Akt Phosphorylates and Negatively Regulates Apoptosis Signal-Regulating Kinase 1

doi:10.1128/MCB.21.3.893-901.2001

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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-inducingproteins. Here we describe a novel functional interaction betweenAkt and apoptosis signal-regulating kinase 1 (ASK1), a mitogen-activatedprotein kinase kinase kinase. Akt decreased ASK1 kinase activitystimulated by both oxidative stress and overexpression in 293cells by phosphorylating a consensus Akt site at serine 83 ofASK1. Activation of the phosphoinositide 3-kinase (PI3-K)/Aktpathway also inhibited the serum deprivation-induced activityof endogenous ASK1 in L929 cells. An association between Akt andASK1 was detected in cells by coimmunoprecipitation. Phosphorylationby Akt inhibited ASK1-mediated c-Jun N-terminal kinase and activatingtranscription factor 2 activities in intact cells. Finally, activationof the PI3-K/Akt pathway reduced apoptosis induced by ASK1 ina manner dependent on phosphorylation of serine 83 of ASK1. Theseresults provide the first direct link between Akt and the familyof stress-activatedkinases.

^* 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.

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