Distinct roles of EGF repeats for the Notch signaling system
Distinct roles of EGF repeats for the Notch signaling system
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DOI：
10.1016/j.yexcr.2004.09.016
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发表时间：
2005-01-15
影响因子：
3.7
通讯作者：
Yamaguchi, A
中科院分区：
文献类型：
--
作者：
Sakamoto, K;Chao, WS;Yamaguchi, A
Noch是一种单程跨膜受体，在不同物种和发育环境中调节细胞命运选择。Notch信号通过其胞内结构域作为转录激活剂进行传递，并通过蛋白水解酶从质膜中释放出来。这一过程是由Notch和DSL(Delta，Senate，Lag-2)配体之间的表皮生长因子(EGF)重复的细胞间结合启动的，但具体机制尚不清楚。在这里，我们证明了Notch1可以推出同源二聚体，这是通过其EGF基序实现的。Notch1二聚体的形成随着配体的递呈而增加，HES1启动子被刺激，这意味着受体同源二聚化是Notch信号转导的重要起始步骤。EGF基序还可以作为对包括肿瘤坏死因子-α转换酶在内的蛋白酶的保护作用。这阻止了Notch1的非配体依赖的激活。Notch EGF图案的多重功能。比如防止结构性激活。与配体的相互作用和均二聚的侧向作用。似乎构成了Notch信号系统的关键要素。(C)2004 Elsevier Inc.保留所有权利。
Notch is a single-pass transmembrane receptor that mediates cell fate choice in various species and developmental contexts. The Notch signal is transduced by its intracellular domain, which acts as a transcriptional activator, and is released from the plasma membrane by proteolytic cleavages. This process is initiated by intercellular association of the epidermal growth factor (EGF) repeats between Notch and the DSL (Delta, Senate, Lag-2) ligands but the detailed mechanism is yet to be clarified. Here we demonstrate that Notch1 can forth homodimers, which is achieved by its EGF motifs. The Notch1 dimer formation increased in response to ligand presentation and HES1 promoter was stimulated, implying that receptor homodimerization is an important initial step in Notch signal transduction. EGF motifs also serve as a protection against proteases, including TNF-alpha converting enzyme. which prevents Notch1 from ligand-independent activation. Multiple functions of the Notch EGF motifs. such as the prevention of constitutive activation. reciprocal interaction with the ligands and lateral interaction for homodimerization. appear to constitute crucial elements of the Notch signaling system. (C) 2004 Elsevier Inc. All rights reserved.