Regulation of MEF2 transcriptional activity by calcineurin/mAKAP complexes

The calcium/calmodulin-dependent protein phosphatase calcineurin is required for the induction of transcriptional events that initiate and promote myogenic differentiation. An important effector for calcineurin in striated muscle is the transcription factor myocyte enhancer factor 2 (MEF2). The targ...

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Bibliographic Details
Published in:Experimental cell research 2013-02, Vol.319 (4), p.447-454
Main Authors: Li, Jinliang, Vargas, Maximilian A.X., Kapiloff, Michael S., Dodge-Kafka, Kimberly L.
Format: Article
Language:English
Subjects:
A Kinase Anchor Proteins - genetics
A Kinase Anchor Proteins - metabolism
A Kinase Anchor Proteins - physiology
AKAP
Animals
Animals, Newborn
Binding sites
Calcineurin
Calcineurin - genetics
Calcineurin - metabolism
Calcineurin - physiology
Cells, Cultured
Cellular biology
Gene Expression Regulation
MEF2
MEF2 Transcription Factors
Mice
Multiprotein Complexes - genetics
Multiprotein Complexes - metabolism
Multiprotein Complexes - physiology
Muscular system
Myocytes, Cardiac - metabolism
Myocytes, Cardiac - physiology
Myogenic Regulatory Factors - genetics
Myogenic Regulatory Factors - metabolism
Myogenic Regulatory Factors - physiology
Peptides
Protein Binding - physiology
Protein phosphatase
Proteins
Rats
Rats, Sprague-Dawley
Scaffold
Transcription, Genetic
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Summary:The calcium/calmodulin-dependent protein phosphatase calcineurin is required for the induction of transcriptional events that initiate and promote myogenic differentiation. An important effector for calcineurin in striated muscle is the transcription factor myocyte enhancer factor 2 (MEF2). The targeting of the enzyme and substrate to specific intracellular compartments by scaffold proteins often confers specificity in phosphatase activity. We now show that the scaffolding protein mAKAP organizes a calcineurin/MEF2 signaling complex in myocytes, regulating gene transcription. A calcineurin/mAKAP/MEF2 complex can be isolated from C2C12 cells and cardiac myocytes, and the calcineurin/MEF2 association is dependent on mAKAP expression. We have identified a peptide comprising the calcineurin binding domain in mAKAP that can disrupt the binding of the phosphatase to the scaffold in vivo. Dominant interference of calcineurin/mAKAP binding blunts the increase in MEF2 transcriptional activity seen during myoblast differentiation, as well as the expression of endogenous MEF2-target genes. Furthermore, disruption of calcineurin binding to mAKAP in cardiac myocytes inhibits adrenergic-induced cellular hypertrophy. Together these data illustrate the importance of calcineurin anchoring by the mAKAP scaffold for MEF2 regulation. ► Calcineurin regulates MEF2 activity in striated muscle. ► mAKAP is a calcineurin scaffold in striated muscle. ► The mAKAP/calcineurin interaction can be disrupted using a competitive binding peptide. ► Disruption of the interaction prevents differentiation-induced MEF2 gene transcription in C2C12 cells. ► Disruption of the interaction also prevents induction of cardiac hypertrophy in neonatal cardiac myocytes.
ISSN:0014-4827
1090-2422
DOI:10.1016/j.yexcr.2012.12.016