Feedback regulation mediated by Bcl-2 and DARPP-32 regulates inositol 1,4,5-trisphosphate receptor phosphorylation and promotes cell survival

Proc Natl Acad Sci U S A. 2014 Jan 21;111(3):1186-91. doi: 10.1073/pnas.1323098111. Epub 2014 Jan 6.

Abstract

Bcl-2 interacts with the inositol 1,4,5-trisphosphate receptor (InsP3R) and thus prevents InsP3-induced Ca(2+) elevation that induces apoptosis. Here we report that Bcl-2 binds dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), a protein kinase A (PKA)-activated and calcineurin (CaN)-deactivated inhibitor of protein phosphatase 1 (PP1). Bcl-2 docks DARPP-32 and CaN in a complex on the InsP3R, creating a negative feedback loop that prevents exaggerated Ca(2+) release by decreasing PKA-mediated InsP3R phosphorylation. T-cell activation increases PKA activity, phosphorylating both the InsP3R and DARPP-32. Phosphorylated DARPP-32 inhibits PP1, enhancing InsP3R phosphorylation and Ca(2+) release. Elevated Ca(2+) activates CaN, which dephosphorylates DARPP-32 to dampen Ca(2+) release by eliminating PP1 inhibition to enable it to dephosphorylate the InsP3R. Knocking down either Bcl-2 or DARPP-32 abrogates this feedback mechanism, resulting in increased Ca(2+) elevation and apoptosis. This feedback mechanism appears to be exploited by high levels of Bcl-2 in chronic lymphocytic leukemia cells, repressing B-cell receptor-induced Ca(2+) elevation and apoptosis.

Keywords: calcium; cancer; lymphocyte; signal transduction; signaling.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Brain / metabolism
  • Calcineurin / metabolism
  • Calcium / metabolism
  • Cell Line, Tumor
  • Cell Survival
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Dopamine and cAMP-Regulated Phosphoprotein 32 / metabolism*
  • Gene Expression Regulation*
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism*
  • Jurkat Cells
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
  • Mice
  • Phosphorylation
  • Protein Binding
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • RNA Interference
  • Signal Transduction

Substances

  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • Inositol 1,4,5-Trisphosphate Receptors
  • PPP1R1B protein, human
  • Ppp1r1b protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • Cyclic AMP-Dependent Protein Kinases
  • Calcineurin
  • Calcium