TRAF2とOTUD7Bは,mTORC2シグナリングを調節するユビキチン依存のスイッチを制御する
Bin Wang1,2, Zuliang Jie3, Donghyun Joo3
1Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
Nature
|May 11, 2017
まとめ
Gタンパク質結合受容体キナーゼ2 (GRK2) は,Gタンパク質結合受容体 (GPCR) のシグナリングを調節する. この研究では,GRK2
科学分野:
- 細胞信号と分子生物学
- 生化学と酵素学
- 癌の生物学と分子メカニズム
背景:
- ラパミシン (mTOR) 経路のメカニズム的ターゲットは,栄養素と成長因子信号を統合する細胞の成長と代謝に不可欠です.
- mTORC1とmTORC2という2つの異なる複合体で機能し,その異常は癌や代謝障害などの疾患に関連しています.
- mTORC1とmTORC2のダイナミック・アセンブリと機能的なスイッチングを制御する正確なメカニズムは,まだ完全に理解されていません.
研究 の 目的:
- mTORC2複合体の形成と活性化を調節するGβL (MLST8としても知られている) の役割を明らかにする.
- GβLのユビキチン化を調節する特定のユビキチンリガゼとデウビキチン酵素を特定する.
- 変化したGβLのユビキチン化がmTORC2の活性,下流信号伝達,および腫瘍形成に与える影響を調査する.
主な方法:
- 人間とマウスの細胞におけるGβLのユビキチン化状態を調査した.
- タンパク質とタンパク質の相互作用と複合体の形成 (mTORC1 vs. mTORC2) を評価するために生化学的測定を用いた.
- 遺伝子操作 (変異,欠損) と in vivo モデル (例えば,Kras駆動肺腫瘍形成) を使って,機能的な結果を調べた.
主要な成果:
- TRAF2E3リガゼによるGβLのK63結合ポリウビキチネーションは,GβL- SIN1の相互作用を妨害することによってmTORC1の形成を促進する.
- OTUD7BによるGβLのデウビキチン化は,GβL- SIN1の相互作用を促進し,成長信号によるmTORC2の組み立てと活性化を促します.
- ユビキチネーションを損なうGβLの変異または断絶はmTORC2の形成を促進し,AKTシグナル伝達と腫瘍発生を増加させます.
- ネズミにおけるOtud7bの遺伝的消去は,AKTの活性化とKras主導の肺癌を抑制する.
結論:
- GβLのユビキチン化状態は,mTORC2のダイナミックな組立と活性化を制御する重要なスイッチとして機能する.
- TRAF2とOTUD7Bは,GβLユビキチネーションの反対の調節をオーケストラし,それによってmTORC1/mTORC2バランスを調整する.
- このユビキチネーションに依存するメカニズムは,生理学的状態と癌の発達の両方でmTORC2の活性を調節するために不可欠です.
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