非正規のノッチ・コンプレックスは,アデレンス・ジャンクションと血管障壁機能を調節する
William J Polacheck1,2, Matthew L Kutys1,2, Jinling Yang1,2
1The Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA.
Nature
|November 22, 2017
まとめ
シーア・ストレスはNOTCH1を活性化します これは血管壁の整合性にとって重要な受容体です この非正規の経路は,転写とは関係なく,NOTCH1sのトランスメブラン領域を使用して,アデレンス結合を組み立て,血管機能を維持します.
科学分野:
- 血管生物学
- セル・シグナル
- バイオ物理学
背景:
- 内皮は血管の重要な障壁となり 輸送と炎症を制御します
- ヘモダイナミック・シーア・ストレスは内皮のバリア機能に不可欠ですが,その背後にあるメカニズムは不明です.
研究 の 目的:
- 切断ストレスが内皮のバリア機能を維持するメカニズムを解明する.
- 血管壁の整合性を調節する NOTCH1 の役割を調査する.
主な方法:
- 精製された微小容器の器官型モデルを使用した.
- マウスモデルを用いて検証した.
- NOTCH1の活性化とそのアデレンス結合への下流効果を調査した.
主要な成果:
- 切断ストレスは,NOTCH1のDLL4依存の活性化を引き起こし,そのトランスメブラン領域を暴露する.
- NOTCH1トランスメブラン領域は,内皮のバリア機能を回復するのに十分です.
- このドメインは,RAC1を活性化する受容体複合体 (VE-カデリン,LAR,TRIO) を促進し,アデレンス結合組を駆動する.
結論:
- NOTCH1の非正規的,転写独立の信号経路は,血管障壁機能を調節する.
- この経路は,アデレンス・ジャンクション・アセンブリを介して細胞骨格の再構築と転写プログラムをつなぎます.
- NOTCH1は血管生物学において二重の役割を果たし,正規の転写と非正規のシグナル伝達の両方を含む.
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