A Drosophila TNF-receptor-associated factor (TRAF) binds the Ste20 kinase Misshapen and activates Jun kinase
A Drosophila TNF-receptor-associated factor (TRAF) binds the Ste20 kinase Misshapen and activates Jun kinase
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DOI：
10.1016/s0960-9822(99)80023-2
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发表时间：
1999-01-28
期刊：
影响因子：
9.2
通讯作者：
Skolnik, EY
中科院分区：
文献类型：
--
作者：
Liu, HZ;Su, YC;Skolnik, EY
已经鉴定了在其激酶结构域中与Ste 20密切相关的两个蛋白激酶家族-p21活化蛋白激酶（Pak）和SPS 1家族[1-3]。与Pak家族成员相反，SPS 1家族成员不结合并且不被GTP结合的p21 Rac和Cdc 42激活。我们最近将SPS 1家族的一个成员Misshapen（Msn）置于果蝇c-Jun氨基末端（JNK）促分裂原活化蛋白（MAP）激酶模块的遗传上游[4]。果蝇中JNK激活失败导致胚胎死亡，因为这些胚胎不能刺激背侧闭合[5-8]。Msn可能在果蝇中作为MAP激酶发挥作用，通过尚未定义的MAP激酶激活JNK途径。我们已经确定了果蝇肿瘤坏死因子受体相关因子，DTRAF 1，通过筛选Msn相互作用的蛋白质，使用酵母双杂交系统。与已显示激活JNK的哺乳动物TRAF相反，DTRAF 1缺乏氨基末端“环指”结构域，并且仅由其TRAF结构域组成的截短的DTRAF 1的过表达激活JNK。我们还鉴定了另一种DTRAF，DTRAF 2，其含有氨基末端环指结构域。Msn特异性结合DTRAF 1的TRAF结构域，但不结合DTRAF 2的TRAF结构域。因此，在果蝇中，DTRAF 1是通过与Msn相互作用并激活Msn来调节JNK通路的上游分子的良好候选者。与这一想法一致，显性负性Msn突变蛋白的表达阻断了DTRAF 1对JNK的激活。此外，Msn与DTRAF 1的共表达导致JNK的协同激活。我们已经将这些观察结果中的一些扩展到哺乳动物同源的Msn，NCK相互作用激酶（NIK），这表明TRAFs在调节哺乳动物中的Ste 20激酶中也起着至关重要的作用。
Two families of protein kinases that are closely related to Ste20 in their kinase domain have been identified - the p21-activated protein kinase (Pak) and SPS1 families [1-3]. In contrast to Pak family members, SPS1 family members do not bind and are not activated by GTP-bound p21Rac and Cdc42. We recently placed a member of the SPS1 family, called Misshapen (Msn), genetically upstream of the c-Jun amino-terminal (JNK) mitogen-activated protein (MAP) kinase module in Drosophila [4]. The failure to activate JNK in Drosophila leads to embryonic lethality due to the failure of these embryos to stimulate dorsal closure [5-8]. Msn probably functions as a MAP kinase kinase kinase kinase in Drosophila, activating the JNK pathway via an, as yet, undefined MAP kinase kinase kinase. We have identified a Drosophila TNF-receptor-associated factor, DTRAF1, by screening for Msn-interacting proteins using the yeast two-hybrid system. In contrast to the mammalian TRAFs that have been shown to activate JNK, DTRAF1 lacks an aminoterminal 'Ring finger' domain, and overexpression of a truncated DTRAF1, consisting of only its TRAF domain, activates JNK. We also identified another DTRAF, DTRAF2, that contains an amino-terminal Ring-finger domain. Msn specifically binds the TRAF domain of DTRAF1 but not that of DTRAF2. In Drosophila, DTRAF1 is thus a good candidate for an upstream molecule that regulates the JNK pathway by interacting with, and activating, Msn. Consistent with this idea, expression of a dominant-negative Msn mutant protein blocks the activation of JNK by DTRAF1. Furthermore, coexpression of Msn with DTRAF1 leads to the synergistic activation of JNK. We have extended some of these observations to the mammalian homolog of Msn, Nck-interacting kinase (NIK), suggesting that TRAFs also play a critical role in regulating Ste20 kinases in mammals.