Role of TRAF3 and -6 in the activation of the NF-κB and JNK pathways by X-linked ectodermal dysplasia receptor
Role of TRAF3 and -6 in the activation of the NF-κB and JNK pathways by X-linked ectodermal dysplasia receptor
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DOI：
10.1074/jbc.m207923200
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发表时间：
2002-11-22
影响因子：
4.8
通讯作者：
Chaudhary, PM
中科院分区：
文献类型：
--
作者：
Sinha, SK;Zachariah, S;Chaudhary, PM
X-连锁外胚层发育不良受体（XEDAR）是最近分离的肿瘤坏死因子受体家族的成员，其已被证明在胚胎发育期间在外胚层衍生物中高度表达并结合外胚层发育不良蛋白-A2（EDA-A2）。通过使用具有XEDAR稳定表达的293 F细胞的亚克隆，我们报告XEDAR以EDA-A2依赖的方式激活NF-κ B和JNK通路。用EDA-A2处理导致TRAF 3和TRAF-6募集到聚集的XEDAR复合物，表明这些衔接子在XEDAR信号传导的近端方面的中心作用。TRAF 3和-6、IKK 1/IKK α、IKK 2/IKK β和NEMO/IKK γ参与XEDAR诱导的NF-κ B活化，而XEDAR诱导的JNK活化似乎是通过依赖于TRAF 3、TRAF 6和ASK 1的途径介导的。缺失和点突变研究描绘了XEDAR胞质结构域中的两个不同区域，它们分别参与与TRAF 3和-6的结合，并在NF-κ B和JNK途径的激活中发挥主要作用。总之，我们的结果确立了TRAF 3和TRAF 6在XEDAR信号传导和外胚层分化过程中的主要作用。
X-linked ectodermal dysplasia receptor (XEDAR) is a recently isolated member of the tumor necrosis factor receptor family that has been shown to be highly expressed in ectodermal derivatives during embryonic development and binds to ectodysplasin-A2 (EDA-A2). By using a subclone of 293F cells with stable expression of XEDAR, we report that XEDAR activates the NF-kappaB and JNK pathways in an EDA-A2-dependent fashion. Treatment with EDA-A2 leads to the recruitment of TRAF3 and -6 to the aggregated XEDAR complex, suggesting a central role of these adaptors in the proximal aspect of XEDAR signaling. Whereas TRAF3 and -6, IKK1/IKKalpha, IKK2/IKKbeta, and NEMO/IKKgamma are involved in XEDAR-induced NF-kappaB activation, XEDAR-induced JNK activation seems to be mediated via a pathway dependent on TRAF3, TRAF6, and ASK1. Deletion and point mutagenesis studies delineate two distinct regions in the cytoplasmic domain of XEDAR, which are involved in binding to TRAF3 and -6, respectively, and play a major role in the activation of the NF-kappaB and JNK pathways. Taken together, our results establish a major role of TRAF3 and -6 in XEDAR signaling and in the process of ectodermal differentiation.