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

Gregory Kranias; Lauren F Watt; Helen Carpenter; Jeff Holst; Russell Ludowyke; Stefan Strack; Alistair T.R Sim; Nicole M Verrills

doi:10.1016/j.cellsig.2010.07.017

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

Journal article

Peer reviewed

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

Gregory Kranias, Lauren F Watt, Helen Carpenter, Jeff Holst, Russell Ludowyke, Stefan Strack, Alistair T.R Sim and Nicole M Verrills

Cellular signalling, Vol.22(12), pp.1882-1890

2010

DOI: 10.1016/j.cellsig.2010.07.017

PMID: 20688157

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Abstract

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.

Degranulation

p38 MAP kinase

Mast cell

PP2A

Asthma

Details

Title: Subtitle: Protein phosphatase 2A carboxymethylation and regulatory B subunits differentially regulate mast cell degranulation
Creators: Gregory Kranias - School of Biomedical Sciences, Faculty of Health, University of Newcastle, Callaghan, NSW 2308, Australia
Lauren F Watt - School of Biomedical Sciences, Faculty of Health, University of Newcastle, Callaghan, NSW 2308, Australia
Helen Carpenter - School of Biomedical Sciences, Faculty of Health, University of Newcastle, Callaghan, NSW 2308, Australia
Jeff Holst - Centre for Immunology, St. Vincent's Hospital, University of New South Wales, Sydney, NSW 2010, Australia
Russell Ludowyke - Centre for Immunology, St. Vincent's Hospital, University of New South Wales, Sydney, NSW 2010, Australia
Stefan Strack - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
Alistair T.R Sim - School of Biomedical Sciences, Faculty of Health, University of Newcastle, Callaghan, NSW 2308, Australia
Nicole M Verrills - School of Biomedical Sciences, Faculty of Health, University of Newcastle, Callaghan, NSW 2308, Australia
Resource Type: Journal article
Publication Details: Cellular signalling, Vol.22(12), pp.1882-1890
Publisher: Elsevier Inc
DOI: 10.1016/j.cellsig.2010.07.017
PMID: 20688157
ISSN: 0898-6568
eISSN: 1873-3913
Language: English
Date published: 2010
Academic Unit: Pathology; Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9984040467502771

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