Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.
Cells. 2020 Sep 29;9(10):2212. doi: 10.3390/cells9102212.
The Notch family comprises a group of four ligand-dependent receptors that control evolutionarily conserved developmental and homeostatic processes and transmit signals to the microenvironment. NOTCH undergoes remodeling, maturation, and trafficking in a series of post-translational events, including glycosylation, ubiquitination, and endocytosis. The regulatory modifications occurring in the endoplasmic reticulum/Golgi precede the intramembrane γ-secretase proteolysis and the transfer of active NOTCH to the nucleus. Hence, NOTCH proteins coexist in different subcellular compartments and undergo continuous relocation. Various factors, including ion concentration, enzymatic activity, and co-regulatory elements control Notch trafficking. Interfering with these regulatory mechanisms represents an innovative therapeutic way to bar oncogenic Notch signaling. In this review, we briefly summarize the role of Notch signaling in cancer and describe the protein modifications required for NOTCH to relocate across different subcellular compartments. We focus on the functional relationship between these modifications and the corresponding therapeutic options, and our findings could support the development of trafficking modulators as a potential alternative to the well-known γ-secretase inhibitors.
Notch 家族由一组四个配体依赖性受体组成，它们控制着进化上保守的发育和动态平衡过程，并向微环境传递信号。Notch 在一系列翻译后事件中经历重塑、成熟和运输，包括糖基化、泛素化和内吞作用。内质网/高尔基体中发生的调节修饰先于跨膜 γ-分泌酶蛋白水解和活性 Notch 向核内的转移。因此，Notch 蛋白存在于不同的亚细胞区室中，并不断重新定位。各种因素，包括离子浓度、酶活性和共调节元件，控制 Notch 运输。干扰这些调节机制代表了阻止致癌 Notch 信号的创新治疗方法。在这篇综述中，我们简要总结了 Notch 信号在癌症中的作用，并描述了 Notch 跨不同亚细胞区室重新定位所需的蛋白修饰。我们重点介绍了这些修饰之间的功能关系及其相应的治疗选择，我们的发现可能支持将运输调节剂作为众所周知的 γ-分泌酶抑制剂的潜在替代物进行开发。
