The death domain kinase RIP is essential for TRAIL (Apo2L)-induced activation of IκB kinase and c-Jun N-terminal kinase
The death domain kinase RIP is essential for TRAIL (Apo2L)-induced activation of IκB kinase and c-Jun N-terminal kinase
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DOI：
10.1128/mcb.20.18.6638-6645.2000
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发表时间：
2000-09-01
影响因子：
5.3
通讯作者：
Liu, ZG
中科院分区：
文献类型：
--
作者：
Lin, Y;Devin, A;Liu, ZG
肿瘤坏死因子相关的凋亡诱导配体(TRAIL)(APO2配体[Apo2L])是肿瘤坏死因子超家族的一员，具有选择性抗肿瘤活性。尽管已知TRAIL(Apo2L)通过TRAIL-R1(DR4)和TRAIL-R2(DR5)等受体诱导细胞凋亡并激活核因子-kappaB和Jun N末端激酶(JNK)，但其信号转导通路的组成尚不清楚。在这份报告中，我们证明了死亡区域激酶RIP在TRAIL诱导的I kappa B激酶(IKK)和JNK激活中是必不可少的。我们发现，显性负性突变体RIP(559-671)的异位表达阻断了TRAIL诱导的IKK和JNK的激活。在RIP缺失的成纤维细胞中，TRAIL不能激活IKK，只能部分激活JNK。免疫沉淀法检测TRAIL处理后TRAIL-R1复合体中内源性RIP蛋白的表达。更重要的是，我们发现RIP不参与TRAIL诱导的细胞凋亡。此外，我们还证明了肿瘤坏死因子受体相关因子2(TRAF2)在TRAIL诱导的IKK激活中的作用很小，尽管它是TRAIL介导的JNK激活所必需的。这些结果表明，作为肿瘤坏死因子信号转导途径的关键因子，死亡域激酶RIP在TRAIL诱导的IKK和JNK激活中也起着关键作用。
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) (Apo2 Ligand [Apo2L]) is a member of the TNF superfamily and has been shown to have selective antitumor activity. Although it is known that TRAIL (Apo2L) induces apoptosis and activates NF-kappa B and Jun N-terminal kinase (JNK) through receptors such as TRAIL-R1 (DR4) and TRAIL-R2 (DR5), the components of its signaling cascade have not been well defined. In this report, we demonstrated that the death domain kinase RIP is essential for TRAIL-induced I kappa B kinase (IKK) and JNK activation. We found that ectopic expression of the dominant negative mutant RIP, RIP(559-671), blocks TRAIL-induced IKK and JNK activation. In the RIP null fibroblasts, TRAIL failed to activate IKK and only partially activated JNK. The endogenous RIP protein was detected by immunoprecipitation in the TRAIL-R1 complex after TRAIL treatment. More importantly, we found that RIP is not involved in TRAIL-induced apoptosis. In addition, we also demonstrated that the TNF receptor-associated factor 2 (TRAF2) plays little role in TRAIL-induced IKK activation although it is required for TRAIL-mediated JNK activation. These results indicated that the death domain kinase RIP, a key factor in TNF signaling, also plays a pivotal role in TRAIL-induced IKK and JNK activation.