- Title
- Protein phosphatase 2A carboxymethylation and regulatory B subunits differentially regulate mast cell degranulation
- Creator
- Kranias, Gregory; Watt, Lauren F.; Carpenter, Helen; Holst, Jeff; Ludowyke, Russell; Strack, Stefan; Sim, Alistair T. R.; Verrills, Nicole M.
- Relation
- Cellular Signalling Vol. 22, Issue 12, p. 1882-1890
- Publisher Link
- http://dx.doi.org/10.1016/j.cellsig.2010.07.017
- Publisher
- Elsevier
- Resource Type
- journal article
- Date
- 2010
- Description
- 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 μM) inhibits mast cell degranulation. Strikingly, we now show that a low concentration of okadaic acid (0.1 μM) 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.
- Subject
- mast cell; asthma; degranulation; PP2A; p38 MAP kinase
- Identifier
- http://hdl.handle.net/1959.13/927462
- Identifier
- uon:10155
- Identifier
- ISSN:0898-6568
- Language
- eng
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