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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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14-3-3 Proteins
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Amino Acid Sequence
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Animals
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Binding Sites / genetics
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Carrier Proteins / antagonists & inhibitors*
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Death
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Cell Line
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Humans
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In Vitro Techniques
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Models, Biological
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Models, Molecular
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Molecular Sequence Data
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Phosphorylation
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Protein Kinases / metabolism*
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Protein Structure, Tertiary
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Proteins / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Sequence Homology, Amino Acid
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Serine / metabolism
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Tyrosine 3-Monooxygenase*
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bcl-Associated Death Protein
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bcl-X Protein
Substances
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14-3-3 Proteins
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BAD protein, human
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BCL2L1 protein, human
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Carrier Proteins
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Proteins
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Proto-Oncogene Proteins c-bcl-2
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Recombinant Proteins
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bcl-Associated Death Protein
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bcl-X Protein
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Serine
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Tyrosine 3-Monooxygenase
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Protein Kinases