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14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation
1Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
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.
Insights
Survival signals phosphorylate the proapoptotic protein BAD, inactivating it and promoting cell survival. This process involves sequential phosphorylation events and 14-3-3 protein recruitment, revealing a key mechanism in apoptosis regulation.
Area of Science:
- Cellular Biology
- Molecular Biology
- Biochemistry
Background:
- The Bcl-2 family regulates apoptosis, with prodeath members interacting with prosurvival members via their BH3 domain.
- Dysregulation of apoptosis is implicated in various diseases, including cancer and neurodegeneration.
Purpose of the Study:
- To elucidate the mechanism by which survival signals inactivate the proapoptotic protein BAD.
- To investigate the role of phosphorylation in regulating BAD activity and its interaction with prosurvival Bcl-2 proteins.
Main Methods:
- Phosphorylation site analysis of the BAD protein.
- Investigation of protein-protein interactions between BAD and Bcl-2 family members.
- Assessment of the role of 14-3-3 proteins in BAD regulation.
Main Results:
- Survival factors induce phosphorylation of BAD at Ser-155 within its BH3 domain.
- Phosphorylation at Ser-155 requires prior phosphorylation at Ser-136, which recruits 14-3-3 proteins.
- 14-3-3 proteins enhance accessibility of Ser-155 to kinases, and Ser-155 phosphorylation disrupts BAD binding to prosurvival Bcl-2 proteins, promoting cell survival.
Conclusions:
- Survival signals inactivate proapoptotic BAD through sequential phosphorylation events.
- 14-3-3 proteins act as cofactors in regulating these sequential phosphorylation events.
- This mechanism provides a novel target for therapeutic interventions aimed at modulating apoptosis.