Rasのキナーゼ抑制剤は,セラミド活性化タンパク質キナーゼである
1Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Cell
|April 4, 1997
まとめ
Ras (KSR) のキナーゼ抑制剤は,セラミド活性化タンパク質 (CAP) キナーゼとして識別されます. KSRはスフィンゴミエリン経路経由で,Raf-1を活性化させ,TNFαシグナル伝達を開始して,トランスメブラン信号伝達を媒介する.
科学分野:
- 細胞の信号伝達経路は,
- 分子生物学は分子生物学である.
- シグナルトランスデュークション.
背景:
- セラミド活性化タンパク質 (CAP) キナーゼは,スフィンゴミエリン経路を通じてトランスメブランシグナル伝達を媒介する.
- CAPキナーゼは,Raf-1をリン酸化して活性化することによって,炎症性腫瘍死滅因子α (TNFα) の作用を開始する.
研究 の 目的:
- CAPキナーゼの分子同一性を特定するために.
- スフィンゴミエリン経路とTNFαシグナル伝達におけるKinase Suppressor of Ras (KSR) の役割を調査する.
主な方法:
- カエノラブディティス・エレガンズとドロソフィラのKSRの遺伝子識別.
- マウスKSRの生化学的特徴,オートフォスフォリレーションと膜結合特性を含む.
- TNFαとセラミドの類似体に対する反応として,Raf-1とのKSRの相互作用とRaf-1のリン酸化の分析.
- 天然のセラミドやその他の脂質第2伝達物質を用いたインビトロキナーゼアッセイ.
主要な成果:
- Ras (KSR) のキナーゼ抑制剤は,CAPキナーゼとして特定されました.
- マウスKSRは,100kDaの膜に結合したポリペプチドとして機能し,自己リン酸化する.
- KSRの過剰発現は,構成的なRaf-1の活性化につながる.
- TNFアルファおよびセラミド類は,KSRの自己リン酸化,Raf-1との複合体形成,およびその後のRaf-1活性化を著しく強化します.
- KSRは,CAPキナーゼが標的とする同じ部位であるThr269のRaf-1を特にリン酸化する.
結論:
- KSRはCAPキナーゼとして機能し,スフィンゴミエリン経路において重要な役割を果たします.
- KSRは,Raf-1をリン酸化して活性化することによって,TNFα誘発信号伝達を媒介する.
- これらの発見は,トランスメブランシグナル伝達と炎症反応の重要な構成要素を明らかにします.
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