Members of the MEF2 family of transcription factors bind as homo- and heter
odimers to the MEF2 site found in the promoter regions of numerous muscle-s
pecific, growth- or stress-induced genes. We showed previously that the tra
nsactivation activity of MEF2C is stimulated by p38 mitogen-activated prote
in (MAP) kinase. In this study, we examined the potential role of the p38 M
AP kinase pathway in regulating the other MEF2 family members. We found tha
t MEF2A, but not MEF2B or MEF2D, is a substrate for p38. Among the four p38
group members, p38 is the most potent kinase for MEF2A. Threonines 312 and
319 within the transcription activation domain of MEF2A are the regulatory
sites phosphorylated by p38. Phosphorylation of MEF2A in a MEF2A-MEF2D het
erodimer enhances MEF2-dependent gene expression. These results demonstrate
that the MAP kinase signaling pathway can discriminate between different M
EF2 isoforms and can regulate MEF2-dependent genes through posttranslationa
l activation of preexisting MEF2 protein.