Canonical and non-canonical Notch ligands.
Canonical and non-canonical Notch ligands.
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DOI：
10.1016/s0070-2153(10)92003-6
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发表时间：
2010
影响因子：
--
通讯作者：
Weinmaster, Gerry
中科院分区：
文献类型：
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作者：
D'Souza, Brendan;Meloty-Kapella, Laurence;Weinmaster, Gerry
规范的Notch配体通过调节多种细胞命运决定和细胞过程，诱导Notch信号对正常胚胎发育和组织动态平衡至关重要。Notch信号的激活通常受到与配体表达细胞的直接相互作用的严格控制，而异常调节的Notch信号与发育异常和癌症有关。虽然正则Notch配体负责Notch信号的大部分，但也发现了一组结构上不相关的非正则配体，它们激活Notch并可能对Notch信号的多效性做出贡献。正则和非正则配体的可溶性形式已经被分离出来，其中一些可以阻断Notch信号转导，并可以作为这一途径的天然抑制剂。配基活性也可以在配基表达水平上受到其他信号通路的间接调节，在时空上划分Notch信号活性，并将Notch信号整合到一个协调发育事件的分子网络中。在这里，我们回顾了Notch配体作为Notch信号激活剂和抑制剂的双重作用的分子机制。此外，还提出了Notch配体独立于Notch发挥作用的证据。我们还讨论了配体的翻译后修饰、内吞作用、蛋白分解和时空表达如何调节其信号活性。
Notch signaling induced by canonical Notch ligands is critical for normal embryonic development and tissue homeostasis through the regulation of a variety of cell fate decisions and cellular processes. Activation of Notch signaling is normally tightly controlled by direct interactions with ligand-expressing cells and dysregulated Notch signaling is associated with developmental abnormalities and cancer. While canonical Notch ligands are responsible for the majority of Notch signaling, a diverse group of structurally unrelated non-canonical ligands has also been identified that activate Notch and likely contribute to the pleiotropic effects of Notch signaling. Soluble forms of both canonical and non-canonical ligands have been isolated, some of which block Notch signaling and could serve as natural inhibitors of this pathway. Ligand activity can also be indirectly regulated by other signaling pathways at the level of ligand expression, serving to spatio-temporally compartmentalize Notch signaling activity and integrate Notch signaling into a molecular network that orchestrates developmental events. Here, we review the molecular mechanisms underlying the dual role of Notch ligands as activators and inhibitors of Notch signaling. Additionally, evidence that Notch ligands function independent of Notch are presented. We also discuss how ligand post-translational modification, endocytosis, proteolysis and spatio-temporal expression regulate their signaling activity.