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Science 26 November 1999:
Vol. 286. no. 5445, pp. 1741 - 1744
DOI: 10.1126/science.286.5445.1741
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Reports

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}immv.unizh.ch

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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
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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
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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
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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
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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
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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
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Partitioning-Defective Protein 6 Regulates Insulin-Dependent Glycogen Synthesis via Atypical Protein Kinase C.
P. Weyrich, K. Kapp, G. Niederfellner, M. Melzer, R. Lehmann, H.-U. Haring, and R. Lammers (2004)
Mol. Endocrinol. 18, 1287-1300
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Protein Kinase B/Akt Regulates Coxsackievirus B3 Replication through a Mechanism Which Is Not Caspase Dependent.
M. Esfandiarei, H. Luo, B. Yanagawa, A. Suarez, D. Dabiri, J. Zhang, and B. M. McManus (2004)
J. Virol. 78, 4289-4298
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Preferential Inhibition of Akt and Killing of Akt-Dependent Cancer Cells by Rationally Designed Phosphatidylinositol Ether Lipid Analogues.
S. S. Castillo, J. Brognard, P. A. Petukhov, C. Zhang, J. Tsurutani, C. A. Granville, M. Li, M. Jung, K. A. West, J. G. Gills, et al. (2004)
Cancer Res. 64, 2782-2792
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Dynamic Changes in C-Raf Phosphorylation and 14-3-3 Protein Binding in Response to Growth Factor Stimulation: DIFFERENTIAL ROLES OF 14-3-3 PROTEIN BINDING SITES.
M. Hekman, S. Wiese, R. Metz, S. Albert, J. Troppmair, J. Nickel, M. Sendtner, and U. R. Rapp (2004)
J. Biol. Chem. 279, 14074-14086
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Androgen Receptor in Prostate Cancer.
C. A. Heinlein and C. Chang (2004)
Endocr. Rev. 25, 276-308
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Inhibition of Phosphorylation of a Forkhead Transcription Factor Sensitizes Human Ovarian Cancer Cells to Cisplatin.
E. Arimoto-Ishida, M. Ohmichi, S. Mabuchi, T. Takahashi, C. Ohshima, J. Hayakawa, A. Kimura, K. Takahashi, Y. Nishio, M. Sakata, et al. (2004)
Endocrinology 145, 2014-2022
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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
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Transient Phosphatidylinositol 3-Kinase Inhibition Protects Immature Primary Cortical Neurons from Oxidative Toxicity via Suppression of Extracellular Signal-regulated Kinase Activation.
D. J. Levinthal and D. B. DeFranco (2004)
J. Biol. Chem. 279, 11206-11213
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C. elegans SUR-6/PR55 cooperates with LET-92/protein phosphatase 2A and promotes Raf activity independently of inhibitory Akt phosphorylation sites.
G. Kao, S. Tuck, D. Baillie, and M. V. Sundaram (2004)
Development 131, 755-765
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SU1498, an Inhibitor of Vascular Endothelial Growth Factor Receptor 2, Causes Accumulation of Phosphorylated ERK Kinases and Inhibits Their Activity in Vivo and in Vitro.
G. Boguslawski, P. W. McGlynn, K. A. Harvey, and A. T. Kovala (2004)
J. Biol. Chem. 279, 5716-5724
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Activation of the ERK1/2 and p38 Mitogen-activated Protein Kinase Pathways Mediates Fibroblast Growth Factor-induced Growth Arrest of Chondrocytes.
A. Raucci, E. Laplantine, A. Mansukhani, and C. Basilico (2004)
J. Biol. Chem. 279, 1747-1756
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Phosphatidylinositide 3-Kinase Priming Couples c-FLIP to T Cell Activation.
L.-W. Fang, T.-S. Tai, W.-N. Yu, F. Liao, and M.-Z. Lai (2004)
J. Biol. Chem. 279, 13-18
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Roles of Phosphatidylinositol 3'-Kinase and Mammalian Target of Rapamycin/p70 Ribosomal Protein S6 Kinase in K-Ras-Mediated Transformation of Intestinal Epithelial Cells.
J. Shao, B. M. Evers, and H. Sheng (2004)
Cancer Res. 64, 229-235
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Estrogen Inhibits Paclitaxel-Induced Apoptosis via the Phosphorylation of Apoptosis Signal-Regulating Kinase 1 in Human Ovarian Cancer Cell Lines.
S. Mabuchi, M. Ohmichi, A. Kimura, Y. Nishio, E. Arimoto-Ishida, N. Yada-Hashimoto, K. Tasaka, and Y. Murata (2004)
Endocrinology 145, 49-58
   Abstract »    Full Text »    PDF »


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