Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases
Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases
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DOI：
10.1016/j.molcel.2005.04.001
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发表时间：
2005-04-29
期刊：
影响因子：
16
通讯作者：
Saito, H
中科院分区：
文献类型：
--
作者：
Takekawa, M;Tatebayashi, K;Saito, H
哺乳动物丝裂原活化蛋白激酶（MAPK）级联反应控制各种细胞事件，从细胞生长到细胞凋亡，以响应外部刺激。在哺乳动物MAP激酶激酶（MAPKKs）中发现了一个保守的对接位点，称为DVD，其属于三个主要亚家族，即MEK 1、MKK 4/7和MKK 3/6。DVD位点与其特异性上游MAP激酶（MAPKKK）结合，包括MTK 1（MEKK 4）、ASK 1、TAK 1、TAO 2、MEKK 1和Raf-1。DVD位点是紧邻MAPKK催化结构域C-末端侧的约20个氨基酸的延伸。在DVD网站的突变强烈抑制MAPKKs结合，并被激活，他们的特异性MAPKKKs，在体外和体内。DVD位点突变体在体内不能被各种外界刺激激活。合成DVD寡肽抑制特异性MAPK活化，在体外和体内，证明了至关重要的DVD对接MAPK信号。
Mammalian mitogen-activated protein kinase (MAPK) cascades control various cellular events, ranging from cell growth to apoptosis, in response to external stimuli. A conserved docking site, termed DVD, is found in the mammalian MAP kinase kinases (MAPKKs) belonging to the three major subfamilies, namely MEK1, MKK4/7, and MKK3/6. The DVD sites bind to their specific upstream MAP kinase kinase kinases (MAPKKKs), including MTK1 (MEKK4), ASK1, TAK1, TAO2, MEKK1, and Raf-1. DVD site is a stretch of about 20 amino acids immediately on the C-terminal side of the MAPKK catalytic domain. Mutations in the DVD site strongly inhibited MAPKKs from binding to, and being activated by, their specific MAPKKKs, both in vitro and in vivo. DVD site mutants could not be activated by various external stimuli in vivo. Synthetic DVD oligopeptides inhibited specific MAPKK activation, both in vitro and in vivo, demonstrating the critical importance of the DVD docking in MAPK signaling.