GTPasesのRASおよびRHOファミリーは,異なるフォスフォイノシチド3キナーゼ同型を直接調節する
Ralph Fritsch1, Inge de Krijger, Kornelia Fritsch
1Signal Transduction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
Cell
|May 28, 2013
まとめ
RASタンパク質は,いくつかのフォスホイノシチド3キナーゼ (PI3Ks) を活性化しますが,p110βは活性化しません. 代わりに,RHO GTPases RAC1とCDC42はp110βを活性化し,細胞シグナル伝達と線維症に影響を与えます.
科学分野:
- 分子生物学は分子生物学である.
- 細胞シグナル伝達 細胞信号伝達
- がん研究 がん研究
背景:
- RASタンパク質は,そのRAS結合領域 (RBD) を通してp110α,p110γ,p110δのような特定のタイプIフォスホイノシチド3キナーゼ (PI3K) を活性化します.
- PI3Kのp110β同型は,Gタンパク質結合受容体 (GPCR) 信号伝達,PTEN喪失がん,血小板機能に関与しています.
- 小型GTPasesによるp110β PI3Kイソフォームの規制メカニズムは,以前は不明でした.
研究 の 目的:
- フォスホイノシチド3キナーゼ (PI3K) のp110βイソフォームの調節を調査する.
- p110βと相互作用し,p110βを活性化する特定の小さなGTPasesを特定する.
- ケモタキシスなどの細胞プロセスにおけるp110β調節の役割と,肺線維症などの疾患モデルにおける役割を解明する.
主な方法:
- バイオケミカルアッセイを用いてRASとp110βの相互作用を調査した.
- p110βのRBD.に対する結合パートナーとして,RAC1とCDC42を特定した.
- PI3Kの活性,化学作用,肺線維症を評価するために,p110β RBDの変異を有する線維芽細胞とマウスモデルを使用した.
- GPCRsのダウンストリームでRACの活性化を媒介するDock180/Elmo1の役割を調べました.
主要な成果:
- RASタンパク質は,PI3Kのp110β同型と相互作用したり,活性化したりしません.
- RAC1とCDC42は,小型のGTPaseのRHOサブファミリーのメンバーで,直接p110βに結合し,そのRBD経由でp110βを活性化します.
- GPCRsはDock180/Elmo1を通じてRACを活性化させる信号を送り,RACは線維芽細胞のp110βと相互作用する.
- p110β RBDに変異があるマウスは,PI3Kの活性が低下し,化学反応が不全し,実験用の肺線維症に対する耐性を示した.
結論:
- RASとRHOファミリーのGTPaseは,異なるPI3K同型体を差異的に調節する.
- RAC1とCDC42は,p110β PI3Kイソフォームの直接活性化剤である.
- GPCRsの下流のRAC活性化は,p110β媒介の細胞機能と線維反応において重要な役割を果たします.
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