title: Regulation of MEF2 transcriptional activity by calcineurin/mAKAP complexes.
abstract: 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.
authors.affiliation: Cardiac Signal Transduction and Cellular Biology Laboratory, Interdisciplinary Stem Cell Institute, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL 33101, United States.
authors.forename: Jinliang
authors.initials: J
authors.lastname: Li
authors.forename: Maximilian A X
authors.initials: MA
authors.lastname: Vargas
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kapiloff
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Dodge-Kafka
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D064326:MEF2 Transcription Factors; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic
chemical_list: D054758:A Kinase Anchor Proteins; C484293:Akap6 protein, rat; D064326:MEF2 Transcription Factors; D046912:Multiprotein Complexes; D018006:Myogenic Regulatory Factors; D019703:Calcineurin