細胞の増殖・分化のシグナルの伝達機構

• 研究課題/領域番号: 06283221
• 研究種目: 特定領域研究(A)
• 配分区分: 補助金
• 研究機関: 大阪大学
• 研究代表者: 高井 義美 大阪大学, 医学系研究科, 教授 (60093514)
• 研究分担者: 佐々木 卓也 大阪大学, 医学系研究科, 助教授 (40241278) ; 田中 一馬 大阪大学, 医学部, 助教授 (60188290)
• 研究期間 (年度): 1994 – 1999
• 研究課題ステータス: 完了 (1999年度)
• 配分額: 215,000千円 (直接経費: 215,000千円); 1999年度: 41,000千円 (直接経費: 41,000千円); 1998年度: 40,000千円 (直接経費: 40,000千円); 1997年度: 39,000千円 (直接経費: 39,000千円); 1996年度: 35,000千円 (直接経費: 35,000千円); 1995年度: 30,000千円 (直接経費: 30,000千円); 1994年度: 30,000千円 (直接経費: 30,000千円)
• キーワード: 低分子量G蛋白質 / がん / Rho / Rab / アクチン細胞骨格 / 細胞内小胞輸送 / 細胞運動 / 浸潤・転移 / 低分子量GTP結合蛋白質 / 細胞骨格 / ERM / Rho GDI / BNI1 / CD44 / アクチン / Ras / MAPキナーゼ / B-Raf / 14-3-3蛋白質 / Smg GDS / ERM-CD44系

研究概要

RhoやRab低分子量G蛋白質を介するシグナル伝達経路の異常が、がん細胞の浸潤や転移に関与している可能性が考えられている。本研究において、私共は、RhoとRab低分子量G蛋白質に焦点をしぼり、その活性化機構、作用機構、および生理機能、さらに私共が見い出した新しい接着系につき解析を行い、以下の結果を得た。
(1)Rhoの活性化機構:私共は、チロシンホスファターゼSHP-2が、Rho低分子量G蛋白質の活性化を制御し、細胞運動の制御に関与していることを明らかにした。また、Cdc42のGDP/GTP交換促進蛋白質であるFrabinとCdc42を介する系が細胞運動の最も上流に位置する可能性を示した。
(2)Rhoの作用機構:私共は、出芽酵母において、Rhoの標的蛋白質であるBNI1を見い出しているが、BNI1がアクチン細胞骨格を介して微小管系細胞骨格をも制御していることを明らかにした。
(3)Rho系とRab系の協調的作用:Rho系とRab系が、協調的に作用してCadherinやHGF受容体を含む小胞の輸送を制御して、細胞の運動や接着を制御していることを明らかにした。また、Rab11の標的蛋白質であるRabphilin-11を見い出し、Rab11-Rabphilin-11複合体が細胞運動に関与することを示した。
(4)NAP系の生理機能:新しい接着系であるNAP(Nectin-Afadin-Ponsin)系の構成分子であるAfadinの遺伝子ノックアウトマウスの解析等から、NAP系が細胞間接着の形成の最も上流に位置し、他の細胞間接着装置を制御する可能性を示した。
このように、私共は、本年度の研究予定をほぼ達成することができた。

研究成果

• [文献書誌] Umikawa, M.: "Association of frabin with the actin cytoskeleton is essential for microspike formation through activation of Cdc42 small G protein"J. Biol. Chem.. 274・36. 25197-25200 (1999)
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• [文献書誌] Takahashi, K.: "Nectin/PRR : An immunoglobulin-like cell adhesion molecule recruited to cadherin-based adherens junctions through interaction with afadin, a PDZ domain-containing protein"J. Cell Biol.. 144・3. 539-549 (1999)
• [文献書誌] Ikeda, W.: "Afadin : a key molecule essential for structural organization of cell-cell junctions of polarised epithelia during embryogenesis"J. Cell Biol.. 146・5. 1117-1132 (1999)
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• [文献書誌] Fukui,K.: "Isolation and characterization of a GTPase activating protein specific for the Rab3 subfamily of small G proteins" J.Biol.Chem.272. 4655-4658 (1997)
• [文献書誌] Takeuchi,M.: "SAPAPs-A family of PSD-95/SAP90- associated proteins localized at postsynaptic density" J.Biol.Chem.(in press). (1997)
• [文献書誌] Imamura,H.: "Bnilp and Bnrlp - Downstream targets of the Rho family small G proteins which interact with profilin and regulate actin cytoskeleton in Saccharomyces cerevisiae" EMBO J.(in press). (1997)
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