title: BAD Ser-155 phosphorylation regulates BAD/Bcl-XL interaction and cell survival.
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.
authors.affiliation: Cell Signaling Technology, Beverly, MA 01915, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Tan
authors.forename: M R
authors.initials: MR
authors.lastname: Demeter
authors.forename: H
authors.initials: H
authors.lastname: Ruan
authors.forename: M J
authors.initials: MJ
authors.lastname: Comb
mesh_terms: D048948:14-3-3 Proteins; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008928:Mitochondria / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D012694:Serine / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein
chemical_list: D048948:14-3-3 Proteins; C494819:BAD protein, human; C494811:BCL2L1 protein, human; D002352:Carrier Proteins; D018076:DNA, Complementary; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D012694:Serine; D014446:Tyrosine 3-Monooxygenase; D005982:Glutathione Transferase; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases