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

Anna Terrin, Stefania Monterisi, Alessandra Stangherlin, Anna Zoccarato, Andreas Koschinski, Nicoletta C. Surdo, Marco Mongillo, Akira Sawa, Niove E. Jordanides, Joanne C. Mountford, Manuela Zaccolo

Research output: Contribution to journalArticlepeer-review

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. AP9-anchored, centrosomal PKA showed a reduced activation threshold as a consequence of increased auto-phosphorylation 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.

Original languageEnglish (US)
Pages (from-to)607-621
Number of pages15
JournalJournal of Cell Biology
Volume198
Issue number4
DOIs
StatePublished - Aug 2012

ASJC Scopus subject areas

  • Cell Biology

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