Skip to main content

Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56δ stabilizes its antiapoptotic activity.

Publication ,  Journal Article
Low, ICC; Loh, T; Huang, Y; Virshup, DM; Pervaiz, S
Published in: Blood
October 2, 2014

Bcl-2 is frequently overexpressed in hematopoietic malignancies, and selective phosphorylation at ser70 enhances its antiapoptotic activity. Phospho-ser70 is dephosphorylated by specific heterotrimers of protein phosphatase 2A (PP2A). We report here that a mild pro-oxidant intracellular milieu induced by either pharmacological inhibition or genetic knockdown of superoxide dismutase 1 (SOD1) inhibits the functional holoenzyme assembly of PP2A and prevents Bcl-2 ser70 dephosphorylation. This redox-dependent regulation of Bcl-2 phosphorylation is due to nitrosative modification of B56δ, which we identify as the regulatory subunit mediating PP2A-dependent Bcl-2 dephosphorylation. Redox inhibition of PP2A results from peroxynitrite-mediated nitration of a conserved tyrosine residue within B56δ (B56δ(Y289)). Although nitrated B56δ(Y289) binds efficiently to ser70-phosphorylated Bcl-2, this specific modification inhibits the recruitment of the PP2A catalytic core (A and C subunits). Furthermore, inhibition of B56δ(Y289) nitration restores PP2A holoenzyme assembly, thereby permitting S70 dephosphorylation of Bcl-2 and inhibiting its antiapoptotic activity. More important, in primary cells derived from clinical lymphomas, Bcl-2 phosphorylation at S70 directly correlates with B56δ nitration and repression of SOD1, but inversely correlates with B56δ interaction with the PP2A-C catalytic subunit. These data underscore the role of a pro-oxidant milieu in chemoresistance of hematopoietic and other cancers via selective targeting of tumor suppressors such as PP2A.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

October 2, 2014

Volume

124

Issue

14

Start / End Page

2223 / 2234

Location

United States

Related Subject Headings

  • Tyrosine
  • Superoxide Dismutase-1
  • Superoxide Dismutase
  • Serine
  • Proto-Oncogene Proteins c-bcl-2
  • Protein Phosphatase 2
  • Phosphorylation
  • Oxidation-Reduction
  • Nitrogen
  • Neoplasms
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Low, I. C. C., Loh, T., Huang, Y., Virshup, D. M., & Pervaiz, S. (2014). Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56δ stabilizes its antiapoptotic activity. Blood, 124(14), 2223–2234. https://doi.org/10.1182/blood-2014-03-563296
Low, Ivan Cherh Chiet, Thomas Loh, Yiqing Huang, David M. Virshup, and Shazib Pervaiz. “Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56δ stabilizes its antiapoptotic activity.Blood 124, no. 14 (October 2, 2014): 2223–34. https://doi.org/10.1182/blood-2014-03-563296.
Low ICC, Loh T, Huang Y, Virshup DM, Pervaiz S. Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56δ stabilizes its antiapoptotic activity. Blood. 2014 Oct 2;124(14):2223–34.
Low, Ivan Cherh Chiet, et al. “Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56δ stabilizes its antiapoptotic activity.Blood, vol. 124, no. 14, Oct. 2014, pp. 2223–34. Pubmed, doi:10.1182/blood-2014-03-563296.
Low ICC, Loh T, Huang Y, Virshup DM, Pervaiz S. Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56δ stabilizes its antiapoptotic activity. Blood. 2014 Oct 2;124(14):2223–2234.

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

October 2, 2014

Volume

124

Issue

14

Start / End Page

2223 / 2234

Location

United States

Related Subject Headings

  • Tyrosine
  • Superoxide Dismutase-1
  • Superoxide Dismutase
  • Serine
  • Proto-Oncogene Proteins c-bcl-2
  • Protein Phosphatase 2
  • Phosphorylation
  • Oxidation-Reduction
  • Nitrogen
  • Neoplasms