ERK5 is a novel type of mitogen-activated protein kinase containing a transcriptional activation domain

Previous studies have shown that upregulation of the orphan steroid recepto r Nur77 is required for the apoptosis of immature T cells in response to an tigen receptor signals. Transcriptional upregulation of Nur77 in response t o antigen receptor signaling involves two binding sites for the MEF2 family of transcription factors located in the Nur77 promoter. Calcium signals gr eatly increase the activity of MEF2D in T cells via a posttranslational mec hanism. The mitogen-activated protein (MAP) kinase ERK5 was isolated in a y east two-hybrid screen using the MADS-MEF2 domain of MEF2D as bait. ERK5 re sembles the other MAP kinase family members in its N-terminal half, but it also contains a 400-amino-acid C-terminal domain of previously uncharacteri zed function. We report here that the C-terminal region of ERK5 contains a MEF2-interacting domain and, surprisingly, also a potent transcriptional ac tivation domain. These domains are both required for coactivation of MEF2D by ERK5. The MEF2-ERK5 interaction was found to be activation dependent in vivo and inhibitable in vitro by the calcium-sensitive MEF2 repressor Cabin 1. The transcriptional activation domain of ERK5 is required for maximal M EF2 activity in response to calcium flux in T cells, and it can activate th e endogenous Nur77 gene when constitutively recruited to the Nur77 promoter via MEF2 sites. These studies provide insights into a mechanism whereby ME F2 activity can respond to calcium signaling and suggest a novel, unexpecte d mechanism of MAP kinase function.