低分子量G蛋白質による細胞の増殖、運動の制御機構

• Project/Area Number: 09254103
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas (A)
• Allocation Type: Single-year Grants
• Research Institution: Hiroshima University
• Principal Investigator: 菊池 章 広島大学, 医学部, 教授 (10204827)
• Co-Investigator(Kenkyū-buntansha): 松田 道行 国立国際医療センター研究所, 臨床病理研究部, 部長 (10199812) ; 服部 成介 国立精神神経センター, 神経研究所・診断研究部, 室長 (50143508) ; 佐藤 孝哉 東京工業大学, 生命理工学部, 寄附講座教員 (20251655) ; 大矢 禎一 東京大学, 大学院・新領域創成科学研究科, 教授 (20183767) ; 松井 泰 東京大学, 大学院・理学系研究科, 助手 (50229407) ; 金保 安則 東京工業大学, 生命理工学部, 助教授 (00214437) ; 東江 昭夫 東京大学, 大学院・理学系研究科, 教授 (90029249)
• Project Period (FY): 1997 – 1999
• Project Status: Completed (Fiscal Year 1999)
• Budget Amount: ¥92,000,000 (Direct Cost: ¥92,000,000); Fiscal Year 1999: ¥32,000,000 (Direct Cost: ¥32,000,000); Fiscal Year 1998: ¥32,000,000 (Direct Cost: ¥32,000,000); Fiscal Year 1997: ¥28,000,000 (Direct Cost: ¥28,000,000)
• Keywords: 発がん / 転移 / 低分子量G蛋白質 / Ras / Rho / 酵母 / Ral / RasGRF1 / GAP1m / CalDAGI / cAMP-GEF / PLD / 細胞増殖 / 細胞運動

Research Abstract

低分子量G蛋白質RasとRhoの細胞増殖や運動における役割を解析した。Ras/RalGDS/Ral/RalBP1/POB1の下流にEps15とEpsinが存在して、インスリンとEGF依存性の受容体のエンドサイトーシスを制御した。RasのGDP/GTP交換反応促進蛋白質Ras-GRF1が、G蛋白質共役型受容体刺激によりチロシンリン酸化され、DHドメインを介してRacのGDP/GTP交換反応を促進した。SH2領域およびRasGRF相同領域をもつ新規因子ChatはCasに結合し、MAPキナーゼによりリン酸化された。Rap1の不活性化因子Rap1GAPのファミリーである新規蛋白質Rap1GAPIIのN末端側のGolocoモチーフが三量体G蛋白質Giのαサブユニットに刺激依存性に結合し、Rap1を不活化した。Rac1依存性のラッフル膜形成にARF6とPI(4)P5Kαが関与した。酵母Rho3の不活性型と結合する蛋白質として単離したRab型G蛋白質Ypt11は、Rho3の標的蛋白質Myo2とも結合し、Myo2の活性がYpt11により制御された。翻訳後修飾を受けている酵母Rho1はその標的蛋白質であるグルカン合成酵素を活性化すると共にFks1とも効率よく結合した。酵母Rho1の標的タンパク質でフォルミンファミリーに属するBNI1が細胞膜表面の極性マーカーとして働き、細胞質微小管と相互作用して核分裂の方向を制御した。
これらの結果から、低分子量G蛋白質のGDP/GTP交換反応促進蛋白質(RasGRF,C3G,Dbl)がチロシンキナーゼにより活性化されることが明らかになった。また、低分子量G蛋白質間の制御機構が酵母から哺乳動物細胞まで普遍的に存在すると考えられた。さらに、Rho1がアクチン系と微小管系の両者を制御する可能性が示唆された。

Research Products

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