Kato Y, Kravchenko V V, Tapping R I, Han J, Ulevitch R J, Lee J D
The Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
EMBO J. 1997 Dec 1;16(23):7054-66. doi: 10.1093/emboj/16.23.7054.
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.
大丝裂原活化蛋白激酶1（BMK1），也称为细胞外信号调节激酶5（ERK5），是一种丝裂原活化蛋白（MAP）激酶成员，其生物学作用在很大程度上尚不明确。我们之前已经表明，大鼠平滑肌细胞中BMK1的活性受氧化剂上调。在此，我们描述了一种组成型活性形式的丝裂原活化蛋白激酶激酶MEK5（D），其在体内选择性激活BMK1而不激活其他MAP激酶。通过利用MEK5（D），我们确定肌细胞增强因子2（MEF2）转录因子家族的一个成员MEF2C是BMK1的蛋白质底物。BMK1通过磷酸化该转录因子中氨基酸位置387处的丝氨酸残基，显著增强MEF2C的反式激活活性。血清也是BMK1诱导的MEF2C磷酸化的有效刺激物，因为BMK1的显性负性形式特异性抑制血清诱导的MEF2C激活。MEF2C激活的一个结果是c-jun基因转录增加。综上所述，这些结果强烈表明，在某些细胞类型中，MEK5/BMK1 MAP激酶信号通路通过转录因子MEF2C调节血清诱导的早期基因表达。
