PKA and PDE4D3 anchoring to AKAP9 provides distinct regulation of cAMP signals at the centrosome

Terrin, A. et al. (2012) PKA and PDE4D3 anchoring to AKAP9 provides distinct regulation of cAMP signals at the centrosome. Journal of Cell Biology, 198(4), pp. 607-621. (doi:10.1083/jcb.201201059)

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Publisher's URL: http://dx.doi.org/10.1083/jcb.201201059

Abstract

Previous work has shown that the protein kinase A (PKA)–regulated phosphodiesterase (PDE) 4D3 binds to A kinase–anchoring proteins (AKAPs). One such protein, AKAP9, localizes to the centrosome. In this paper, we investigate whether a PKA–PDE4D3–AKAP9 complex can generate spatial compartmentalization of cyclic adenosine monophosphate (cAMP) signaling at the centrosome. Real-time imaging of fluorescence resonance energy transfer reporters shows that centrosomal PDE4D3 modulated a dynamic microdomain within which cAMP concentration selectively changed over the cell cycle. AKAP9-anchored, centrosomal PKA showed a reduced activation threshold as a consequence of increased autophosphorylation of its regulatory subunit at S114. Finally, disruption of the centrosomal cAMP microdomain by local displacement of PDE4D3 impaired cell cycle progression as a result of accumulation of cells in prophase. Our findings describe a novel mechanism of PKA activity regulation that relies on binding to AKAPs and consequent modulation of the enzyme activation threshold rather than on overall changes in cAMP levels. Further, we provide for the first time direct evidence that control of cell cycle progression relies on unique regulation of centrosomal cAMP/PKA signals.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Zaccolo, Professor Manuela and Jordanides, Ms Niove and Mountford, Dr Joanne
Authors: Terrin, A., Monterisi, S., Stangherlin, A., Zoccarato, A., Koschinski, A., Surdo, N. C., Mongillo, M., Sawa, A., Jordanides, N..E., Mountford, J.C., and Zaccolo, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Journal of Cell Biology
Journal Abbr.:J. Cell Biol.
ISSN:0021-9525
ISSN (Online):1540-8140
Published Online:20 August 2012
Copyright Holders:Copyright © 2012 The Authors
First Published:First published in Journal of Cell Biology 2012 198(4):607-621
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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