Adam-Klages S, Adam D, Wiegmann K, Struve S, Kolanus W, Schneider-Mergener J, Krönke M
Institut für Immunologie, Christian-Albrechts-Universität Kiel, Federal Republic of Germany.
Cell. 1996 Sep 20;86(6):937-47. doi: 10.1016/s0092-8674(00)80169-5.
The initiation of intracellular signaling events through the 55 kDa tumor necrosis factor-receptor (TNF-R55) appears to depend on protein intermediates that interact with specific cytoplasmic domains of TNF-R55. By combined use of the yeast interaction trap system and a peptide scanning library, the novel WD-repeat protein FAN has been identified, which specifically binds to a cytoplasmic nine amino acid binding motif of TNF-R55. This region has been previously recognized as a distinct functional domain that is both required and sufficient for the activation of neutral sphingomyelinase (N-SMase). Overexpression of full-length FAN enhanced N-SMase activity in TNF-treated cells, while truncated mutants of FAN produced dominant negative effects. The data suggest that FAN regulates ceramide production by N-SMase, which is a crucial step in TNF signaling.
通过55 kDa肿瘤坏死因子受体（TNF-R55）启动细胞内信号事件似乎依赖于与TNF-R55特定胞质结构域相互作用的蛋白质中间体。通过联合使用酵母相互作用陷阱系统和肽扫描文库，已鉴定出新型WD重复蛋白FAN，它特异性结合TNF-R55的胞质九氨基酸结合基序。该区域先前已被确认为一个独特的功能域，对于中性鞘磷脂酶（N-SMase）的激活既是必需的也是充分的。全长FAN的过表达增强了TNF处理细胞中的N-SMase活性，而FAN的截短突变体产生了显性负效应。数据表明FAN通过N-SMase调节神经酰胺的产生，这是TNF信号传导中的关键步骤。
