Protein phosphatase 2A dephosphorylation of phosphoserine 112 plays the gatekeeper role for BAD-mediated apoptosis

Chi-Wu Chiang, Cindy Kanies, Kwang Woon Kim, Wei Bin Fang, Christina Parkhurst, Minhui Xie, Travis Henry, Elizabeth Yang

Research output: Contribution to journalArticle

124 Citations (Scopus)

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-XL 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 withdrawall-induced apoptosis.

Original languageEnglish
Pages (from-to)6350-6362
Number of pages13
JournalMolecular and Cellular Biology
Volume23
Issue number18
DOIs
Publication statusPublished - 2003 Sep 1

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Phosphoserine
Protein Phosphatase 2
Apoptosis
Phosphorylation
Serine
Interleukin-3
Phosphoprotein Phosphatases
Phosphoric Monoester Hydrolases

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Chiang, Chi-Wu ; Kanies, Cindy ; Kim, Kwang Woon ; Fang, Wei Bin ; Parkhurst, Christina ; Xie, Minhui ; Henry, Travis ; Yang, Elizabeth. / Protein phosphatase 2A dephosphorylation of phosphoserine 112 plays the gatekeeper role for BAD-mediated apoptosis. In: Molecular and Cellular Biology. 2003 ; Vol. 23, No. 18. pp. 6350-6362.
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Protein phosphatase 2A dephosphorylation of phosphoserine 112 plays the gatekeeper role for BAD-mediated apoptosis. / Chiang, Chi-Wu; Kanies, Cindy; Kim, Kwang Woon; Fang, Wei Bin; Parkhurst, Christina; Xie, Minhui; Henry, Travis; Yang, Elizabeth.

In: Molecular and Cellular Biology, Vol. 23, No. 18, 01.09.2003, p. 6350-6362.

Research output: Contribution to journalArticle

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AU - Chiang, Chi-Wu

AU - Kanies, Cindy

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