Direct interaction between myocyte enhancer factor 2 (MEF2) and protein phosphatase 1alpha represses MEF2-dependent gene expression.
The myocyte enhancer factor 2 (MEF2) transcription factors play important roles in neuronal, cardiac, and skeletal muscle tissues. MEF2 serves as a nuclear sensor, integrating signals from several signaling cascades through protein-protein interactions with kinases, chromatin remodeling factors, and other transcriptional regulators. Here, we report a novel interaction between the catalytic subunit of protein phosphatase 1alpha (PP1alpha) and MEF2. Interaction occurs within the nucleus, and binding of PP1alpha to MEF2 potently represses MEF2-dependent transcription. The interaction utilizes uncharacterized domains in both PP1alpha and MEF2, and PP1alpha phosphatase activity is not obligatory for MEF2 repression. Moreover, a MEF2-PP1alpha regulatory complex leads to nuclear retention and recruitment of histone deacetylase 4 to MEF2 transcription complexes. PP1alpha-mediated repression of MEF2 overrides the positive influence of calcineurin signaling, suggesting PP1alpha exerts a dominant level of control over MEF2 function. Indeed, PP1alpha-mediated repression of MEF2 function interferes with the prosurvival effect of MEF2 in primary hippocampal neurons. The PP1alpha-MEF2 interaction constitutes a potent locus of control for MEF2-dependent gene expression, having potentially important implications for neuronal cell survival, cardiac remodeling in disease, and terminal differentiation of vascular, cardiac, and skeletal muscle.
Perry
R L S
RL
Department of Biology, York University, 4700 Keele St., Toronto, Ontario, Canada M3J 1P3. jmcderm@yorku.ca.
Yang
C
C
Soora
N
N
Salma
J
J
Marback
M
M
Naghibi
L
L
Ilyas
H
H
Chan
J
J
Gordon
J W
JW
McDermott
J C
JC
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D026161:MADS Domain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D008954:Models, Biological; D008969:Molecular Sequence Data; D018006:Myogenic Regulatory Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D054645:Protein Phosphatase 1 / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; D018006:Myogenic Regulatory Factors; D011993:Recombinant Fusion Proteins; D054645:Protein Phosphatase 1