation in A375 Human Melanoma Cells.
S. Merighi, A. Benini, P. Mirandola, S. Gessi, K. Varani, E. Leung, S. Maclennan, and P. A. Borea (2005)
J. Biol. Chem. 280, 19516-19526
   Abstract »    Full Text »    PDF »
Insulin and IGF-I stimulate the formation of the eukaryotic initiation factor 4F complex and protein synthesis in C2C12 myotubes independent of availability of external amino acids.
W.-H. Shen, D. W Boyle, P. Wisniowski, A. Bade, and E. A Liechty (2005)
J. Endocrinol. 185, 275-289
   Abstract »    Full Text »    PDF »
The macrophage inhibitory cytokine integrates AKT/PKB and MAP kinase signaling pathways in breast cancer cells.
W. Wollmann, M. L. Goodman, P. Bhat-Nakshatri, H. Kishimoto, R. J. Goulet Jr, S. Mehrotra, A. Morimiya, S. Badve, and H. Nakshatri (2005)
Carcinogenesis 26, 900-907
   Abstract »    Full Text »    PDF »
Molecular and Genetic Studies Imply Akt-mediated Signaling Promotes Protein Kinase C{beta}II Alternative Splicing via Phosphorylation of Serine/Arginine-rich Splicing Factor SRp40.
N. A. Patel, S. Kaneko, H. S. Apostolatos, S. S. Bae, J. E. Watson, K. Davidowitz, D. S. Chappell, M. J. Birnbaum, J. Q. Cheng, and D. R. Cooper (2005)
J. Biol. Chem. 280, 14302-14309
   Abstract »    Full Text »    PDF »
Enhancement of the Therapeutic Efficacy of Taxol by the Mitogen-Activated Protein Kinase Kinase Inhibitor CI-1040 in Nude Mice Bearing Human Heterotransplants.
H. M. McDaid, L. Lopez-Barcons, A. Grossman, M. Lia, S. Keller, R. Perez-Soler, and S. Band Horwitz (2005)
Cancer Res. 65, 2854-2860
   Abstract »    Full Text »    PDF »
Insulin-Like Growth Factor 1 Inhibits Extracellular Signal-Regulated Kinase to Promote Neuronal Survival via the Phosphatidylinositol 3-Kinase/Protein Kinase A/c-Raf Pathway.
S. Subramaniam, N. Shahani, J. Strelau, C. Laliberte, R. Brandt, D. Kaplan, and K. Unsicker (2005)
J. Neurosci. 25, 2838-2852
   Abstract »    Full Text »    PDF »
Inhibition of Src-like Kinases Reveals Akt-dependent and -independent Pathways in Insulin-like Growth Factor I-mediated Oligodendrocyte Progenitor Survival.
Q.-L. Cui, W.-H. Zheng, R. Quirion, and G. Almazan (2005)
J. Biol. Chem. 280, 8918-8928
   Abstract »    Full Text »    PDF »
Ras-MAPK Pathways.
A. Chan (2005)
Sci. STKE 2005, tr5
   Abstract »    Full Text »    PDF »
Insulin-like Growth Factor-1 (IGF-1) Inversely Regulates Atrophy-induced Genes via the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin (PI3K/Akt/mTOR) Pathway.
E. Latres, A. R. Amini, A. A. Amini, J. Griffiths, F. J. Martin, Y. Wei, H. C. Lin, G. D. Yancopoulos, and D. J. Glass (2005)
J. Biol. Chem. 280, 2737-2744
   Abstract »    Full Text »    PDF »
Regulation of Endocytosis, Nuclear Translocation, and Signaling of Fibroblast Growth Factor Receptor 1 by E-Cadherin.
D. M. Bryant, F. G. Wylie, and J. L. Stow (2005)
Mol. Biol. Cell 16, 14-23
   Abstract »    Full Text »    PDF »
Regulation of Embryonic Stem Cell Self-renewal by Phosphoinositide 3-Kinase-dependent Signaling.
N. R. D. Paling, H. Wheadon, H. K. Bone, and M. J. Welham (2004)
J. Biol. Chem. 279, 48063-48070
   Abstract »    Full Text »    PDF »
Conditional Activation of Akt in Adult Skeletal Muscle Induces Rapid Hypertrophy.
K.-M. V. Lai, M. Gonzalez, W. T. Poueymirou, W. O. Kline, E. Na, E. Zlotchenko, T. N. Stitt, A. N. Economides, G. D. Yancopoulos, and D. J. Glass (2004)
Mol. Cell. Biol. 24, 9295-9304
   Abstract »    Full Text »    PDF »
Oxidative Stress Affects the Integrin-Linked Kinase Signaling Pathway After Transient Focal Cerebral Ischemia.
A. Saito, T. Hayashi, S. Okuno, T. Nishi, and P. H. Chan (2004)
Stroke 35, 2560-2565
   Abstract »    Full Text »    PDF »
MAP Kinase Phosphatase 3 (MKP3) Interacts with and Is Phosphorylated by Protein Kinase CK2{alpha}.
M. Castelli, M. Camps, C. Gillieron, D. Leroy, S. Arkinstall, C. Rommel, and A. Nichols (2004)
J. Biol. Chem. 279, 44731-44739
   Abstract »    Full Text »    PDF »
Phospho-Akt Overexpression in Non-Small Cell Lung Cancer Confers Significant Stage-Independent Survival Disadvantage.
O. David, J. Jett, H. LeBeau, G. Dy, J. Hughes, M. Friedman, and A. R. Brody (2004)
Clin. Cancer Res. 10, 6865-6871
   Abstract »    Full Text »    PDF »

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