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Science 26 November 1999:
Vol. 286. no. 5445, pp. 1738 - 1741
DOI: 10.1126/science.286.5445.1738
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Reports

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: david.glass{at}regpha.com

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Phosphatidylinositol 3-Kinase Activates ERK in Primary Sensory Neurons and Mediates Inflammatory Heat Hyperalgesia through TRPV1 Sensitization.
Z.-Y. Zhuang, H. Xu, D. E. Clapham, and R.-R. Ji (2004)
J. Neurosci. 24, 8300-8309
   Abstract »    Full Text »    PDF »
Constitutive activation of the MEK/ERK pathway mediates all effects of oncogenic H-ras expression in primary erythroid progenitors.
J. Zhang and H. F. Lodish (2004)
Blood 104, 1679-1687
   Abstract »    Full Text »    PDF »
Involvement of 3-Phosphoinositide-dependent Protein Kinase-1 in the MEK/MAPK Signal Transduction Pathway.
S. Sato, N. Fujita, and T. Tsuruo (2004)
J. Biol. Chem. 279, 33759-33767
   Abstract »    Full Text »    PDF »
Molecular and Cellular Determinants of Skeletal Muscle Atrophy and Hypertrophy.
V. Sartorelli and M. Fulco (2004)
Sci. STKE 2004, re11
   Abstract »    Full Text »    PDF »
Erk1/2 Phosphorylation and Reactive Oxygen Species Formation via Nitric Oxide and Akt-1/Raf-1 Crosstalk in Cultured Rat Cerebellar Granule Cells Exposed to the Organic Solvent 1,2,4-Trimethylcyclohexane.
O. Myhre, S. H. Sterri, I. L. Bogen, and F. Fonnum (2004)
Toxicol. Sci. 80, 296-303
   Abstract »    Full Text »    PDF »
Cross-talk between the survival kinases during early reperfusion: its contribution to ischemic preconditioning.
D. J Hausenloy, M. M Mocanu, and D. M Yellon (2004)
Cardiovasc Res 63, 305-312
   Abstract »    Full Text »    PDF »
Opposing Extracellular Signal-Regulated Kinase and Akt Pathways Control Schwann Cell Myelination.
T. Ogata, S. Iijima, S. Hoshikawa, T. Miura, S.-i. Yamamoto, H. Oda, K. Nakamura, and S. Tanaka (2004)
J. Neurosci. 24, 6724-6732
   Abstract »    Full Text »    PDF »
The Hepatitis E Virus Open Reading Frame 3 Protein Activates ERK through Binding and Inhibition of the MAPK Phosphatase.
A. Kar-Roy, H. Korkaya, R. Oberoi, S. K. Lal, and S. Jameel (2004)
J. Biol. Chem. 279, 28345-28357
   Abstract »    Full Text »    PDF »
Lipopolysaccharide-Induced Macrophage Inflammatory Response Is Regulated by SHIP.
H. Fang, R. A. Pengal, X. Cao, L. P. Ganesan, M. D. Wewers, C. B. Marsh, and S. Tridandapani (2004)
J. Immunol. 173, 360-366
   Abstract »    Full Text »    PDF »
Activation of the MAP kinase pathway by c-Kit is PI-3 kinase dependent in hematopoietic progenitor/stem cell lines.
E. Wandzioch, C. E. Edling, R. H. Palmer, L. Carlsson, and B. Hallberg (2004)
Blood 104, 51-57
   Abstract »    Full Text »    PDF »
SHP-2 Positively Regulates Myogenesis by Coupling to the Rho GTPase Signaling Pathway.
M. I. Kontaridis, S. Eminaga, M. Fornaro, C. I. Zito, R. Sordella, J. Settleman, and A. M. Bennett (2004)
Mol. Cell. Biol. 24, 5340-5352
   Abstract »    Full Text »    PDF »
Calcium Activation of ERK Mediated by Calmodulin Kinase I.
J. M. Schmitt, G. A. Wayman, N. Nozaki, and T. R. Soderling (2004)
J. Biol. Chem. 279, 24064-24072
   Abstract »    Full Text »    PDF »
Regulation of Na+ transport by aldosterone: signaling convergence and cross talk between the PI3-K and MAPK1/2 cascades.
Q. Tong, R. E. Booth, R. T. Worrell, and J. D. Stockand (2004)
Am J Physiol Renal Physiol 286, F1232-F1238
   Abstract »    Full Text »    PDF »
LGI1, a Putative Tumor Metastasis Suppressor Gene, Controls in Vitro Invasiveness and Expression of Matrix Metalloproteinases in Glioma Cells through the ERK1/2 Pathway.
P. Kunapuli, C. S. Kasyapa, L. Hawthorn, and J. K. Cowell (2004)
J. Biol. Chem. 279, 23151-23157
   Abstract »    Full Text »    PDF »
Dual Regulation of MMP-2 Expression by the Type 1 Insulin-like Growth Factor Receptor: THE PHOSPHATIDYLINOSITOL 3-KINASE/Akt AND Raf/ERK PATHWAYS TRANSMIT OPPOSING SIGNALS.
D. Zhang, M. Bar-Eli, S. Meloche, and P. Brodt (2004)
J. Biol. Chem. 279, 19683-19690
   Abstract »    Full Text »    PDF »
PIKE (Phosphatidylinositol 3-Kinase Enhancer)-A GTPase Stimulates Akt Activity and Mediates Cellular Invasion.
J.-Y. Ahn, R. Rong, T. G. Kroll, E. G. Van Meir, S. H. Snyder, and K. Ye (2004)
J. Biol. Chem. 279, 16441-16451
   Abstract »    Full Text »    PDF »
The Inositol 3-Phosphatase PTEN Negatively Regulates Fc{gamma} Receptor Signaling, but Supports Toll-Like Receptor 4 Signaling in Murine Peritoneal Macrophages.
X. Cao, G. Wei, H. Fang, J. Guo, M. Weinstein, C. B. Marsh, M. C. Ostrowski, and S. Tridandapani (2004)
J. Immunol. 172, 4851-4857
   Abstract »    Full Text »    PDF »
Androgen Receptor in Prostate Cancer.
C. A. Heinlein and C. Chang (2004)
Endocr. Rev. 25, 276-308
   Abstract »    Full Text »    PDF »
Extracellular Signal-Regulated Kinases Regulate Dendritic Growth in Rat Sympathetic Neurons.
I.-J. Kim, K. M. Drahushuk, W.-Y. Kim, E. A. Gonsiorek, P. Lein, D. A. Andres, and D. Higgins (2004)
J. Neurosci. 24, 3304-3312
   Abstract »    Full Text »    PDF »
Inhibition of Ligand-independent ERK1/2 Activity in Kidney Proximal Tubular Cells Deprived of Soluble Survival Factors Up-regulates Akt and Prevents Apoptosis.
D. Sinha, S. Bannergee, J. H. Schwartz, W. Lieberthal, and J. S. Levine (2004)
J. Biol. Chem. 279, 10962-10972
   Abstract »    Full Text »    PDF »


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