“Shaping” of cell signaling via AKAP-tethered PDE4D: Probing with AKAR2-AKAP5 biosensor

Journal of Molecular Signaling

Craig C Malbon²  Hsien-yu Wang¹  Salih S Koçer² 

[1] Department of Physiology and Biophysics, SUNY at Stony Brook, School of Medicine, Stony Brook, New York 11794-8661, USA;Department of Pharmacological Sciences, Health Sciences Center, BST-7, SUNY at Stony Brook, School of Medicine, Stony Brook, New York 11794-8651, USA

关键词: Tethered;    Scaffold;    Protein kinase A;    PDE4D;    β-adrenergic receptor;    AKAR2;    AKAP12;    AKAP5;   

Others  :  803081
DOI  :  10.1186/1750-2187-7-4

 received in 2012-03-22, accepted in 2012-04-15,  发布年份 2012

【 摘 要 】

Background

PKA, a key regulator of cell signaling, phosphorylates a diverse and important array of target molecules and is spatially docked to members of the A-kinase Anchoring Protein (AKAP) family. AKAR2 is a biosensor which yields a FRET signal in vivo, when phosphorylated by PKA. AKAP5, a prominent member of the AKAP family, docks several signaling molecules including PKA, PDE4D, as well as GPCRs, and is obligate for the propagation of the activation of the mitogen-activated protein kinase cascade from GPCRs to ERK1,2.

Results

Using an AKAR2-AKAP5 fusion “biosensor”, we investigated the spatial-temporal activation of AKAP5 undergoing phosphorylation by PKA in response to β-adrenergic stimulation. The pattern of PKA activation reported by AKAR2-AKAP5 is a more rapid and spatially distinct from those “sensed” by AKAR2-AKAP12. Spatial-temporal restriction of activated PKA by AKAP5 was found to “shape” the signaling response. Phosphatase PDE4D tethered to AKAP5 also later reverses within 60 s elevated intracellular cyclic AMP levels stimulated by β-adrenergic agonist. AKAP12, however, fails to attenuate the rise in cyclic AMP over this time. Fusion of the AKAP5 PDE4D-binding-domain to AKAP12 was found to accelerate a reversal of accumulation of intracellular cyclic AMP.

Conclusion

AKAPs, which are scaffolds with tethered enzymes, can “shape” the temporal and spatial aspects of cell signaling.

【 授权许可】

   
2012 Kocer et al.; licensee BioMed Central Ltd.

【 图 表 】

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