Phosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation

MacKenzie, K. F., Wallace, D. A., Hill, E. V., Anthony, D. F., Henderson, D. J.P., Houslay, D. M., Arthur, J. S. C., Baillie, G. S. and Houslay, M. D. (2011) Phosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation. Biochemical Journal, 435(3), pp. 755-769. (doi:10.1042/BJ20101184)

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Publisher's URL: http://dx.doi.org/10.1042/BJ20101184

Abstract

Cyclic AMP phosphodiesterase-4 (PDE4) isoforms underpin compartmentalised cAMP signalling in mammalian cells through targeting to specific signalling complexes. Their importance is apparent as PDE4 selective inhibitors exert profound anti-inflammatory effects and act as cognitive enhancers. The p38 MAPK signalling cascade is a key signal transduction pathway involved in the control of cellular immune, inflammatory and stress responses. Here we show that phosphodiesterase-4A5 (PDE4A5) is phosphorylated at Ser147, within the regulatory UCR1 domain conserved amongst PDE4 long isoforms, by the p38 MAPK activated kinase, MK2 (MAPKAPK2). Phosphorylation by MK2, while not altering PDE4A5 activity, markedly attenuates PDE4A5 activation through phosphorylation by protein kinase A (PKA). This modification confers amplification of intracellular cAMP accumulation in response to adenylyl cyclase activation by attenuating a major desensitization system to cAMP. Such re-programming of cAMP accumulation is recapitulated in wild-type primary macrophages, but not MK2/3 null macrophages. Phosphorylation by MK2 also triggers a conformational change in PDE4A5 that attenuates PDE4A5 interaction with proteins whose binding involves UCR2, such as DISC1 and AIP, but not the UCR2-independent interacting scaffold protein, beta-arrestin. Long PDE4 isoforms thus provide a novel node for cross-talk between the cAMP and p38 MAPK signalling systems at the level of MK2.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Houslay, Professor Miles and Baillie, Professor George and Anthony, Dr Diana
Authors: MacKenzie, K. F., Wallace, D. A., Hill, E. V., Anthony, D. F., Henderson, D. J.P., Houslay, D. M., Arthur, J. S. C., Baillie, G. S., and Houslay, M. D.
College/School:College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Biochemical Journal
Publisher:Portland Press Ltd.
ISSN:0264-6021
ISSN (Online):1470-8728
Published Online:13 April 2011
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
438301Phosphodiesterase-4 isoforms - intracellular targeting, regulation and potential therapeutic targetsMiles HouslayMedical Research Council (MRC)G0600765Institute of Neuroscience and Psychology
432501Transatlantic networks of excellence in cardiovascular diseaseMiles HouslayFoundation Leducq (LEDUCQ-VIL)06 CVD 02Institute of Neuroscience and Psychology