Protein phosphatase 2A carboxymethylation and regulatory B subunits differentially regulate mast cell degranulation

Cell Signal. 2010 Dec;22(12):1882-90. doi: 10.1016/j.cellsig.2010.07.017. Epub 2010 Aug 2.


Asthma is characterised by antigen-mediated mast cell degranulation resulting in secretion of inflammatory mediators. Protein phosphatase 2A (PP2A) is a serine/threonine protein phosphatase composed of a catalytic (PP2A-C) subunit together with a core scaffold (PP2A-A) subunit and a variable, regulatory (PP2A-B) subunit. Previous studies utilising pharmacological inhibition of protein phosphatases have suggested a positive regulatory role for PP2A in mast cell degranulation. In support of this we find that a high okadaic acid concentration (1μM) inhibits mast cell degranulation. Strikingly, we now show that a low concentration of okadaic acid (0.1μM) has the opposite effect, resulting in enhanced degranulation. Selective downregulation of the PP2A-Cα subunit by short hairpin RNA also enhanced degranulation of RBL-2H3 mast cells, suggesting that the primary role of PP2A is to negatively regulate degranulation. PP2A-B subunits are responsible for substrate specificity, and carboxymethylation of the PP2A-C subunit alters B subunit binding. We show here that carboxymethylation of PP2A-C is dynamically altered during degranulation and inhibition of methylation decreases degranulation. Moreover downregulation of the PP2A-Bα subunit resulted in decreased MK2 phosphorylation and degranulation, whilst downregulation of the PP2A-B'δ subunit enhanced p38 MAPK phosphorylation and degranulation. Taken together these data show that PP2A is both a positive and negative regulator of mast cell degranulation, and this differential role is regulated by carboxymethylation and specific PP2A-B subunit binding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Degranulation / physiology*
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • Mast Cells / physiology*
  • Methylation
  • Models, Biological
  • Okadaic Acid / pharmacology
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism
  • Phosphoprotein Phosphatases / physiology
  • Phosphorylation
  • Protein Phosphatase 2 / metabolism*
  • Protein Subunits / metabolism*
  • RNA, Small Interfering / metabolism
  • Rats
  • Transfection
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Protein Subunits
  • RNA, Small Interfering
  • Okadaic Acid
  • p38 Mitogen-Activated Protein Kinases
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2