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Molecular and Cellular Biology, July 2009, p. 3845-3852, Vol. 29, No. 14
0270-7306/09/$08.00+0     doi:10.1128/MCB.00279-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Mcl-1 Integrates the Opposing Actions of Signaling Pathways That Mediate Survival and Apoptosis{triangledown}

Caroline Morel,1 Scott M. Carlson,2 Forest M. White,2 and Roger J. Davis1*

Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605,1 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 021392

Received 3 March 2009/ Returned for modification 12 March 2009/ Accepted 30 April 2009

Mcl-1 is a member of the Bcl2-related protein family that is a critical mediator of cell survival. Exposure of cells to stress causes inhibition of Mcl-1 mRNA translation and rapid destruction of Mcl-1 protein by proteasomal degradation mediated by a phosphodegron created by glycogen synthase kinase 3 (GSK3) phosphorylation of Mcl-1. Here we demonstrate that prior phosphorylation of Mcl-1 by the c-Jun N-terminal protein kinase (JNK) is essential for Mcl-1 phosphorylation by GSK3. Stress-induced Mcl-1 degradation therefore requires the coordinated activity of JNK and GSK3. Together, these data establish that Mcl-1 functions as a site of signal integration between the proapoptotic activity of JNK and the prosurvival activity of the AKT pathway that inhibits GSK3.

* Corresponding author. Mailing address: Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605. Phone: (508) 856-8070. Fax: (508) 856-3210. E-mail: Roger.Davis{at}Umassmed.Edu

{triangledown} Published ahead of print on 11 May 2009.

Molecular and Cellular Biology, July 2009, p. 3845-3852, Vol. 29, No. 14
0270-7306/09/$08.00+0     doi:10.1128/MCB.00279-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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