Kato Y, Tapping R I, Huang S, Watson M H, Ulevitch R J, Lee J D
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Nature. 1998 Oct 15;395(6703):713-6. doi: 10.1038/27234.
Epidermal growth factor (EGF) induces cell proliferation in a variety of cell types by binding to a prototype transmembrane tyrosine kinase receptor. Ligation of this receptor by EGF activates Erk1 and Erk2, members of the mitogen-activated protein (MAP) kinase family, through a Ras-dependent signal transduction pathway. Despite our detailed understanding of these events, the exact mechanism by which EGF causes cells to proliferate is unclear. Big MAP kinase (Bmk1), also known as Erk5, is a member of the MAP kinase family that is activated in cells in response to oxidative stress, hyperosmolarity and treatment with serum. Here we show that EGF is a potent activator of Bmk1. In contrast to Erk1/2, EGF-mediated activation of Bmk1 occurs independently of Ras and requires the MAP-kinase kinase Mek5. Expression of a dominant-negative form of Bmk1 blocks EGF-induced cell proliferation and prevents cells from entering the S phase of the cell cycle. These results demonstrate that Bmk1 is part of a distinct MAP-kinase signalling pathway that is required for EGF-induced cell proliferation and progression through the cell cycle.
表皮生长因子（EGF）通过与一种典型的跨膜酪氨酸激酶受体结合，在多种细胞类型中诱导细胞增殖。EGF与该受体的结合通过Ras依赖性信号转导途径激活有丝分裂原活化蛋白（MAP）激酶家族的成员Erk1和Erk2。尽管我们对这些事件有详细的了解，但EGF促使细胞增殖的确切机制尚不清楚。大MAP激酶（Bmk1），也称为Erk5，是MAP激酶家族的成员，在细胞中响应氧化应激、高渗和血清处理而被激活。在此我们表明，EGF是Bmk1的有效激活剂。与Erk1/2不同，EGF介导的Bmk1激活独立于Ras发生，并且需要MAP激酶激酶Mek5。显性负性形式的Bmk1的表达阻断EGF诱导的细胞增殖，并阻止细胞进入细胞周期的S期。这些结果表明，Bmk1是EGF诱导的细胞增殖和细胞周期进程所需的独特MAP激酶信号通路的一部分。
