Muscle A-kinase-anchoring protein-{beta}-bound calcineurin toggles active and repressive transcriptional complexes of myocyte enhancer factor 2D [Cell Biology] (Journal of Biological Chemistry)

Myocyte enhancer factor 2 (MEF2) transcription factors are key regulators of the development and adult phenotype of diverse tissues, including skeletal and cardiac muscles. Controlled by multiple post-translational modifications, MEF2D is an effector for the Ca2+/calmodulin-dependent protein phosphatase calcineurin (CaN, PP2B, and PPP3). CaN-catalyzed dephosphorylation promotes the desumoylation and acetylation of MEF2D, increasing its transcriptional activity. Both MEF2D and CaN bind the scaffold protein muscle A-kinase-anchoring protein ? (mAKAP?), which is localized to the nuclear envelope, such that C2C12 skeletal myoblast differentiation and neonatal rat ventricular myocyte hypertrophy are inhibited by mAKAP? signalosome targeting. Using immunoprecipitation and DNA-binding assays, we now show that the formation of mAKAP? signalosomes is required for MEF2D dephosphorylation, desumoylation, and acetylation in C2C12 cells. Reduced MEF2D phosphorylation was coupled to a switch from type IIa histone deacetylase to p300 histone acetylase binding that correlated with increased MEF2D-dependent gene expression and ventricular myocyte hypertrophy. Together, these results highlight the importance of mAKAP? signalosomes for regulating MEF2D activity in striated muscle, affirming mAKAP? as a nodal regulator in the myocyte intracellular signaling network.