The notch ligands, Delta1 and Jagged2, are substrates for presenilin-dependent "γ-secretase" cleavage
The notch ligands, Delta1 and Jagged2, are substrates for presenilin-dependent "γ-secretase" cleavage
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DOI：
10.1074/jbc.c200711200
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发表时间：
2003-03-07
影响因子：
4.8
通讯作者：
Sisodia, SS
中科院分区：
文献类型：
--
作者：
Ikeuchi, T;Sisodia, SS
进化上保守的Notch信号传导途径参与细胞命运特化，并由Notch受体与Notch配体Delta、Serrate和Jagged之间的分子相互作用介导。在这份报告中，我们证明，像Notch，Delta 1和锯齿状2是受早老素（PS）依赖性，膜内的“γ-分泌酶”的加工，导致可溶性细胞内衍生物的生产。此外，与家族性阿尔茨海默病相关突变PSI的表达损害Notch S3/NICD的产生的观察平行，我们表明，在表达突变PS1的细胞中，Delta 1细胞质衍生物的PS依赖性产生也减少。这些研究使我们得出结论，一个类似的分子装置负责Notch及其配体的膜内加工。为了评估细胞质衍生物对核转录事件的潜在作用，我们表达了Delta 1-Gal 4VP 16嵌合体，并证明了基于内切酶的报告基因的显著转录刺激。我们的研究结果提供的建议，Delta 1和锯齿状蛋白2发挥双重作用，作为激活剂的Notch受体信号和受体介导的核信号事件通过γ-分泌酶产生的胞质结构域。
The evolutionary conserved Notch signaling pathway is involved in cell fate specification and mediated by molecular interactions between the Notch receptors and the Notch ligands, Delta, Serrate, and Jagged. In this report, we demonstrate that like Notch, Delta1 and Jagged2 are subject to presenilin (PS)-dependent, intramembranous "gamma-secretase" processing, resulting in the production of soluble intracellular derivatives. Moreover, and paralleling the observation that expression of familial Alzheimer's disease-linked mutant PSI compromises production of Notch S3/NICD, we show that the PS-dependent production of Delta1 cytoplasmic derivatives are also reduced in cells expressing mutant PS1. These studies led us to conclude that a similar molecular apparatus is responsible for intramembranous processing of Notch and it's ligands. To assess the potential role of the cytoplasmic derivative on nuclear transcriptional events, we expressed a Delta1-Gal4VP16 chimera and demonstrated marked transcriptional stimulation of a luciferase-based reporter. Our findings offer the proposal that Delta1 and Jagged2 play dual roles as activators of Notch receptor signaling and as receptors that mediate nuclear signaling events via gamma-secretase-generated cytoplasmic domains.