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Protein Phosphatase 2A Dephosphorylation of Phosphoserine 112 Plays the Gatekeeper Role for BAD-Mediated Apoptosis
- Source :
- Molecular and Cellular Biology. 23:6350-6362
- Publication Year :
- 2003
- Publisher :
- Informa UK Limited, 2003.
-
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.
- Subjects :
- Tyrosine 3-Monooxygenase
Phosphatase
bcl-X Protein
Apoptosis
Biology
environment and public health
Binding, Competitive
Serine
Dephosphorylation
Mice
Phosphoserine
chemistry.chemical_compound
Phosphoprotein Phosphatases
Animals
Humans
Protein Phosphatase 2
Enzyme Inhibitors
Phosphorylation
Threonine
Cell Growth and Development
Oxazoles
Molecular Biology
Cells, Cultured
Binding Sites
3T3 Cells
Cell Biology
Protein phosphatase 2
Cell biology
enzymes and coenzymes (carbohydrates)
14-3-3 Proteins
Proto-Oncogene Proteins c-bcl-2
Biochemistry
chemistry
Mutation
Marine Toxins
bcl-Associated Death Protein
Carrier Proteins
Subjects
Details
- ISSN :
- 10985549
- Volume :
- 23
- Database :
- OpenAIRE
- Journal :
- Molecular and Cellular Biology
- Accession number :
- edsair.doi.dedup.....12cdfd3dc86912a15b2e33d2d0df305d