14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation.

Datta SR, Katsov A, Hu L, Petros A, Fesik SW, Yaffe MB, Greenberg ME
Mol Cell. 2000 6 (1): 41-51

PMID: 10949026

The Bcl-2 homology 3 (BH3) domain of prodeath Bcl-2 family members mediates their interaction with prosurvival Bcl-2 family members and promotes apoptosis. We report that survival factors trigger the phosphorylation of the proapoptotic Bcl-2 family member BAD at a site (Ser-155) within the BAD BH3 domain. When BAD is bound to prosurvival Bcl-2 family members, BAD Ser-155 phosphorylation requires the prior phosphorylation of Ser-136, which recruits 14-3-3 proteins that then function to increase the accessibility of Ser-155 to survival-promoting kinases. Ser-155 phosphorylation disrupts the binding of BAD to prosurvival Bcl-2 proteins and thereby promotes cell survival. These findings define a mechanism by which survival signals inactivate a proapoptotic Bcl-2 family member, and suggest a role for 14-3-3 proteins as cofactors that regulate sequential protein phosphorylation events.

MeSH Terms (23)

14-3-3 Proteins Amino Acid Sequence Animals bcl-Associated Death Protein bcl-X Protein Binding Sites Carrier Proteins Cell Death Cell Line Humans In Vitro Techniques Models, Biological Models, Molecular Molecular Sequence Data Phosphorylation Protein Kinases Proteins Protein Structure, Tertiary Proto-Oncogene Proteins c-bcl-2 Recombinant Proteins Sequence Homology, Amino Acid Serine Tyrosine 3-Monooxygenase

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