1999 年度実績報告書

細胞の増殖・分化のシグナルの伝達機構

研究課題

研究課題/領域番号	06283221
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)
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
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

(21件)

すべてその他

すべて文献書誌 (21件)

[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)
[文献書誌] Mammoto, A.: "RabllBP/Rabphilin-11 - A downstream target of rab11 small G protein implicated in vesicle recycling"J. Biol. Chem.. 274・36. 25517-25524 (1999)
[文献書誌] Kawabe, H.: "nArgBP2, a novel neural member of Ponsin/ArgBR2/Vinexin family that interacts with Synapse-associated protein 90/postsynaptic density-95-associated protein (SAPAP)"J. Biol. Chem.. 274・43. 30914-30918 (1999)
[文献書誌] Mandai, K.: "Ponsin/SH3P12 : An 1-afadin- and vinculin-binding protein localized at cell-cell and cell-matrix adherens junctions"J. Cell Biol.. 144・5. 1001-1017 (1999)
[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)
[文献書誌] Nakano, K.: "Distinct actions and cooperative roles of ROCK and mDia in Rho small G protein-induced reorganization of the actin cytoskeleton in MDCK cells"Mol. Biol. Cell. 10・8. 2481-2491 (1999)
[文献書誌] Fujiwara, T.: "Bnilp regulates microtubule-dependent nuclear migration through the actin cytoskeleton in Saccharomyces cerevisiae"Mol. Cell. Biol.. 19・12. 8016-8027 (1999)
[文献書誌] Sakisaka, T.: "Different behavior of l-afadin and neurabin-II during the formation and destruction of cell-cell adherens junction"Oncogene. 18・8. 1609-1618 (1999)
[文献書誌] Irie, M.: "Isolation and characterization of mammalian homologues of Caenorhabditis elegans lin-7 - localization at cell-cell junctions"Oncogene. 18・18. 2811-2817 (1999)
[文献書誌] Kodama, A.: "Involvement of Cdc42 small G protein in cell-cell adhesion, migration, and morphology of MDCK cells"Oncogene. 18・27. 3996-4006 (1999)
[文献書誌] Togawa, A.: "Progressive impairment of kidneys and reproductive organs in mice lacking Rho GDIα"Oncogene. 18・39. 5373-5380 (1999)
[文献書誌] Kamei, T.: "Coendocytosis of cadherin and c-Met coupled to disruption of cell-cell adhesion in MDCK cells - Regulation by Rho, Rac, and Rab small G proteins"Oncogene. 18・48. 6776-6784 (1999)
[文献書誌] Kikyo, M.: "An FH domein-containing Bnrip is a multifunctional protein interacting with a variety of cytoskeletal proteins in Saccharomyces cerevisiae"Oncogene. 18・50. 7046-7054 (1999)
[文献書誌] Ide, N.: "Localization of membrane-associated guanylate kinase (MAGI) -1/BAI-associated protein (BAP) 1 at tight junctions of epithelial cells"Oncogene. 18・54. 7810-7815 (1999)
[文献書誌] Asakura, T.: "Similar and differential behavior between the nectin-afadin-ponsin and cadherin-catenin systems during the formation and disruption of the polarised junctional alignment in epithelial cells"Genes Cells. 4・10. 573-581 (1999)
[文献書誌] Miyahara, M.: "Interaction of nectin with afadin is necessary for its clustering at cell-cell contact sites but not for its cis dimerization or trans interaction"J. Biol. Chem.. 275・1. 613-618 (2000)
[文献書誌] Satoh-Horikawa, K.: "Nectin-3 : A new member of immunoglobulin-like cell adhesion molecules that shows homophilic and heterophilic cell-cell adhesion activities"J. Biol. Chem.. (in press). (2000)
[文献書誌] Ide, N.: "Distinct localization of the S-SCAM and PSD-95/SAP90 families at cell-cell junctions"Oncogene. (in press). (2000)
[文献書誌] Sakisaka, T.: "Requirement of interaction of Nectin-1/HveC with afadin for efficient entry of herpes simplex virus type 1"J. Virol.. (in press). (2000)
[文献書誌] Mammoto, A.: "Physical and functional interaction of rabphilin-11 with mammalian sec13 protein. implication in vesicle trafficking"J. Biol. Chem.. (in press). (2000)

1999 年度 実績報告書

細胞の増殖・分化のシグナルの伝達機構

研究代表者

高井 義美 大阪大学, 医学系研究科, 教授 (60093514)

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)

[文献書誌] Mammoto, A.: "RabllBP/Rabphilin-11 - A downstream target of rab11 small G protein implicated in vesicle recycling"J. Biol. Chem.. 274・36. 25517-25524 (1999)

[文献書誌] Kawabe, H.: "nArgBP2, a novel neural member of Ponsin/ArgBR2/Vinexin family that interacts with Synapse-associated protein 90/postsynaptic density-95-associated protein (SAPAP)"J. Biol. Chem.. 274・43. 30914-30918 (1999)

[文献書誌] Mandai, K.: "Ponsin/SH3P12 : An 1-afadin- and vinculin-binding protein localized at cell-cell and cell-matrix adherens junctions"J. Cell Biol.. 144・5. 1001-1017 (1999)

[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)

[文献書誌] Nakano, K.: "Distinct actions and cooperative roles of ROCK and mDia in Rho small G protein-induced reorganization of the actin cytoskeleton in MDCK cells"Mol. Biol. Cell. 10・8. 2481-2491 (1999)

[文献書誌] Fujiwara, T.: "Bnilp regulates microtubule-dependent nuclear migration through the actin cytoskeleton in Saccharomyces cerevisiae"Mol. Cell. Biol.. 19・12. 8016-8027 (1999)

[文献書誌] Sakisaka, T.: "Different behavior of l-afadin and neurabin-II during the formation and destruction of cell-cell adherens junction"Oncogene. 18・8. 1609-1618 (1999)

[文献書誌] Irie, M.: "Isolation and characterization of mammalian homologues of Caenorhabditis elegans lin-7 - localization at cell-cell junctions"Oncogene. 18・18. 2811-2817 (1999)

[文献書誌] Kodama, A.: "Involvement of Cdc42 small G protein in cell-cell adhesion, migration, and morphology of MDCK cells"Oncogene. 18・27. 3996-4006 (1999)

[文献書誌] Togawa, A.: "Progressive impairment of kidneys and reproductive organs in mice lacking Rho GDIα"Oncogene. 18・39. 5373-5380 (1999)

[文献書誌] Kamei, T.: "Coendocytosis of cadherin and c-Met coupled to disruption of cell-cell adhesion in MDCK cells - Regulation by Rho, Rac, and Rab small G proteins"Oncogene. 18・48. 6776-6784 (1999)

[文献書誌] Kikyo, M.: "An FH domein-containing Bnrip is a multifunctional protein interacting with a variety of cytoskeletal proteins in Saccharomyces cerevisiae"Oncogene. 18・50. 7046-7054 (1999)

[文献書誌] Ide, N.: "Localization of membrane-associated guanylate kinase (MAGI) -1/BAI-associated protein (BAP) 1 at tight junctions of epithelial cells"Oncogene. 18・54. 7810-7815 (1999)

[文献書誌] Asakura, T.: "Similar and differential behavior between the nectin-afadin-ponsin and cadherin-catenin systems during the formation and disruption of the polarised junctional alignment in epithelial cells"Genes Cells. 4・10. 573-581 (1999)

[文献書誌] Miyahara, M.: "Interaction of nectin with afadin is necessary for its clustering at cell-cell contact sites but not for its cis dimerization or trans interaction"J. Biol. Chem.. 275・1. 613-618 (2000)

[文献書誌] Satoh-Horikawa, K.: "Nectin-3 : A new member of immunoglobulin-like cell adhesion molecules that shows homophilic and heterophilic cell-cell adhesion activities"J. Biol. Chem.. (in press). (2000)

[文献書誌] Ide, N.: "Distinct localization of the S-SCAM and PSD-95/SAP90 families at cell-cell junctions"Oncogene. (in press). (2000)

[文献書誌] Sakisaka, T.: "Requirement of interaction of Nectin-1/HveC with afadin for efficient entry of herpes simplex virus type 1"J. Virol.. (in press). (2000)

[文献書誌] Mammoto, A.: "Physical and functional interaction of rabphilin-11 with mammalian sec13 protein. implication in vesicle trafficking"J. Biol. Chem.. (in press). (2000)

1999 年度実績報告書

高井義美大阪大学, 医学系研究科, 教授 (60093514)