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Molecular and Cellular Biology, August 2009, p. 4167-4176, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.01067-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Serine 58 of 14-3-3{zeta} Is a Molecular Switch Regulating ASK1 and Oxidant Stress-Induced Cell Death{triangledown} ,{dagger}

Jibin Zhou,1 Zhili Shao,1 Risto Kerkela,1 Hidenori Ichijo,4 Anthony J. Muslin,5 Celia Pombo,6 and Thomas Force1,2,3*

Center for Translational Medicine,1 Program in Cell and Developmental Biology,2 Cardiology Division, Thomas Jefferson University, Philadelphia, Pennsylvania,3 Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan,4 Center for Cardiovascular Research, John Milliken Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri,5 Laboratory of Cell Signaling and Cancer Research, Department of Physiology, School of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain6

Received 8 July 2008/ Returned for modification 1 October 2008/ Accepted 12 May 2009

Oxidant stress is a ubiquitous stressor with negative impacts on multiple cell types. ASK1 is a central mediator of oxidant injury, but while mechanisms of its inhibition, such as sequestration by 14-3-3 proteins and thioredoxin, have been identified, mechanisms of activation have remained obscure and the signaling pathways regulating this are not clear. Here, we report that phosphorylation of 14-3-3{zeta} at serine 58 (S58) is dynamically regulated in the cell and that the phosphorylation status of S58 is a critical factor regulating oxidant stress-induced cell death. Phosphorylation of S58 releases ASK1 from 14-3-3{zeta}, and ASK1 then activates stress-activated protein kinases, leading to cell death. While several members of the mammalian sterile 20 (Mst) family of kinases can phosphorylate S58 when overexpressed, we identify Ste20/oxidant stress response kinase 1 (SOK-1), an Mst family member known to be activated by oxidant stress, as a central endogenous regulator of S58 phosphorylation and thereby of ASK1-mediated cell death. Our findings identify a novel pathway that regulates ASK1 activation and oxidant stress-induced cell death.

* Corresponding author. Mailing address: Center for Translational Medicine, Thomas Jefferson University, College Building, Rm. 316, 1025 Walnut St., Philadelphia, PA 19107. Phone: (215) 503-9520. Fax: (215) 503-5731. E-mail: thomas.force{at}jefferson.edu

{triangledown} Published ahead of print on 18 May 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2009, p. 4167-4176, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.01067-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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