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Molecular and Cellular Biology, June 1999, p. 4028-4038, Vol. 19, No. 6
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Targeting of p38 Mitogen-Activated Protein Kinases to MEF2 Transcription Factors

Shen-Hsi Yang,dagger Alex Galanis,dagger and Andrew D. Sharrocks*

Department of Biochemistry and Genetics, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, United Kingdom

Received 28 December 1998/Returned for modification 8 February 1999/Accepted 12 March 1999

Mitogen-activated protein (MAP) kinase-mediated signalling to the nucleus is an important event in the conversion of extracellular signals into a cellular response. However, the existence of multiple MAP kinases which phosphorylate similar phosphoacceptor motifs poses a problem in maintaining substrate specificity and hence the correct biological response. Both the extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) subfamilies of MAP kinases use a second specificity determinant and require docking to their transcription factor substrates to achieve maximal substrate activation. In this study, we demonstrate that among the different MAP kinases, the MADS-box transcription factors MEF2A and MEF2C are preferentially phosphorylated and activated by the p38 subfamily members p38alpha and p38beta 2. The efficiency of phosphorylation in vitro and transcriptional activation in vivo of MEF2A and MEF2C by these p38 subtypes requires the presence of a kinase docking domain (D-domain). Furthermore, the D-domain from MEF2A is sufficient to confer p38 responsiveness on different transcription factors, and reciprocal effects are observed upon the introduction of alternative D-domains into MEF2A. These results therefore contribute to our understanding of signalling to MEF2 transcription factors and demonstrate that the requirement for substrate binding by MAP kinases is an important facet of three different subclasses of MAP kinases (ERK, JNK, and p38).

* Corresponding author. Present address: School of Biological Sciences, 2.205 Stopford Building, University of Manchester, Oxford Rd., Manchester M13 9PT, United Kingdom. Phone: 0044-161 275 5979. Fax: 0044-161 275 5082. E-mail: a.d.sharrocks{at}man.ac.uk.

dagger Present address: School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.

Molecular and Cellular Biology, June 1999, p. 4028-4038, Vol. 19, No. 6
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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