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Vol. 60, Issue 6, 1325-1331, December 2001

14-3-3 Inhibits Bad-Induced Cell Death through Interaction with Serine-136

Shane C. Masters, Hongzhu Yang, Sandeep Robert Datta, Michael E. Greenberg, and Haian Fu

Graduate Programs in Molecular and Systems Pharmacology (S.C.M.) and Biochemistry and Cell & Developmental Biology (H.Y.) and the Department of Pharmacology (H.F.), Emory University School of Medicine, Atlanta, Georgia; and the Department of Neurobiology, Harvard Medical School, Boston, Massachusetts (S.R.D., M.E.G.)

14-3-3 proteins are a family of multifunctional phosphoserine binding molecules that can serve as effectors of survival signaling. Understanding the molecular basis for the prosurvival effect of 14-3-3 may lead to the development of agents useful in the treatment of disorders involving dysregulated apoptosis. One target of 14-3-3 is the proapoptotic Bcl-2 family member Bad. Serine phosphorylation of Bad is associated with 14-3-3 binding and inhibition of Bad-induced cell death, but the relative contributions of the three known phosphorylation sites to 14-3-3 binding have not been established. Here we demonstrate that S136 of Bad is vital for 14-3-3 interaction, but S112 seems to be dispensable. 14-3-3/Bad interaction was strictly dependent on the presence of phosphorylated S136 in vitro, in yeast, and in mammalian cells. However, mutation of S112 did not affect 14-3-3 binding. The death caused by wild-type and S112A Bad, but not that caused by S136A Bad, could be almost completely abrogated by 14-3-3. These data support a critical role for 14-3-3 in regulating Bad proapoptotic activity. The effect of 14-3-3 on Bad is controlled largely by phosphorylation of S136, whereas S112 may represent a 14-3-3-independent pathway.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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