Targeting of p38 mitogen-activated protein kinases to MEF2 transcription factors

Mitogen-activated protein (MAP) kinase-mediated signalling to the nucleus i s an important event in the conversion of extracellular signals into a cell ular response. However, the existence of multiple MAP kinases which phospho rylate similar phosphoacceptor motifs poses a problem in maintaining substr ate specificity and hence the correct biological response. Both the extrace llular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) su bfamilies of MAP kinases use a second specificity determinant and require d ocking; to their transcription factor substrates to achieve maximal substra te activation. In this study, we demonstrate that among the different MAP k inases, the MADS-box transcription factors MEF2A and MEF2C are preferential ly phosphorylated and activated by the p38 subfamily members p38 alpha and p38 beta(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 f rom MEF2A is sufficient to confer p38 responsiveness on different transcrip tion 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 far substrate binding by MAP kinases is an important f acet of three different subclasses of MAP kinases (ERK, JNK, and p38).