細胞の増殖・分化のシグナル伝達機構

1998 Fiscal Year Annual Research Report

• Project/Area Number: 06283221
• Research Institution: Osaka University
• Principal Investigator: 高井 義美 大阪大学, 医学部, 教授 (60093514)
• Co-Investigator(Kenkyū-buntansha): 田中 一馬 大阪大学, 医学部, 助教授 (60188290)
• Keywords: 低分子量G蛋白質 / Rho / Rab / アクチン細胞骨格 / 細胞内小胞輸送 / 細胞運動 / がん / 浸潤・転移

Research Abstract

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、および生理機能につき解析を行い、以下の結果を得た。
(1) Rhoの活性化機構:MDCK細胞のTPAによる細胞遊走の際には、Rhoが時間的・空間的にON、OFFとなり、ストレスファイバーの再構成や接着斑の形成を介して細胞運動を制御していることを明らかにした。
(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(動物細胞ではmDia)がアクチンの重合過程を制御していることを明らかにしているが、このBNI1を細胞膜へ局在させる蛋白質としてSPA2を見い出し、さらにSPA2に結合する因子が細胞質分裂に関与するセプチンであることを見い出した。また、動物細胞においては、BNI1系(mDia系)とともにセリン/スレオニンキナーゼであるROCKの機能を検討し、Rhoによるアクチン細胞骨格の再編成には、BNI1系(mDia系)とROCK系の両者が重要であることを明らかにした。
(3) RF10系とRab系の協調的作用機構:Rho系とRab系が、協調的に作用してインテグリンやカドヘリンなどの接着分子やHGF受容体(c-Met)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。
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。

Research Products

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• [Publications] Mochida,S.: "Role of the Doc2α-Munc13-1 interaction in the neurotransmitter release process." Proc.Natl.Acad.Sci.USA. 95・19. 11418-11422 (1998)
• [Publications] Fujiwara,T.: "Rholp-Bnilp-Spa2p interactions-Implication in localization of Bnilp at the bud site and regulation of the actin cytoskeleton in Saccharomyces cerevisiae." Mol.Biol.Cell. 9・5. 1221-1223 (1998)
• [Publications] Imamura,H.: "Rho and Rab small G proteins coordinately reorganize stress fibers and focal adhesions in MDCK cells." Mol.Biol.Cell. 9・9. 2561-2575 (1998)
• [Publications] Asakura,T.: "Isolation and characterization of a novel actin filament-binding protein from Saccharomyces cerevisiase." Oncogene. 16・1. 121-130 (1998)
• [Publications] Umikawa,M.: "Interaction of Rholp target Bnilp and F-actin-binding elongation factor 1d-Implication in Rholp-regulated reorganization of the actin cytoskeleton in Saccharomyces cerevisiae." Oncogene. 16・15. 2011-2016 (1998)
• [Publications] Takahashi,K.: "Interaction of Radixin with Rho small G protein GDP/GTP exchange protein Dbl." Oncogene. 16・25. 3279-3284 (1998)
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• [Publications] Tanaka,K.: "Control of reorganization of the actin cytoskeleton by Rho family small GTP-binding proteins in yeast." Curr.Opin.Cell Biol.10・1. 112-116 (1998)
• [Publications] Sasaki,T.: "The Rho small G protein family-Rho GDI system as a temporal and spatial determinant for cytoskeletal control." Biochim.Biophys.Res.Commun.245・3. 641-645 (1998)
• [Publications] Yao,I.: "MAGUIN-A novel neuronal membrane-associated guanylate kinase-interacting protein." J.Biol.Chem.(in press). (1999)
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• [Publications] Orita,S.et.al.: "Frontiers of Neural Development" Springer-Verlag Tokyo Inc.,Tokyo, 444-449 (1999)