The Fn14 cytoplasmic tall binds tumour-necrosis-factor-receptor-associated factors 1, 2, 3 and 5 and mediates nuclear factor-κB activation
The Fn14 cytoplasmic tall binds tumour-necrosis-factor-receptor-associated factors 1, 2, 3 and 5 and mediates nuclear factor-κB activation
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DOI：
10.1042/bj20021730
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发表时间：
2003-04-15
影响因子：
4.1
通讯作者：
Winkles, JA
中科院分区：
文献类型：
--
作者：
Brown, SAN;Richards, CM;Winkles, JA
14是生长因子诱导的立即早期应答基因，编码102个氨基酸的I型跨膜蛋白。人Fn 14蛋白最近被鉴定为肿瘤坏死因子（TNF）超家族成员TWEAK（TNF样弱凋亡诱导剂）的细胞表面受体。在本文中，我们报告，人TWEAK胞外结构域也可以结合小鼠Fn 14蛋白。此外，位点特异性诱变和定向酵母双杂交相互作用测定显示，TNFR相关因子（TRAF）1、2、3和5衔接子分子在重叠但不相同的氨基酸序列基序处结合鼠Fn 14胞质尾。我们还发现，TWEAK治疗静止NIH 3 T3细胞刺激抑制kappaB α磷酸化和转录激活的核因子-kappaB（NF-κ B）增强子/荧光素酶报告构建体。瞬时转染NIH 3 T3细胞中Fn 14过表达也促进NF-κ B活化，这种细胞反应需要完整的TRAF结合位点。这些结果表明，Fn 14是一种功能性TWEAK受体，可以与四个不同的TRAF家族成员，并刺激NF-κ B转录因子信号通路。
14 is a growth-factor-inducible immediate-early-response gene encoding a 102-amino-acid type I transmembrane protein. The human Fn14 protein was recently identified as a cell-surface receptor for the tumour necrosis factor (TNF) superfamily member named TWEAK (TNF-like weak inducer of apoptosis). In the present paper, we report that the human TWEAK extracellular domain can also bind the murine Fn14 protein. Furthermore, site-specific mutagenesis and directed yeast two-hybrid interaction assays revealed that the TNFR-associated factor (TRAF) 1, 2, 3 and 5 adaptor molecules bind the murine Fn14 cytoplasmic tail at an overlapping, but non-identical, amino acid sequence motif. We also found that TWEAK treatment of quiescent NIH 3T3 cells stimulates inhibitory kappaBalpha phosphorylation and transcriptional activation of a nuclear factor-kappaB (NF-kappaB) enhancer/luciferase reporter construct. Fn14 overexpression in transiently transfected NIH 3T3 cells also promotes NF-kappaB activation, and this cellular response requires an intact TRAF binding site. These results indicate that Fn14 is a functional TWEAK receptor that can associate with four distinct TRAF family members and stimulate the NF-kappaB transcription factor signalling pathway.