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Mol. Cell. Biol. 21 (3): 893-901

Copyright © 2001 by the American Society for Microbiology. All rights reserved.

Molecular and Cellular Biology, February 2001, p. 893-901, Vol. 21, No. 3
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.3.893-901.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Akt Phosphorylates and Negatively Regulates Apoptosis Signal-Regulating Kinase 1

Albert H. Kim,1 Gus Khursigara,1 Xuan Sun,2 Thomas F. Franke,2 and Moses V. Chao1,*

Molecular Neurobiology Program, Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, New York 10016,1 and Department of Pharmacology, Columbia University, New York, New York 100322

Received 28 July 2000/Returned for modification 20 September 2000/Accepted 7 November 2000

The Akt family of serine/threonine-directed kinases promotes cellular survival in part by phosphorylating and inhibiting death-inducing proteins. Here we describe a novel functional interaction between Akt and apoptosis signal-regulating kinase 1 (ASK1), a mitogen-activated protein kinase kinase kinase. Akt decreased ASK1 kinase activity stimulated by both oxidative stress and overexpression in 293 cells by phosphorylating a consensus Akt site at serine 83 of ASK1. Activation of the phosphoinositide 3-kinase (PI3-K)/Akt pathway also inhibited the serum deprivation-induced activity of endogenous ASK1 in L929 cells. An association between Akt and ASK1 was detected in cells by coimmunoprecipitation. Phosphorylation by Akt inhibited ASK1-mediated c-Jun N-terminal kinase and activating transcription factor 2 activities in intact cells. Finally, activation of the PI3-K/Akt pathway reduced apoptosis induced by ASK1 in a manner dependent on phosphorylation of serine 83 of ASK1. These results provide the first direct link between Akt and the family of stress-activated kinases.

* Corresponding author. Mailing address: Skirball Institute, NYU Medical Center, 540 First Ave., Rm. 5-15, New York, NY 10016. Phone: (212) 263-0721. Fax: (212) 263-0723. E-mail: chao{at}

Molecular and Cellular Biology, February 2001, p. 893-901, Vol. 21, No. 3
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.3.893-901.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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Mol. Cell. Biol. 25, 8732-8747
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Angiopoietin-1 Attenuates H2O2-induced SEK1/JNK Phosphorylation through the Phosphatidylinositol 3-Kinase/Akt Pathway in Vascular Endothelial Cells.
T. Murakami, H. Takagi, K. Suzuma, I. Suzuma, H. Ohashi, D. Watanabe, T. Ojima, E. Suganami, M. Kurimoto, H. Kaneto, et al. (2005)
J. Biol. Chem. 280, 31841-31849
   Abstract »    Full Text »    PDF »
Cross-talk between JIP3 and JIP1 during Glucose Deprivation: SEK1-JNK2 AND Akt1 ACT AS MEDIATORS.
J. J. Song and Y. J. Lee (2005)
J. Biol. Chem. 280, 26845-26855
   Abstract »    Full Text »    PDF »
Cross-talk between Signaling Pathways Regulates Alternative Splicing: A NOVEL ROLE FOR JNK.
F. Pelisch, M. Blaustein, A. R. Kornblihtt, and A. Srebrow (2005)
J. Biol. Chem. 280, 25461-25469
   Abstract »    Full Text »    PDF »
Dissociation of Akt1 from its negative regulator JIP1 is mediated through the ASK1-MEK-JNK signal transduction pathway during metabolic oxidative stress: a negative feedback loop.
J. J. Song and Y. J. Lee (2005)
J. Cell Biol. 170, 61-72
   Abstract »    Full Text »    PDF »
Up-regulation of GRP78 and antiapoptotic signaling in murine peritoneal macrophages exposed to insulin.
U. K. Misra and S. V. Pizzo (2005)
J. Leukoc. Biol. 78, 187-194
   Abstract »    Full Text »    PDF »
ArgBP2{gamma} Interacts with Akt and p21-activated Kinase-1 and Promotes Cell Survival.
Z.-q. Yuan, D. Kim, S. Kaneko, M. Sussman, G. M. Bokoch, G. D. Kruh, S. V. Nicosia, J. R. Testa, and J. Q. Cheng (2005)
J. Biol. Chem. 280, 21483-21490
   Abstract »    Full Text »    PDF »
Pharmacologic inhibitors of PI3K/Akt potentiate the apoptotic action of the antileukemic drug arsenic trioxide via glutathione depletion and increased peroxide accumulation in myeloid leukemia cells.
A. M. Ramos, C. Fernandez, D. Amran, P. Sancho, E. de Blas, and P. Aller (2005)
Blood 105, 4013-4020
   Abstract »    Full Text »    PDF »
The Role of p70S6K in Hepatic Stellate Cell Collagen Gene Expression and Cell Proliferation.
E. Gabele, S. Reif, S. Tsukada, R. Bataller, Y. Yata, T. Morris, L. W. Schrum, D. A. Brenner, and R. A. Rippe (2005)
J. Biol. Chem. 280, 13374-13382
   Abstract »    Full Text »    PDF »
Elevated PTEN Levels Account for the Increased Sensitivity of Ethanol-exposed Cells to Tumor Necrosis Factor-induced Cytotoxicity.
N. Shulga, J. B. Hoek, and J. G. Pastorino (2005)
J. Biol. Chem. 280, 9416-9424
   Abstract »    Full Text »    PDF »
Interleukin-13 augments transforming growth factor-{beta}1-induced tissue inhibitor of metalloproteinase-1 expression in primary human airway fibroblasts.
X. Zhou, J. B. Trudeau, K. J. Schoonover, J. I. Lundin, S. M. Barnes, M. J. Cundall, and S. E. Wenzel (2005)
Am J Physiol Cell Physiol 288, C435-C442
   Abstract »    Full Text »    PDF »
Critical Role of Endogenous Akt/IAPs and MEK1/ERK Pathways in Counteracting Endoplasmic Reticulum Stress-induced Cell Death.
P. Hu, Z. Han, A. D. Couvillon, and J. H. Exton (2004)
J. Biol. Chem. 279, 49420-49429
   Abstract »    Full Text »    PDF »
Protein Phosphatase 4 Is a Positive Regulator of Hematopoietic Progenitor Kinase 1.
G. Zhou, J. S. Boomer, and T.-H. Tan (2004)
J. Biol. Chem. 279, 49551-49561
   Abstract »    Full Text »    PDF »
Gonadotropin-Releasing Hormone Induces Apoptosis of Prostate Cancer Cells: Role of c-Jun NH2-Terminal Kinase, Protein Kinase B, and Extracellular Signal-Regulated Kinase Pathways.
S. Kraus, G. Levy, T. Hanoch, Z. Naor, and R. Seger (2004)
Cancer Res. 64, 5736-5744
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Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling.
N. T. Ihle, R. Williams, S. Chow, W. Chew, M. I. Berggren, G. Paine-Murrieta, D. J. Minion, R. J. Halter, P. Wipf, R. Abraham, et al. (2004)
Mol. Cancer Ther. 3, 763-772
   Abstract »    Full Text »    PDF »
PIKE-A is amplified in human cancers and prevents apoptosis by up-regulating Akt.
J.-Y. Ahn, Y. Hu, T. G. Kroll, P. Allard, and K. Ye (2004)
PNAS 101, 6993-6998
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Activation of Apoptosis Signal-regulating Kinase 1 by Reactive Oxygen Species through Dephosphorylation at Serine 967 and 14-3-3 Dissociation.
E. H. Goldman, L. Chen, and H. Fu (2004)
J. Biol. Chem. 279, 10442-10449
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Phorbol 12-Myristate 13-Acetate Protects Jurkat Cells from Methylglyoxal-Induced Apoptosis by Preventing c-Jun N-Terminal Kinase-Mediated Leakage of Cytochrome c in an Extracellular Signal-Regulated Kinase-Dependent Manner.
Y. Takagi, J. Du, X.-Y. Ma, I. Nakashima, and F. Nagase (2004)
Mol. Pharmacol. 65, 778-787
   Abstract »    Full Text »    PDF »
Protein kinase activation and myocardial ischemia/reperfusion injury.
S. C Armstrong (2004)
Cardiovasc Res 61, 427-436
   Abstract »    Full Text »    PDF »
Akt Phosphorylation and Stabilization of X-linked Inhibitor of Apoptosis Protein (XIAP).
H. C. Dan, M. Sun, S. Kaneko, R. I. Feldman, S. V. Nicosia, H.-G. Wang, B. K. Tsang, and J. Q. Cheng (2004)
J. Biol. Chem. 279, 5405-5412
   Abstract »    Full Text »    PDF »
Use of Red-Shifted Dyes in a Fluorescence Polarization AKT Kinase Assay for Detection of Biological Activity in Natural Product Extracts.
T. C. Turek-Etienne, M. Lei, J. S. Terracciano, E. F. Langsdorf, R. W. Bryant, R. F. Hart, and A. C. Horan (2004)
J Biomol Screen 9, 52-61
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Tobacco Carcinogen-Induced Cellular Transformation Increases Activation of the Phosphatidylinositol 3'-Kinase/Akt Pathway in Vitro and in Vivo.
K. A. West, I. R. Linnoila, S. A. Belinsky, C. C. Harris, and P. A. Dennis (2004)
Cancer Res. 64, 446-451
   Abstract »    Full Text »    PDF »

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