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mTORC1の活性抑制は,後期エンドソーマルフォスファディチルノシトール3,4-ビスホスファートによる

Andrea L Marat¹, Alexander Wallroth¹, Wen-Ting Lo¹

¹Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Robert-Roessle-Strasse 10, 13125 Berlin, Germany.

Science (New York, N.Y.)

|June 3, 2017

まとめ

PI3KC2βによって生成されるフォスファチチドリノシトール3,4-二リン酸 [PI(3,4) P2]は,ラパミシン複合体1 (mTORC1) 経路の機械的標的の新型抑制剤として作用する. この発見は栄養不足の時に細胞の成長を制御する新しいメカニズムを明らかにしています

科学分野:

細胞生物学
分子生物学
生物化学

背景:

ラパミシン複合体1 (mTORC1) のメカニズムの標的は細胞の成長を調節し,栄養素によって活性化されます.
クラスIのフォスファディチリノシトール3キナーゼ (PI3Ks) は,プラズマ膜でのmTORC1をフォスファディチリノシトール3,4,5-トリスホスファート [PI(3,4,5) P3]の産生で刺激する.

研究の目的:

成長因子欠乏時にmTORC1活動を抑制するメカニズムを調査する.
リソソームと遅いエンドソーム (LyLEs) でmTORC1シグナル伝達の新しいレギュレータを特定する.

主な方法:

クラスIIのPI3Kβ (PI3KC2β) とその産物であるフォスファディチルイノシトール3,4-ビスホスファート[PI(3,4) P2]がmTORC1の調節における役割を調査した.
mTORC1の活性,タンパク質対タンパク質の相互作用,および脂質の局所化を評価するための技術を使用した.

主要な成果:

mTORC1の負の調節体として,LyLEsでPI3KC2βによって合成されたPI(3,4) P2を特定した.
PI3KC2βが欠けている細胞でmTORC1の過剰活性化が観察された.
成長因子欠乏がmTORC1のラプターサブユニットとPI3KC2βの結合を誘導することを示した.
局所PI ((3,4) P2の合成が,mTORC1を抑制して,ラプター結合を阻害する14-3-3タンパク質に促進することを示した.

結論:

PI3KC2β媒介の局所PI(3,4) P2合成は,mTORC1を停止するための重要なメカニズムである.
この経路は,栄養素や成長因子の不足の条件下でmTORC1の信号を抑制する予期せぬ経路を提供する.

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