Lethal giant discs, a novel C2-domain protein, restricts notch activation during endocytosis
Lethal giant discs, a novel C2-domain protein, restricts notch activation during endocytosis
复制标题
DOI：
10.1016/j.cub.2006.09.031
复制
发表时间：
2006-11-21
期刊：
影响因子：
9.2
通讯作者：
Haider, Georg
中科院分区：
文献类型：
--
作者：
Childress, Jennifer L.;Acar, Melih;Haider, Georg
Notch信号通路在动物的生长和模式形成中起着核心作用，它的失控会导致许多人类疾病，包括癌症[1，2]。肿瘤抑制因子致死性巨型盘(IGD)的突变可诱导果蝇成像盘的强烈Notch激活和过度生长[3-5]。然而，编码LGD的基因及其在Notch途径中的功能尚未确定。在这里，我们报告了LGD是一种新的、保守的C2结构域蛋白，它调节Notch受体的运输。在IGD突变细胞中，Notch以一种不依赖于配体的方式积聚在早期内体上并发出信号。这种表型类似于当细胞失去内体途径成分时所看到的，如皮疹和Vps25[6-9]。有趣的是，在IGD突变细胞中，Notch的激活需要早期的内体成分HrS，这表明HrS对LGD是上位的。这些数据表明，LGD影响HRs和晚期内体成分Vps25之间的Notch转运。综上所述，我们的数据确定LGD是一种新的肿瘤抑制蛋白，它通过靶向Notch降解或循环来调节Notch信号。
The Notch signaling pathway plays a central role in animal growth and patterning, and its deregulation leads to many human diseases, including cancer [1, 2]. Mutations in the tumor suppressor lethal giant discs (Igd) induce strong Notch activation and hyperplastic overgrowth of Drosophila imaginal discs [3-5]. However, the gene that encodes Lgd and its function in the Notch pathway have not yet been identified. Here, we report that Lgd is a novel, conserved C2-domain protein that regulates Notch receptor trafficking. Notch accumulates on early endosomes in Igd mutant cells and signals in a ligand-independent manner. This phenotype is similar to that seen when cells lose endosomal-pathway components such as Erupted and Vps25 [6-9]. Interestingly, Notch activation in Igd mutant cells requires the early endosomal component Hrs, indicating that Hrs is epistatic to Lgd. These data suggest that Lgd affects Notch trafficking between the actions of Hrs and the late endosomal component Vps25. Taken together, our data identify Lgd as a novel tumor-suppressor protein that regulates Notch signaling by targeting Notch for degradation or recycling.