血管新生は,PI3Kのp110alpha同型を選択的に必要とし,内皮細胞の移動を制御します

Mariona Graupera¹, Julie Guillermet-Guibert, Lazaros C Foukas

¹Centre for Cell Signalling, Institute of Cancer, Queen Mary, University of London, Charterhouse Square, London EC1M 6BQ, UK.

Nature

|May 2, 2008

まとめ

フォスフォノシチド3キナーゼ (PI3Ks) は,血管の発達に不可欠です. 血管新生中の内皮細胞の移動と血管の再構築に不可欠なのはp110alphaの活性のみです.

科学分野:

分子生物学は分子生物学である.
細胞生物学細胞生物学
発達生物学発達生物学とは

背景:

フォスフォノシチド3キナーゼ (PI3Ks) は,様々な細胞表面受容体の下流にある重要なシグナル伝達酵素である.
p110触媒子単位とp85調節子単位で構成されるクラスIAのPI3Kイソフォームは,血管新生に関与しています.
in vivo血管新生中の内皮細胞におけるPI3Kの特定の役割と同型選択性は,依然としてほとんど不明である.

研究の目的:

アンジオゲネシス中の内皮細胞におけるPI3Kシグナル伝達のインビボ機能と同型選択性を調査する.
血管の発達を調節する重要なPI3Kイソフォームとその下流エフェクターを決定する.

主な方法:

p110alpha 機能を研究するために,至る所に存在するおよび内皮細胞特異的な遺伝子不活性化モデルを使用しました.
評価された胚死亡率,血管新生生芽生え,および血管再構築の欠陥.
小型GTPase RhoA.を介した内皮細胞移動の調節を調査した.

主要な成果:

内皮細胞特異的なp110alphaの不活性化により,血管新生芽生えと血管再構築の深刻な欠陥により,胚の致死性が生じました.
p110alphaの活動は,RhoA.を介して作用する,内皮細胞の移動に不可欠です.
p110alphaは,内皮細胞で高度に発現し,VEGF-A.のようなチロシンキナーゼリガンドによって好ましく誘発されます.
p110βはGPCRリガンド (例えばSDF-1alpha) の下流に信号を送り,p110deltaは内皮細胞におけるPI3K活性に最小限の貢献をしている.

結論:

p110alphaの活動は,血管の発達と血管新生に不可欠であり,内皮細胞自律的な機能を発揮します.
endothelial細胞におけるPI3Kシグナル伝達の in vivo isoform選択性を実証し,p110alphaが重要な役割を果たしています.
アンジオゲネシス中のRhoA経由での内皮細胞移動の重要なレギュレータとしてp110alphaを特定しました.

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