title: Protein phosphatase 2A dephosphorylation of phosphoserine 112 plays the gatekeeper role for BAD-mediated apoptosis.
abstract: BAD, a proapoptotic molecule of the BCL2 family, is regulated by reversible phosphorylation. During survival, BAD is sequestered by 14-3-3 through serine 136 phosphorylation and is dissociated from BCL-X(L) through serine 155 phosphorylation. We report that phosphoserine 112 (pSer112) dephosphorylation functions as a gatekeeper for BAD-mediated apoptosis. During apoptosis, dephosphorylation of pSer112 preceded pSer136 dephosphorylation. Dephosphorylation of pSer112 accelerated dephosphorylation of pSer136, and inhibition of pSer112 dephosphorylation prevented pSer136 dephosphorylation, indicating that dephosphorylation of pSer112 is required for dephosphorylation of pSer136. Protein phosphatase 2A (PP2A) is the major pSer112 phosphatase. PP2A competed with 14-3-3 for BAD binding, and survival factor withdrawal enhanced PP2A association with BAD. Dephosphorylation of the critical residue, pSer136, could only be blocked by inhibition of all known subfamilies of serine/threonine phosphatases, suggesting that multiple phosphatases are involved in pSer136 dephosphorylation. Inhibition of PP2A rescued FL5.12 cells from apoptosis, demonstrating a physiologic role for PP2A-mediated pSer112 dephosphorylation. Thus, PP2A dephosphorylation of pSer112 is the key initiating event regulating the activation of BAD during interleukin-3 withdrawal-induced apoptosis.
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Chi-Wu
authors.initials: CW
authors.lastname: Chiang
authors.forename: Cindy
authors.initials: C
authors.lastname: Kanies
authors.forename: Kwang Woon
authors.initials: KW
authors.lastname: Kim
authors.forename: Wei Bin
authors.initials: WB
authors.lastname: Fang
authors.forename: Christina
authors.initials: C
authors.lastname: Parkhurst
authors.forename: Minhui
authors.initials: M
authors.lastname: Xie
authors.forename: Travis
authors.initials: T
authors.lastname: Henry
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Yang
mesh_terms: D048948:14-3-3 Proteins; D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001665:Binding Sites; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008387:Marine Toxins; D051379:Mice; D009154:Mutation; D010080:Oxazoles / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism*; D054648:Protein Phosphatase 2; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein
chemical_list: D048948:14-3-3 Proteins; C494819:BAD protein, human; C494811:BCL2L1 protein, human; C494820:Bad protein, mouse; C494812:Bcl2l1 protein, mouse; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D008387:Marine Toxins; D010080:Oxazoles; D019253:Proto-Oncogene Proteins c-bcl-2; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D010768:Phosphoserine; C059041:calyculin A; D014446:Tyrosine 3-Monooxygenase; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2