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J. Biol. Chem., Vol. 281, Issue 7, 4423-4433, February 17, 2006
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Control of MEF2 Transcriptional Activity by Coordinated Phosphorylation and Sumoylation*
1
2
From the
Molecular Oncology Group, Department of Medicine, McGill University Health Centre, Montreal, Quebec H3A 1A1, Canada, the Departments of Pharmacology and Neurology, Emory University School of Medicine, Atlanta, Georgia 30322, and the ¶Department of Biochemistry, Hong Kong University of Science and Technology, Clearwater Bay, Kowloon, Hong Kong, China
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 presented 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 identified an essential role for Ser-444 in MEF2D sumoylation and revealed 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.
Received for publication, August 26, 2005 , and in revised form, December 14, 2005.
* This work was supported in part by grants from the Canadian Cancer Society through the National Cancer Institute of Canada, by Canadian Institutes for Health Research (to V. G. and X.-J. Y.), and by National Institutes of Health Grant HD39446 (to Z. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Recipient of a Canadian Institutes for Health Research graduate scholarship.
2 To whom correspondence should be addressed: MUHC-RVH, Rm. H5.41, 687 Pine Ave. West, Montreal, Quebec H3A 1A1, Canada. Tel.: 514-934-1934 (Ext. 34490); Fax: 514-843-1478; E-mail: xiang-jiao.yang{at}mcgill.ca.
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