1993 Fiscal Year Annual Research Report
Project/Area Number |
04253229
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Research Institution | Kobe University |
Principal Investigator |
高井 義美 神戸大学, 医学部, 教授 (60093514)
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Co-Investigator(Kenkyū-buntansha) |
田中 一馬 神戸大学, 医学部, 助手 (60188290)
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Keywords | 低分子量G蛋白質 / Rho / HGF / 細胞運動 / Rho GDI / C3 / TPA感受性因子 / Cキナーゼ |
Research Abstract |
低分子量G蛋白質の中でも、Rasは核遺伝子の発現を介して細胞の増殖や分化を制御していることが判明しているが、私共は本研究でRhoがアクトミオシン系を介して細胞の形態や運動を制御していることを明らかにした。すなわち、ケラチノサイト308R細胞にRhoの活性制御蛋白質であるRho GDIや、RhoをADPリボシル化してその機能を阻害するC3酵素をマイクロインジェクションすると、HGFによる細胞運動が完全に阻害された。このRho GDIやC3の作用は、活性型のRhoやADPリボシル化をうけない変異型Rhoと共にインジェクションすると認められなかった。また、Cキナーゼを活性化するTPAを作用させても細胞運動が引き起こされ、この作用はRho GDIやC3によって阻害された。細胞運動はRasやCa^<2+>とは直接関係していなかった。これらの結果から、HGFの受容体Metは何らかの機構でTPA感受性因子(Cキナーゼ?)を介してRhoを活性化し、その結果、細胞運動が引き起こされると考えられる。現在、TPA感受性因子がどのような機構でRhoの活性を制御しているか、Rhoがどのような機構で細胞運動を制御しているかを解析中である。Rasやその関連蛋白質の遺伝子の異常が細胞の異常増殖を引き起こすことはすでに判明しているが、これらのアナロジーからRhoとその関連蛋白質の遺伝子の異常ががん細胞の浸潤・転移に関与している可能性がでてきた。現在、RhoやRho関連蛋白質の遺伝子が浸潤・転移度の高いがん細胞で異常があるか否かも検討している。一方、Rasの活性制御蛋白質と標的蛋白質であるSmg GDS,REKSは共に私共の研究室で発見したものであるが、これらに関する本年度の研究も順調に進んだ。
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Research Products
(23 results)
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[Publications] Miura,Y.: "Regulation of morphology by rho p21 and its inhibitory GDP/GTP exchange protein(rho GDI) in Swiss 3T3 cells." J.Biol.Chem.268. 510-515 (1993)
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[Publications] Itoh,T.: "The post-translational processing of ras p21 is critical for its stimulation of mitogen-activated protein kinase." J.Biol.Chem.268. 3025-3028 (1993)
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[Publications] Ullrich,O.: "Rab GDP dissociation inhibitor as a general regulator for the membrane association of rab proteins." J.Biol.Chem.268. 18143-18150 (1993)
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[Publications] Burstein,E.S.: "Regulation of the GTPase cycle of the neuronally expressed Ras-like GTP-binding protein Rab3A." J.Biol.Chem.268. 22247-22250 (1993)
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[Publications] Kishida,S.: "Rab3A GTPase-activating protein-inhibiting activity of Rabphilin-3A,a putative Rab3A target protein." J.Biol.Chem.268. 22259-22261 (1993)
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[Publications] Sasaki,T.: "Consequences of weak interaction of rho GDI with the GTP-bound forms of rho p21 and rac p21." J.Biol.Chem.268. 23959-23963 (1993)
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[Publications] Orita,S.: "Comparison of kinetic properties between two mammalian ras p21 GDP/GTP exchange proteins,ras guanine nucleotide-releasing factor and smg GDP dissociation stimulator." J.Biol.Chem.268. 25542-25546 (1993)
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[Publications] Yamaguchi,T.: "Two functionally different domains of rabphilin-3A,rab3A p25/smg p25A-binding and phospholipid and Ca^<2+>-binding domains." J.Biol.Chem.268. 27164-27170 (1993)
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[Publications] Takaishi,K.: "Involvement of rho p21 and its inhibitory GDP/GTP exchange protein(rho GDI) in cell motility." Mol.Cell.Biol.13. 72-79 (1993)
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[Publications] Shirataki,H.: "Rabphilin-3A,a putative target protein for smg p25A/rab3A p25 small GTP-binding protein related to synaptotaqmin." Mol.Cell.Biol.13. 2061-2068 (1993)
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[Publications] Kishi,K.: "Regulation of cytoplasmic division of Xenopus embryo by rho p21 and its inhibitory GDP/GTP exchange protein(rho GDI)." J.Cell Biol.120. 1187-1195 (1993)
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[Publications] Itoh,T.: "A protein factor for ras p21-dependent activation of MAP kinase through MAP kinase-kinase." Proc.Natl.Acad.Sci.USA. 90. 975-979 (1993)
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[Publications] Takaishi,K.: "Involvement of Rho p21 small GTP-binding protein and its regulator in the HGF-induced cell motility." Oncogene. 9. 273-279 (1993)
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[Publications] Kawamura,M.: "Translocation of Ki-ras p21 between membrane and cytoplasm by smg GDS." Biochem.Biophys.Res.Commun.190. 832-841 (1993)
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[Publications] Sasaki,T.: "The nucleotide exchange rates of Rho and Rac small GTP-binding proteins are enhanced to different extents by their regulatory protein Smg GDS." Biochem.Biophys.Res.Commun.194. 1188-1193 (1993)
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[Publications] Sawai,T.: "Combination of arachidonic acid and guanosine 5'-0-(3-thiotriphosphate) induce translocation of rac p21s to membrane and activation of NADPH oxidase in a cell-free system." Biochem.Biophys.Res.Commun.195. 264-269 (1993)
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[Publications] Garrett,M.D.: "Interaction of Sec4 with GDI proteins from bovine brain,drosophila melanogaster and saccharomyces cerevisiae:conservation of GDI membrane dissociation activity." FEBS Lett.331. 233-238 (1993)
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[Publications] Motoike,T.: "Expression of smg p25A/rab 3A guanine nucleotide dissociation inhibitor(GDI) in neurons and glial cells from rat brain." Neuroscience Letters. 156. 87-90 (1993)
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[Publications] Miki,H.: "Association of Ash/Grb-2 with dynamin through the SH3 domain." J.Biol.Chem.(in press). (1994)
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[Publications] Wada,K.: "Localization of Rabphilin-3A,a putative target for Rab3A,at the sites of Ca^<2+>-dependent exocytosis in PC12 cells." Biochem.Biophys.Res.Commun.198. 158-165 (1994)
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[Publications] Yaku,H.: "The Dbl oncogene product as a GDP/GTP exchange protein for the Rho family.Its properties in comparison with those of Smg GDS" Biochem.Biophys.Res.Commun.198. 811-818 (1994)
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[Publications] Nakanishi,H.: "Kinetic properties of Ash/Grb2-interacting GDP/GTP exchange protein." Biochem.Biophys.Res.Commun.198. 1255-1261 (1994)
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[Publications] Nishiyama,T.: "rac p21 is involved in insulin-induced membrane ruffling and rho p21 is involved in hepatocyte growth factor and 12-0-tetradecanoylphorbol-13-acetate(TPA)-induced membrane ruffling in KB cells." Mol.Cell.Biol.(in press). (1994)