Regulation of MEF2 transcriptional activity by calcineurin/mAKAP complexes

Jinliang Li, Maximilian A X Vargas, Michael S Kapiloff, Kimberly L. Dodge-Kafka

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)447-454
Number of pages8
JournalExperimental Cell Research
Volume319
Issue number4
DOIs
StatePublished - Feb 15 2013

Fingerprint

MEF2 Transcription Factors
Calcineurin
Phosphoric Monoester Hydrolases
Cardiac Myocytes
Striated Muscle
Myoblasts
Phosphoprotein Phosphatases
Calmodulin
Adrenergic Agents
Muscle Cells
Hypertrophy
Genes
Proteins
Transcription Factors

Keywords

  • AKAP
  • Calcineurin
  • MEF2
  • Protein phosphatase
  • Scaffold

ASJC Scopus subject areas

  • Cell Biology

Cite this

Regulation of MEF2 transcriptional activity by calcineurin/mAKAP complexes. / Li, Jinliang; Vargas, Maximilian A X; Kapiloff, Michael S; Dodge-Kafka, Kimberly L.

In: Experimental Cell Research, Vol. 319, No. 4, 15.02.2013, p. 447-454.

Research output: Contribution to journalArticle

Li, Jinliang ; Vargas, Maximilian A X ; Kapiloff, Michael S ; Dodge-Kafka, Kimberly L. / Regulation of MEF2 transcriptional activity by calcineurin/mAKAP complexes. In: Experimental Cell Research. 2013 ; Vol. 319, No. 4. pp. 447-454.
@article{19bdde1258c94a5fa5743b053ca1b89e,
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.",
keywords = "AKAP, Calcineurin, MEF2, Protein phosphatase, Scaffold",
author = "Jinliang Li and Vargas, {Maximilian A X} and Kapiloff, {Michael S} and Dodge-Kafka, {Kimberly L.}",
year = "2013",
month = "2",
day = "15",
doi = "10.1016/j.yexcr.2012.12.016",
language = "English",
volume = "319",
pages = "447--454",
journal = "Experimental Cell Research",
issn = "0014-4827",
publisher = "Academic Press Inc.",
number = "4",

}

TY - JOUR

T1 - Regulation of MEF2 transcriptional activity by calcineurin/mAKAP complexes

AU - Li, Jinliang

AU - Vargas, Maximilian A X

AU - Kapiloff, Michael S

AU - Dodge-Kafka, Kimberly L.

PY - 2013/2/15

Y1 - 2013/2/15

N2 - 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.

AB - 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.

KW - AKAP

KW - Calcineurin

KW - MEF2

KW - Protein phosphatase

KW - Scaffold

UR - http://www.scopus.com/inward/record.url?scp=84875498777&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875498777&partnerID=8YFLogxK

U2 - 10.1016/j.yexcr.2012.12.016

DO - 10.1016/j.yexcr.2012.12.016

M3 - Article

VL - 319

SP - 447

EP - 454

JO - Experimental Cell Research

JF - Experimental Cell Research

SN - 0014-4827

IS - 4

ER -