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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}saturn.med.nyu.edu.

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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