A Mutation in EGF Repeat-8 of Notch Discriminates Between Serrate/Jagged and Delta Family Ligands
A Mutation in EGF Repeat-8 of Notch Discriminates Between Serrate/Jagged and Delta Family Ligands
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DOI：
10.1126/science.1224313
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发表时间：
2012-11-30
期刊：
影响因子：
56.9
通讯作者：
Todorov, Alexander
中科院分区：
文献类型：
--
作者：
Aviezer, Hillel;Trope, Yaacov;Todorov, Alexander
Notch信号传导影响许多发育和细胞过程，并与先天性疾病、中风和许多癌症有关。Notch受体结合其配体Delta和Serrate，并且能够在不同的情况下区分它们。然而，Notch中负责这种选择性的特定结构域定义不清。通过果蝇的基因筛选，我们分离出一种突变，Notch（拼图），它影响锯齿信号，但不影响Delta依赖的信号。Notch（jigsaw）在表皮生长因子重复序列-8（EGFr-8）中携带错义突变，并且在锯齿结合中有缺陷。哺乳动物Notch 2中的同源点突变也表现出哺乳动物锯齿状同源物Jagged 1的信号传导缺陷。因此，EGFr-8中进化上保守的缬氨酸对于配体选择性是必不可少的，并提供了研究许多Notch依赖性信号传导事件的分子手柄。
Notch signaling affects many developmental and cellular processes and has been implicated in congenital disorders, stroke, and numerous cancers. The Notch receptor binds its ligands Delta and Serrate and is able to discriminate between them in different contexts. However, the specific domains in Notch responsible for this selectivity are poorly defined. Through genetic screens in Drosophila, we isolated a mutation, Notch(jigsaw), that affects Serrate-but not Delta-dependent signaling. Notch(jigsaw) carries a missense mutation in epidermal growth factor repeat-8 (EGFr-8) and is defective in Serrate binding. A homologous point mutation in mammalian Notch2 also exhibits defects in signaling of a mammalian Serrate homolog, Jagged1. Hence, an evolutionarily conserved valine in EGFr-8 is essential for ligand selectivity and provides a molecular handle to study numerous Notch-dependent signaling events.