A Review of Notch Processing With New Insights Into Ligand-Independent Notch Signaling in T-Cells.
A Review of Notch Processing With New Insights Into Ligand-Independent Notch Signaling in T-Cells.
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DOI：
10.3389/fimmu.2018.01230
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发表时间：
2018
影响因子：
7.3
通讯作者：
Winandy S
中科院分区：
文献类型：
--
作者：
Steinbuck MP;Winandy S
Notch受体是一种进化上高度保守的跨膜蛋白，对广泛的细胞系统至关重要，它的解除调控与大量的发育障碍和恶性肿瘤有关。调节的Notch功能对T细胞的产生至关重要，在T细胞中，异常的Notch信号导致白血病。通过表达在相邻细胞上的受体的一个配体反式激活该受体来激活缺口已经被很好地定义。在这种典型的配体依赖途径中，Notch受体在与配体结合时经历构象变化，受Notch胞外片段的拉力刺激，这是由于受体结合的配体内吞到配体表达细胞内而导致的。受体的这些构象变化允许两个连续的蛋白水解性切割事件发生，从而将受体的胞内区释放到细胞质中。然后，它可以进入细胞核，在那里诱导基因转录。然而，越来越多的证据表明，其他途径也可能诱导Notch信号转导。已经描述了Notch激活的一种配体无关的机制，其中受体的处理是通过细胞内部信号来启动的。这些信号导致Notch内化到内体间隔，在这个微环境中存在的化学变化导致受体处理所需的构象改变。这篇综述将介绍典型的配体依赖和非典型的配体非依赖的Notch激活途径的机制，并在T细胞中Notch信号的背景下讨论后者。
The Notch receptor is an evolutionarily highly conserved transmembrane protein essential to a wide spectrum of cellular systems, and its deregulation has been linked to a vast number of developmental disorders and malignancies. Regulated Notch function is critical for the generation of T-cells, in which abnormal Notch signaling results in leukemia. Notch activation through trans-activation of the receptor by one of its ligands expressed on adjacent cells has been well defined. In this canonical ligand-dependent pathway, Notch receptor undergoes conformational changes upon ligand engagement, stimulated by a pulling-force on the extracellular fragment of Notch that results from endocytosis of the receptor-bound ligand into the ligand-expressing cell. These conformational changes in the receptor allow for two consecutive proteolytic cleavage events to occur, which release the intracellular region of the receptor into the cytoplasm. It can then travel to the nucleus, where it induces gene transcription. However, there is accumulating evidence that other pathways may induce Notch signaling. A ligand-independent mechanism of Notch activation has been described in which receptor processing is initiated via cell-internal signals. These signals result in the internalization of Notch into endosomal compartments, where chemical changes existing in this microenvironment result in the conformational modifications required for receptor processing. This review will present mechanisms underlying both canonical ligand-dependent and non-canonical ligand-independent Notch activation pathways and discuss the latter in the context of Notch signaling in T-cells.
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发表时间：
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影响因子：
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