Identification and characterization of presenilin-independent Notch signaling
Identification and characterization of presenilin-independent Notch signaling
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DOI：
10.1074/jbc.m108238200
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发表时间：
2002-03-08
影响因子：
4.8
通讯作者：
Nye, JS
中科院分区：
文献类型：
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作者：
Berechid, BE;Kitzmann, M;Nye, JS
早老素（PS）蛋白控制Notch胞内结构域进入核之前的蛋白水解裂解。在这里，我们观察到，HES 1启动子的部分激活，可以检测到在PS1/PS2（PS1/2）双空细胞使用Notch 1DeltaE结构或以下Delta 1刺激，尽管明显取消的生产和细胞核积累的Notch胞内结构域。PS1/2非依赖性Notch激活对Notch的生理抑制剂Numblike敏感。与PS依赖性Notch信号传导类似，PS1/2非依赖性Notch信号传导也在低微摩尔范围内被活性γ-分泌酶抑制剂抑制，并且不被非活性类似物抑制。然而，使用Notch 1-Gal 4-VP 16融合蛋白的实验表明，PS 1/2非依赖性活性不释放Gal 4-VP 16，因此不太可能通过膜内切割进行。这些数据表明，一种新的PS1/2-独立的机制在Notch信号转导中发挥部分作用。
Presenilin (PS) proteins control the proteolytic cleavage that precedes nuclear access of the Notch intracellular domain. Here we observe that a partial activation of the HES1 promoter can be detected in PS1/PS2 (PS1/2) double null cells using Notch1DeltaE constructs or following Delta1 stimulation, despite an apparent abolition of the production and nuclear accumulation of the Notch intracellular domain. PS1/2-independent Notch activation is sensitive to Numblike, a physiological inhibitor of Notch. PS1/2-independent Notch signaling is also inhibited by an active gamma-secretase inhibitor in the low micromolar range and is not inhibited by an inactive analogue, similar to PS-dependent Notch signaling. However, experiments using a Notch1-Gal4-VP16 fusion protein indicate that the PS1/2-independent activity does not release Gal4-VP16 and is therefore unlikely to proceed via an intramembranous cleavage. These data reveal that a novel PS1/2-independent mechanism plays a partial role in Notch signal transduction.