Abstract
The BH3 domain of BAD mediates its death-promoting activities via heterodimerization to the Bcl-XL family of death regulators. Growth and survival factors inhibit the death-promoting activity of BAD by stimulating phosphorylation at multiple sites including Ser-112 and Ser-136. Phosphorylation at these sites promotes binding of BAD to 14-3-3 proteins, sequestering BAD away from the mitochondrial membrane where it dimerizes with Bcl-XL to exert its killing effects. We report here that the phosphorylation of BAD at Ser-155 within the BH3 domain is a second phosphorylation-dependent mechanism that inhibits the death-promoting activity of BAD. Protein kinase A, RSK1, and survival factor signaling stimulate phosphorylation of BAD at Ser-155, blocking the binding of BAD to Bcl-XL. RSK1 phosphorylates BAD at both Ser-112 and Ser-155 and rescues BAD-mediated cell death in a manner dependent upon phosphorylation at both sites.
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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Carrier Proteins / chemistry*
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Line
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Cell Survival
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Cytoplasm / metabolism
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DNA, Complementary / metabolism
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Glutathione Transferase / metabolism
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Humans
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Immunoblotting
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Mitochondria / metabolism
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Mitogen-Activated Protein Kinases / metabolism
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Molecular Sequence Data
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Mutagenesis, Site-Directed
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Phosphorylation
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Plasmids / metabolism
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Precipitin Tests
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Protein Structure, Tertiary
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Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / chemistry*
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Recombinant Fusion Proteins / metabolism
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Ribosomal Protein S6 Kinases, 90-kDa*
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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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DNA, Complementary
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Proteins
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Proto-Oncogene Proteins c-bcl-2
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Recombinant Fusion 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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Glutathione Transferase
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RPS6KA1 protein, human
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Ribosomal Protein S6 Kinases, 90-kDa
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Cyclic AMP-Dependent Protein Kinases
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Mitogen-Activated Protein Kinases