タンパク質キナーゼAktによる内皮由来の酸化窒素生成の調節
D Fulton1, J P Gratton, T J McCabe
1Department of Pharmacology, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06536, USA.
Nature
|June 22, 1999
まとめ
セリン/スレオニンタンパク質キナーゼAktは,セリン1179に内皮酸化窒素合成酵素 (eNOS) を直接リン酸化し,それを活性化し,酸化窒素 (NO) の生成を増加させます. この発見は,Aktのシグナル伝達と内皮細胞のNO放出を関連付けています.
科学分野:
- バイオケミストリー バイオケミストリー
- 分子生物学は分子生物学である.
- セルラー・シグナリング
背景:
- 内皮酸化窒素合成酵素 (eNOS) は,血圧,血管再構成,血管新生を調節する.
- 酸化窒素 (NO) 産生におけるeNOSリン酸化の役割と,その原因となるキナーゼは,ほとんど不明のままである.
研究 の 目的:
- eNOSの活性をリン酸化および調節するAktの役割を調査する.
- AktによるeNOSリン酸化の特定の部位と,その機能的結果を特定する.
主な方法:
- AktとeNOSを用いたインビトロキナーゼアッセイ.
- eNOS (S1179A変異体) のサイト指向型変異.
- アデノウイルス媒介の遺伝子転送により,内皮細胞におけるAkt活性が調節される.
主要な成果:
- Aktは,セリン1179でeNOSを直接リン酸化し,酵素の活性化につながり,NOの産生を増加させます.
- 変異したeNOS (S1179A) は,Akt媒介によるリン酸化と活性化に耐性がある.
- 活性化されたAktは,基礎的なNO放出を促進し,抑制されたAktは,血管内皮成長因子によって刺激されたNO生産を減少させます.
結論:
- eNOSは,Aktの新型基板であり,Aktのシグナル伝達とNO生成の間の直接的なリンクを確立しています.
- S1179におけるeNOSのAkt媒介のリン酸化は,内皮細胞におけるNO放出の重要な規制メカニズムである.
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