Control of MEF2 transcriptional activity by coordinated phosphorylation and sumoylation.
A eukaryotic protein is often subject to regulation by multiple modifications like phosphorylation, acetylation, ubiquitination, and sumoylation. How these modifications are coordinated in vivo is an important issue that is poorly understood but is relevant to many biological processes. We recently showed that human MEF2D (myocyte enhancer factor 2D) is sumoylated on Lys-439. Adjacent to the sumoylation motif is Ser-444, which like Lys-439 is highly conserved among MEF2 proteins from diverse species. Here we present [corrected] several lines of evidence to demonstrate that Ser-444 of MEF2D is required for sumoylation of Lys-439. Histone deacetylase 4 (HDAC4) stimulated this modification by acting through Ser-444. In addition, phosphorylation of Ser-444 by Cdk5, a cyclin-dependent kinase known to inhibit MEF2 transcriptional activity, stimulated sumoylation. Opposing the actions of HDAC4 and Cdk5, calcineurin (also known as protein phosphatase 2B) dephosphorylated Ser-444 and inhibited sumoylation of Lys-439. This phosphatase, however, exerted minimal effects on the phosphorylation catalyzed by ERK5, an extracellular signal-regulated kinase known to activate MEF2D. These results identify [corrected] an essential role for Ser-444 in MEF2D sumoylation and reveal [corrected] a novel mechanism by which calcineurin selectively "edits" phosphorylation at different sites, thereby reiterating that interplay between different modifications represents a general mechanism for coordinated regulation of eukaryotic protein functions in vivo.
Grégoire
Serge
S
Molecular Oncology Group, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada.
Tremblay
Annie M
AM
Xiao
Lin
L
Yang
Qian
Q
Ma
Kewei
K
Nie
Jianyun
J
Mao
Zixu
Z
Wu
Zhenguo
Z
Giguère
Vincent
V
Yang
Xiang-Jiao
XJ
D000595:Amino Acid Sequence; D019703:Calcineurin / Q000502:physiology; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000502:physiology; D006655:Histone Deacetylases / Q000494:pharmacology; D006801:Humans; D026161:MADS Domain Proteins / Q000235:genetics* / Q000378:metabolism; D064326:MEF2 Transcription Factors; D008969:Molecular Sequence Data; D018006:Myogenic Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D012097:Repressor Proteins / Q000494:pharmacology; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D014158:Transcription, Genetic
D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578043:MEF2D protein, human; D018006:Myogenic Regulatory Factors; D012097:Repressor Proteins; C117909:SUMO2 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; D019703:Calcineurin; C400300:HDAC4 protein, human; D006655:Histone Deacetylases