Novel TCR-Mediated Mechanisms of Notch Activation and Signaling.
Novel TCR-Mediated Mechanisms of Notch Activation and Signaling.
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DOI：
10.4049/jimmunol.1700070
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发表时间：
2018-02-01
期刊：
影响因子：
--
通讯作者：
Winandy S
中科院分区：
文献类型：
--
作者：
Steinbuck MP;Arakcheeva K;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。Notch信号对T细胞发育尤其重要，其失调导致白血病。虽然没有得到很好的表征，但它继续在外周T细胞中发挥不可或缺的作用，其中可以发生独特的Notch激活模式。与由相邻配体表达细胞引发的典型Notch活化相反，T细胞受体（TCR）刺激足以诱导Notch信号传导。然而，这两种途径之间的相互作用尚未确定。在这份报告中，我们表明Notch激活发生在TCR刺激后几个小时内的外周T细胞中，并且是最佳T细胞激活所必需的。利用一组抑制剂对组件的TCR信号级联，我们证明，Notch激活是通过启动蛋白激酶C诱导的ADAM-金属蛋白酶活性促进。此外，我们的数据表明，通过内吞作用的Notch的内化在这个过程中发挥了作用。鉴于配体介导的Notch刺激依赖于破坏Notch的自抑制结构域的机械拉力，我们假设在不存在配体的T细胞中，这些构象变化是通过内体中的化学调节诱导的，从而导致自抑制和受体活化的缓解。因此，T细胞可能已经进化出一种独特的Notch受体激活方法，这是本研究首次描述。
The Notch receptor is an evolutionarily highly conserved transmembrane protein essential to a wide spectrum of cellular systems. Notch signaling is especially important to T-cell development, and its deregulation leads to leukemia. Although not well characterized, it continues to play an integral role in peripheral T-cells, in which a unique mode of Notch activation can occur. In contrast to canonical Notch activation initiated by adjacent ligand-expressing cells, T-cell receptor (TCR)-stimulation is sufficient to induce Notch signaling. However, the interactions between these two pathways have not been defined. In this report, we show that Notch activation occurs in peripheral T-cells within a few hours post TCR-stimulation and is required for optimal T-cell activation. Utilizing a panel of inhibitors against components of the TCR signaling cascade, we demonstrate that Notch activation is facilitated through initiation of protein kinase C-induced ADAM-metalloprotease activity. Moreover, our data suggest that internalization of Notch via endocytosis plays a role in this process. Whereas ligand-mediated Notch stimulation relies on mechanical pulling forces that disrupt the autoinhibitory domain of Notch, we hypothesized that in T-cells in the absence of ligands, these conformational changes are induced through chemical adjustments in the endosome, causing alleviation of autoinhibition and receptor activation. Thus, T-cells may have evolved a unique method of Notch receptor activation, described for the first time in this study.
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DOI：
10.1083/jcb.200702009
发表时间：
2007-07-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Geffers I;Serth K;Chapman G;Jaekel R;Schuster-Gossler K;Cordes R;Sparrow DB;Kremmer E;Dunwoodie SL;Klein T;Gossler A
通讯作者：
Gossler A
影响因子：
7.3
作者：
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通讯作者：
Kopan R
影响因子：
7.8
作者：
Gupta-Rossi, Neetu;Six, Emmanuelle;LeBail, Odile;Logeat, Frederique;Chastagner, Patricia;Olry, Annie;Israel, Alain;Brou, Christel
通讯作者：
Brou, Christel
影响因子：
4.4
作者：
Adler, SH;Chiffoleau, E;Pear, WS
通讯作者：
Pear, WS
影响因子：
5.3
作者：
Bozkulak, Esra Cagavi;Weinmaster, Gerry
通讯作者：
Weinmaster, Gerry