BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C

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Abstract
Big MAP kinase 1 (BMK1), also known as ERK5, is a mitogen‐activated protein (MAP) kinase member whose biological role is largely undefined. We have shown previously that the activity of BMK1 in rat smooth muscle cells is up‐regulated by oxidants. Here, we describe a constitutively active form of the MAP kinase kinase, MEK5(D), which selectively activates BMK1 but not other MAP kinases in vivo . Through utilization of MEK5(D), we have determined that a member of the MEF2 transcription factor family, MEF2C, is a protein substrate of BMK1. BMK1 dramatically enhances the transactivation activity of MEF2C by phosphorylating a serine residue at amino acid position 387 in this transcription factor. Serum is also a potent stimulator of BMK1‐induced MEF2C phosphorylation, since a dominant‐negative form of BMK1 specifically inhibits serum‐induced activation of MEF2C. One consequence of MEF2C activation is increased transcription of the c‐ jun gene. Taken together, these results strongly suggest that in some cell types the MEK5/BMK1 MAP kinase signaling pathway regulates serum‐induced early gene expression through the transcription factor MEF2C.