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J. Biol. Chem., Vol. 283, Issue 30, 20754-20760, July 25, 2008

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Phosphorylation of Bad at Thr-201 by JNK1 Promotes Glycolysis through Activation of Phosphofructokinase-1^*

Hongbin Deng, Fei Yu, Jianqun Chen, Yingming Zhao^¶, Jialing Xiang^||, and Anning Lin¹

From the Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois 60637, the Institute of Signal Transduction, School of Life Sciences, Nanjing University, Nanjing 210093, China, the ^¶Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, and the ^||Department of Biological, Chemical, and Physical Science, Illinois Institute of Technology, Chicago, Illinois 60616

The mitogen-activated protein kinase JNK1 suppresses interleukin-3 withdrawal-induced cell death through phosphorylation of the BH3-only pro-apoptotic Bcl-2 family protein Bad at Thr-201. It is unknown whether JNK1 regulates glycolysis, an important metabolic process that is involved in cell survival, and if so, whether the regulation depends on Thr-201 phosphorylation of Bad. Here we report that phosphorylation of Bad by JNK1 is required for glycolysis through activation of phosphofructokinase-1 (PFK-1), one of the key enzymes that catalyze glycolysis. Genetic disruption of Jnk1 alleles or silencing of Jnk1 by small interfering RNA abrogates glycolysis induced by growth/survival factors such as serum or interleukin-3. Proteomic analysis identifies PFK-1 as a novel Bad-associated protein. Although the interaction between PFK-1 and Bad is independent of JNK1, Thr-201 phosphorylation of Bad by JNK1 is required for PFK-1 activation. Thus, our results provide a novel molecular mechanism by which JNK1 promotes glycolysis for cell survival.

Received for publication, January 2, 2008 , and in revised form, May 8, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants CA100460 and GM071409 (to A. L.) and CA090516 (to J. X.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Ben May Dept. for Cancer Research, The University of Chicago, Center for Integrative Science Bldg., Rm. W430, 929, East 57th St., Chicago, IL 60637. Tel.: 773-753-1408; Fax: 773-702-4476; E-mail: alin{at}huggins.bsd.uchicago.edu.

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