The involvement of multiple tumor necrosis factor receptor (TNFR)-associated factors in the signaling mechanisms of receptor activator of NF-κB, a member of the TNFR superfamily
The involvement of multiple tumor necrosis factor receptor (TNFR)-associated factors in the signaling mechanisms of receptor activator of NF-κB, a member of the TNFR superfamily
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DOI：
10.1074/jbc.273.51.34120
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发表时间：
1998-12-18
影响因子：
4.8
通讯作者：
Dougall, WC
中科院分区：
文献类型：
--
作者：
Galibert, L;Tometsko, ME;Dougall, WC
NF-κ B受体激活因子（RANK）是最近发现的肿瘤坏死因子受体超家族成员，表达于活化的T细胞和树突状细胞上。其同源配体（RANKL）在树突状细胞功能激活和破骨细胞分化中起重要作用。我们在此证明了RANK与肿瘤坏死因子受体相关因子（TRAFs）1、2、3、5和6在体外和细胞中的相互作用。TRAF/RANK相互作用的结构要求图谱显示，多个TRAF结合位点聚集在RANK胞质尾区的两个不同结构域中。这些TRAF结合结构域显示对于NF-κ B和c-Jun NH 2-末端激酶活性的RANK依赖性诱导具有重要功能。定点突变表明，这些TRAF结合位点的表现。选择性结合不同的TRAF蛋白。特别是，TRAF 6与不同于TRAF 1，2，3和5的膜近端决定簇相互作用。当这种近膜TRAF 6相互作用结构域被删除时，RANK介导的NF-κ B信号传导被完全抑制，而c-Jun NH 2-末端激酶活化被部分抑制。TRAF 6的NH 2-末端截短突变体抑制RANKL介导的NF-κ B活化，但未能影响受体过表达诱导的组成性信号传导，揭示了TRAF 6在配体诱导的活化事件中的选择性作用。
Receptor activator of NF-kappa B (RANK) is a recently identified member of the tumor necrosis factor receptor superfamily and is expressed on activated T cells and dendritic cells. Its cognate ligand (RANKL) plays significant roles in the activation of dendritic cell function and osteoclast differentiation. We demonstrate here the interaction of RANK with tumor necrosis factor receptor-associated factors (TRAFs) 1, 2, 3, 5, and 6 both in vitro and in cells. Mapping of the structural requirements for TRAF/RANK interaction revealed multiple TRAF binding sites clustered in two distinct domains in the RANK cytoplasmic tail. These TRAF binding domains were shown to be functionally important for the RANK-dependent induction of NF-kappa B and c-Jun NH2-terminal kinase activities. Site-directed mutagenesis demonstrated that these TRAF binding sites exhibited. selective binding for different TRAF proteins. In particular, TRAF6 interacted with membrane-proximal determinants distinct from those binding TRAFs 1, 2, 3, and 5. When this membrane-proximal TRAF6 interaction domain was deleted, RANK-mediated NF-kappa B signaling was completely inhibited while c-Jun NH2-terminal kinase activation was partially inhibited. An NH2-terminal truncation mutant of TRAF6 inhibited RANKL-mediated NF-kappa B activation, but failed to affect constitutive signaling induced by receptor overexpression,revealing a selective role for TRAF6 in ligand-induced activation events.