Institut National de la Santé et de la Recherche Médicale, U1004, F-94807 Villejuif, France.
J Cell Biol. 2012 Oct 29;199(3):481-96. doi: 10.1083/jcb.201201133. Epub 2012 Oct 22.
The metalloprotease ADAM10/Kuzbanian catalyzes the ligand-dependent ectodomain shedding of Notch receptors and activates Notch. Here, we show that the human tetraspanins of the evolutionary conserved TspanC8 subfamily (Tspan5, Tspan10, Tspan14, Tspan15, Tspan17, and Tspan33) directly interact with ADAM10, regulate its exit from the endoplasmic reticulum, and that four of them regulate ADAM10 surface expression levels. In an independent RNAi screen in Drosophila, two TspanC8 genes were identified as Notch regulators. Functional analysis of the three Drosophila TspanC8 genes (Tsp3A, Tsp86D, and Tsp26D) indicated that these genes act redundantly to promote Notch signaling. During oogenesis, TspanC8 genes were up-regulated in border cells and regulated Kuzbanian distribution, Notch activity, and cell migration. Furthermore, the human TspanC8 tetraspanins Tspan5 and Tspan14 positively regulated ligand-induced ADAM10-dependent Notch1 signaling. We conclude that TspanC8 tetraspanins have a conserved function in the regulation of ADAM10 trafficking and activity, thereby positively regulating Notch receptor activation.
金属蛋白酶 ADAM10/Kuzbanian 催化 Notch 受体的配体依赖性胞外结构域脱落，并激活 Notch。在这里，我们表明人类进化保守的 TspanC8 亚家族（Tspan5、Tspan10、Tspan14、Tspan15、Tspan17 和 Tspan33）的四跨膜蛋白直接与 ADAM10 相互作用，调节其从内质网的输出，其中四个调节 ADAM10 的表面表达水平。在果蝇中的独立 RNAi 筛选中，鉴定出两个 TspanC8 基因作为 Notch 调节剂。对三个果蝇 TspanC8 基因（Tsp3A、Tsp86D 和 Tsp26D）的功能分析表明，这些基因冗余地发挥作用以促进 Notch 信号传导。在卵发生过程中，TspanC8 基因在边缘细胞中上调，并调节 Kuzbanian 分布、Notch 活性和细胞迁移。此外，人类 TspanC8 四跨膜蛋白 Tspan5 和 Tspan14 正向调节配体诱导的 ADAM10 依赖性 Notch1 信号传导。我们得出结论，TspanC8 四跨膜蛋白在调节 ADAM10 运输和活性方面具有保守功能，从而正向调节 Notch 受体激活。
