The mAKAPβ scaffold regulates cardiac myocyte hypertrophy via recruitment of activated calcineurin

Abstract

mAKAPβ is the scaffold for a multimolecular signaling complex in cardiac myocytes that is required for the induction of neonatal myocyte hypertrophy. We now show that the pro-hypertrophic phosphatase calcineurin binds directly to a single site on mAKAPβ that does not conform to any of the previously reported consensus binding sites. Calcineurin–mAKAPβ complex formation is increased in the presence of Ca 2+/calmodulin and in norepinephrine-stimulated primary cardiac myocytes. This binding is of functional significance because myocytes exhibit diminished norepinephrine-stimulated hypertrophy when expressing a mAKAPβ mutant incapable of binding calcineurin. In addition to calcineurin, the transcription factor NFATc3 also associates with the mAKAPβ scaffold in myocytes. Calcineurin bound to mAKAPβ can dephosphorylate NFATc3 in myocytes, and expression of mAKAPβ is required for NFAT transcriptional activity. Taken together, our results reveal the importance of regulated calcineurin binding to mAKAPβ for the induction of cardiac myocyte hypertrophy. Furthermore, these data illustrate how scaffold proteins organizing localized signaling complexes provide the molecular architecture for signal transduction networks regulating key cellular processes.