The transcription factor MEF2D plays an essential role in the negative selection of immature T cells whereby potentially autoreactive T cells undergo apoptosis. Unlike other members of the MEF2 family, MEF2D does not appear to be regulated by phosphorylation but may be controlled through interactions with other proteins. One such protein is the repressor Cabin 1, which inhibits MEF2D activity. Kasler et al. identified the extracellular signal-regulated and mitogen-activated protein kinase ERK5 in a yeast two-hybrid screen for additional binding partners for MEF2D. T cells transfected with both ERK5 and MEF2D demonstrated a 50-fold increase in reporter gene activity when treated with T cell activators. This enhanced MEF2D transcriptional activation in the presence of full-length ERK5 was dependent on the catalytic activity of ERK5; however, the COOH-terminal region of ERK5 was able to stimulate MEF2D transcriptional activity alone, suggesting that activation of the kinase domain relieves an inhibitory interaction with the COOH-domain, allowing the ERK5-MEF2D interaction to occur. Expression of fusion proteins between the ERK5 COOH-terminal domain and DNA binding domains from either GAL4 or MEF2D demonstrated that the ERK5 COOH-terminal domain can itself act as a transcriptional activator. Cabin 1 was able to compete with ERK5 for MEF2D binding, suggesting the ERK5-MEF2D interaction would require dissociation of Cabin 1 from MEF2D. Thus, the authors propose that T cell activation leads to dissociation of Cabin 1 from MEF2D and activation of ERK5, which alleviates the inhibition of MEF2D-ERK5 binding by the catalytic domain of ERK5. Then, the DNA binding domain of MEF2D may specify the recruitment of the ERK5 transcriptional activator to specific promoters.
Kasler, H.G., Victoria, J., Duramad, O., and Winoto, A. (2000) ERK5 is a novel type of mitogen-activated protein kinase containing a transcriptional activation domain. Mol. Cell. Biol. 20: 8382-8389. [Abstract] [Full Text]