Protein phosphatase 2A carboxymethylation and regulatory B subunits differentially regulate mast cell degranulation
| Autor: | Helen Carpenter, Jeff Holst, Russell I. Ludowyke, Nicole M. Verrills, Alistair T. R. Sim, Lauren F. Watt, Stefan Strack, Gregory Kranias |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Protein subunit
Phosphatase Down-Regulation macromolecular substances Transfection Immunoglobulin E Methylation Models Biological p38 Mitogen-Activated Protein Kinases environment and public health Cell Degranulation chemistry.chemical_compound Cell Line Tumor Okadaic Acid Phosphoprotein Phosphatases medicine Animals Mast Cells Protein Phosphatase 2 Phosphorylation RNA Small Interfering Dose-Response Relationship Drug biology Degranulation Cell Biology Protein phosphatase 2 Okadaic acid Mast cell Molecular biology Rats Protein Subunits enzymes and coenzymes (carbohydrates) medicine.anatomical_structure chemistry embryonic structures biology.protein |
| Zdroj: | Cellular Signalling. 22:1882-1890 |
| ISSN: | 0898-6568 |
| DOI: | 10.1016/j.cellsig.2010.07.017 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect