Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Turku, Finland.
Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Turku, Finland.
Biochim Biophys Acta Mol Cell Res. 2019 Dec;1866(12):118507. doi: 10.1016/j.bbamcr.2019.07.002. Epub 2019 Jul 11.
The developmentally indispensable Notch pathway exhibits a high grade of pleiotropism in its biological output. Emerging evidence supports the notion of post-translational modifications (PTMs) as a modus operandi controlling dynamic fine-tuning of Notch activity. Although, the intricacy of Notch post-translational regulation, as well as how these modifications lead to multiples of divergent Notch phenotypes is still largely unknown, numerous studies show a correlation between the site of modification and the output. These include glycosylation of the extracellular domain of Notch modulating ligand binding, and phosphorylation of the PEST domain controlling half-life of the intracellular domain of Notch. Furthermore, several reports show that multiple PTMs can act in concert, or compete for the same sites to drive opposite outputs. However, further investigation of the complex PTM crosstalk is required for a complete understanding of the PTM-mediated Notch switchboard. In this review, we aim to provide a consistent and up-to-date summary of the currently known PTMs acting on the Notch signaling pathway, their functions in different contexts, as well as explore their implications in physiology and disease. Furthermore, we give an overview of the present state of PTM research methodology, and allude to a future with PTM-targeted Notch therapeutics.
发育必需的 Notch 途径在其生物学产物中表现出高度的多功能性。新出现的证据支持翻译后修饰 (PTMs) 作为一种操作模式的观点，可控制 Notch 活性的动态微调。尽管 Notch 翻译后调控的复杂性以及这些修饰如何导致多种不同的 Notch 表型仍然很大程度上未知，但许多研究表明修饰部位与输出之间存在相关性。这些包括 Notch 调节配体结合的细胞外结构域的糖基化，以及控制 Notch 细胞内结构域半衰期的 PEST 结构域的磷酸化。此外，有几项报道表明，多种 PTM 可以协同作用，或争夺相同的位点以驱动相反的输出。然而，为了全面了解 PTM 介导的 Notch 开关，需要进一步研究复杂的 PTM 串扰。在这篇综述中，我们旨在提供 Notch 信号通路中目前已知的 PTM 作用、它们在不同情况下的功能的一致和最新总结，并探讨它们在生理学和疾病中的意义。此外，我们概述了 PTM 研究方法的现状，并暗示了未来 PTM 靶向 Notch 治疗的前景。
