A non-canonical Notch complex regulates adherens junctions and vascular barrier function.
A non-canonical Notch complex regulates adherens junctions and vascular barrier function.
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DOI：
10.1038/nature24998
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发表时间：
2017-12-14
期刊：
影响因子：
64.8
通讯作者：
Chen CS
中科院分区：
文献类型：
--
作者：
Polacheck WJ;Kutys ML;Yang J;Eyckmans J;Wu Y;Vasavada H;Hirschi KK;Chen CS
将血液与组织分离的血管屏障受到内皮细胞的积极调节，对运输、炎症和止血至关重要。血流动力学剪切应力在维持内皮屏障功能中起关键作用，但其发生机制尚不清楚。在这里，我们使用灌注微血管的工程器官型模型并在小鼠模型中进行验证，我们发现Notch1跨膜受体的激活通过非规范的、转录独立的信号机制直接调节血管屏障功能，该机制驱动粘附体连接组装。剪切应力触发dll4依赖的Notch1蛋白水解激活，揭示Notch1跨膜结构域-介导屏障建立的关键结构域。Notch1跨膜结构域的表达足以挽救Notch1敲除引起的屏障功能缺陷，并通过催化在质膜上形成由VE-cadherin、跨膜蛋白酪氨酸磷酸酶LAR和Rac1 GEF Trio组成的新型受体复合物来实现。该复合体激活Rac1驱动粘附结组装并建立屏障功能。典型Notch转录信号在后生动物中是高度保守的，并且在血管发育的许多过程中是必需的，包括动静脉分化、血管生成和重塑；在这里，我们建立了Notch1调节血管屏障功能的非规范皮质信号通路的存在，从而提供了一种单一受体可能将转录程序与粘附和细胞骨架重塑联系起来的机制。
The vascular barrier that separates blood from tissues is actively regulated by the endothelium and is essential for transport, inflammation, and hemostasis. Hemodynamic shear stress plays a critical role in maintaining endothelial barrier function, but how this occurs remains unknown. Here, using an engineered organotypic model of perfused microvessels and confirming in mouse models, we identify that activation of the Notch1 transmembrane receptor directly regulates vascular barrier function through a non-canonical, transcription independent signaling mechanism that drives adherens junction assembly. Shear stress triggers Dll4-dependent proteolytic activation of Notch1 to reveal the Notch1 transmembrane domain – the key domain that mediates barrier establishment. Expression of the Notch1 transmembrane domain is sufficient to rescue Notch1 knockout-induced defects in barrier function, and does so by catalyzing the formation of a novel receptor complex in the plasma membrane consisting of VE-cadherin, the transmembrane protein tyrosine phosphatase LAR, and the Rac1 GEF Trio. This complex activates Rac1 to drive adherens junction assembly and establish barrier function. Canonical Notch transcriptional signaling is highly conserved throughout metazoans and is required for many processes in vascular development, including arterial-venous differentiation, angiogenesis, and remodeling; here, we establish the existence of a previously unappreciated non-canonical cortical signaling pathway for Notch1 that regulates vascular barrier function, and thus provide a mechanism by which a single receptor might link transcriptional programs with adhesive and cytoskeletal remodeling.
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DOI：
10.1083/jcb.201112098
发表时间：
2012-03-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Roux KJ;Kim DI;Raida M;Burke B
通讯作者：
Burke B
DOI：
10.1083/jcb.201408103
发表时间：
2015-03-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Coon BG;Baeyens N;Han J;Budatha M;Ross TD;Fang JS;Yun S;Thomas JL;Schwartz MA
通讯作者：
Schwartz MA
影响因子：
2.7
作者：
Le Gall, Maude;De Mattel, Cordell;Giniger, Edward
通讯作者：
Giniger, Edward
影响因子：
8.8
作者：
Chen X;Gays D;Milia C;Santoro MM
通讯作者：
Santoro MM
机械变构：Notch蛋白水解激活中力需求的证据。
影响因子：
11.8
作者：
Gordon, Wendy R.;Zimmerman, Brandon;He, Li;Miles, Laura J.;Huang, Jiuhong;Tiyanont, Kittichoat;McArthur, Debbie G.;Aster, Jon C.;Perrimon, Norbert;Loparo, Joseph J.;Blacklow, Stephen C.
通讯作者：
Blacklow, Stephen C.