Activation of NF-κB by RANK requires tumor necrosis factor receptor-associated factor (TRAF) 6 and NF-κB-inducing kinase -: Identification of a novel TRAF6 interaction motif
Activation of NF-κB by RANK requires tumor necrosis factor receptor-associated factor (TRAF) 6 and NF-κB-inducing kinase -: Identification of a novel TRAF6 interaction motif
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DOI：
10.1074/jbc.274.12.7724
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发表时间：
1999-03-19
影响因子：
4.8
通讯作者：
Aggarwal, BB
中科院分区：
文献类型：
--
作者：
Darnay, BG;Ni, J;Aggarwal, BB
肿瘤坏死因子 (TNF) 受体超家族的各个成员通过与 TNF 受体相关因子 (TRAF) 和 NF-kappa B 诱导激酶 (NIK) 相互作用，激活核因子 kappa B (NF-kappa B) 和 c-Jun N 末端激酶 (JNK) 通路。我们之前已经证明，NF-kappa B 受体激活剂 (RANK) 的胞质结构域与 TRAF2、TRAF5 和 TRAF6 相互作用，并且其过表达会激活 NF-kappa B 和 JNK 通路。通过对 RANK 胞质结构域的详细突变分析，我们证明 TRAF2 和 TRAF5 分别与位于 C 末端位置 565-568 和 606-611 的共有 TRAF 结合基序结合。相比之下，TRAF6 与位于 RANK 残基 340 和 358 之间的新基序相互作用。此外，在人胚胎 293 细胞中用 RANK 及其缺失突变体进行的转染实验表明，TRAF6 结合区 (340-358)，而不是 TRAF2 或 TRAF5 结合区，对于 RANK 诱导的 NF-κ B 激活是必要且充分的。此外，NIK 的激酶突变体 (NIK-KM) 抑制 RANK 诱导的 NF-κ B 激活。然而，RANK 介导的 JNK 激活需要含有 TRAF2 结合域的 RANK 远端部分 (427-603)。因此，我们的结果表明，RANK 通过不同的基序与各种 TRAF 相互作用，并通过新的 TRAF6 相互作用基序激活 NF-kappa B，然后激活 MK，从而导致 NF-kappa B 激活，而 RANK 最有可能通过 RANK 中的 TRAF2 相互作用区域激活 JNK。
Various members of the tumor necrosis factor (TNF) receptor superfamily activate nuclear factor kappa B (NF-kappa B) and the c-Jun N-terminal kinase (JNK) pathways through their interaction with TNF receptor-associated factors (TRAFs) and NF-kappa B-inducing kinase (NIK). We have previously shown that the cytoplasmic domain of receptor activator of NF-kappa B (RANK) interacts with TRAF2, TRAF5, and TRAF6 and that its overexpression activates NF-kappa B and JNK pathways. Through a detailed mutational analysis of the cytoplasmic domain of RANK, we demonstrate that TRAF2 and TRAF5 bind to consensus TRAF binding motifs located in the C terminus at positions 565-568 and 606-611, respectively. In contrast, TRAF6 interacts with a novel motif located between residues 340 and 358 of RANK. Furthermore, transfection experiments with RANK and its deletion mutants in human embryonic 293 cells revealed that the TRAF6-binding region (340-358), but not the TRAF2 or TRAF5-binding region, is necessary and sufficient for RANK-induced NF-kappa B activation. Moreover, a kinase mutant of NIK (NIK-KM) inhibited RANK-induced NF-kappa B activation. However, RANK-mediated JNK activation required a distal portion (427-603) of RANK containing the TRAF2-binding domain. Thus, our results indicate that RANK interacts with various TRAFs through distinct motifs and activates NF-kappa B via a novel TRAF6 interaction motif, which then activates MK, thus leading to NF-kappa B activation, whereas RANK most likely activates JNK through a TRAF2-interacting region in RANK.