Journal
CELLULAR SIGNALLING
Volume 22, Issue 12, Pages 1882-1890Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2010.07.017
Keywords
Mast cell; Asthma; Degranulation; PP2A; p38 MAP kinase
Categories
Funding
- National Health and Medical Research Council of Australia
- Asthma Foundation NSW
- Hunter Medical Research Institute
- University of Newcastle
- Australian Postgraduate Awards
- Cancer Institute NSW
- National Health and Medical Research Council
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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 (1 mu M) inhibits mast cell degranulation. Strikingly, we now show that a low concentration of okadaic acid (0.1 mu M) has the opposite effect, resulting in enhanced degranulation. Selective downregulation of the PP2A-C alpha 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-B alpha subunit resulted in decreased MK2 phosphorylation and degranulation, whilst downregulation of the PP2A-B'delta 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. Crown Copyright (C) 2010 Published by Elsevier Inc. All rights reserved.
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