PKA and PDE4D3 anchoring to AKAP9 provides distinct regulation of cAMP signals at the centrosome.
J Cell Biol
; 198(4): 607-21, 2012 Aug 20.
Article
em En
| MEDLINE
| ID: mdl-22908311
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Proteínas Quinases Dependentes de AMP Cíclico
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AMP Cíclico
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Centrossomo
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Domínio Catalítico
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Proteínas do Citoesqueleto
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Nucleotídeo Cíclico Fosfodiesterase do Tipo 4
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Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico
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Proteínas de Ancoragem à Quinase A
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Cell Biol
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Reino Unido