Notch is a conserved cell signalling receptor regulating many aspects of development and tissue homeostasis. Notch is activated by ligand-induced proteolytic cleavages that release the Notch intracellular domain, which relocates to the nucleus to regulate gene transcription. Proteolytic activation first requires mechanical force to be applied to the Notch extracellular domain through an endocytic pulling mechanism transmitted through the ligand/receptor interface. This exposes the proteolytic cleavage site allowing the signal to be initiated following removal of the Notch extracellular domain. Ligands can also act, when expressed in the same cell, through non-productive cis-interactions to inhibit Notch activity. Furthermore, ligand selectivity and Notch activation are regulated by numerous post-translational modifications of the extracellular domain. Additional non-canonical trans and cis interactions with other regulatory proteins may modulate alternative mechanisms of Notch activation that depend on endocytic trafficking of the full-length receptor and proteolytic release of the intracellular domain from endo-lysosomal surface. Mutations of Notch, located in different regions of the protein, are associated with a spectrum of different loss and gain of function phenotypes and offer the possibility to dissect distinct regulatory interactions and mechanisms, particularly when combined with detailed structural analysis of Notch in complex with various regulatory partners.

Notch是一种保守的细胞信号受体，可调节发育和组织动态平衡的许多方面。Notch由配体诱导的蛋白水解切割激活，该切割释放Notch细胞内结构域，后者移至细胞核以调节基因转录。蛋白水解激活首先需要通过通过配体/受体界面传递的内吞作用机制将机械力施加于Notch细胞外域。这暴露了蛋白水解切割位点，从而允许在去除Notch细胞外结构域后启动信号。当在同一细胞中表达时，配体还可以通过非生产性顺式相互作用来抑制Notch活性。此外，配体选择性和Notch激活受细胞外域的许多翻译后修饰调控。与其他调节蛋白的其他非规范反式和顺式相互作用可能会调节Notch激活的替代机制，该机制取决于全长受体的内吞运输和从溶酶体表面的细胞内结构域的蛋白水解释放。Notch的突变位于蛋白质的不同区域，与一系列不同的功能表型丧失和获得相关，并为剖析不同的调节相互作用和机制提供了可能性，尤其是当结合对Notch进行详细的结构分析时，监管伙伴。与其他调节蛋白的其他非规范反式和顺式相互作用可能会调节Notch激活的替代机制，该机制取决于全长受体的内吞运输和从溶酶体表面的细胞内结构域的蛋白水解释放。Notch的突变位于蛋白质的不同区域，与一系列不同的功能表型丧失和获得相关，并为剖析不同的调节相互作用和机制提供了可能性，尤其是当结合对Notch进行详细的结构分析时，监管伙伴。与其他调节蛋白的其他非规范反式和顺式相互作用可能会调节Notch激活的替代机制，该机制取决于全长受体的内吞运输和从溶酶体表面的细胞内结构域的蛋白水解释放。Notch的突变位于蛋白质的不同区域，与一系列不同的功能表型丧失和获得相关，并为剖析不同的调节相互作用和机制提供了可能性，尤其是当结合对Notch进行详细的结构分析时，监管伙伴。