2000 年度実績報告書

細胞増殖のシグナリング機構

研究課題

研究課題/領域番号	12215079
研究種目	特定領域研究(C)
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	萬代研二大阪大学, 医学系研究科, 助手 (50322186) 中西宏之大阪大学, 医学系研究科, 助教授 (80314318) 的崎尚大阪大学, 医学系研究科, 助教授 (80252782) 佐々木卓也徳島大学, 医学部, 教授 (40241278)
キーワード	細胞増殖 / 細胞接着 / 細胞運動 / Nectin-Afadin-Ponsin系 / Frabin-Cdc42系 / Cadherin-Catenin系 / Gab-1 / Rab11
研究概要	細胞接着のシグナル系は細胞の増殖や運動のシグナル系とクロストークし、これらシグナル系の異常は細胞のがん化やがん細胞の浸潤・転移と密接に関連している。これまで私共は、新しい細胞間接着機構であるNectin-Afadin-Ponsin(NAP)系と、新しい細胞運動の制御機構であるFrabin-Cdc42系を見出している。NAP系はCadherin-Catenin系と関連しながら、細胞間接着の形成を制御している。Frabinは、F-アクチン結合蛋白質であり、かつCdc42低分子量G蛋白質の特異的活性化因子である。そこで、本年度の本研究では、NAP系とFrabin-Cdc42系を中心に、細胞の増殖、接着、運動のシグナル系について解析を行い、以下の成果を得た。 (1)NAP系の作用機構:私共は、NAP系がα-Cateninとタイトジャンクションの構成分子ZO-1と連結し、Cadherin-Catenin系とZO-1を細胞間接着にリクルートすることを明らかにした。 (2)Frabin-Cdc42系の作用機構:Frabinは、その直接的なアクチン細胞骨格への作用とCdc42活性化作用が協調的に機能することによって、細胞運動を制御しているを見出した。 (3)細胞の増殖と接着のシグナル系のクロストーク:Cadherinによる細胞接着が、Srcファミリーを介してGab-1のチロシンリン酸化を引き起こし、MAPキナーゼとAktキナーゼを制御していることを明らかにした。 (4)Rabの作用機構:Rab11の標的蛋白質Rabphilin-11に結合する蛋白質として、酵母Sec13pの哺乳類ホモログであるmSec13pを同定し、Rab11-Rabphilin-11系がmSec13pとの相互作用を介して細胞運動を制御していることを明らかにした。このように、本年度の本研究は予想以上に進展し、当初の目的を達成することができた。

研究成果
(22件)

すべてその他

すべて文献書誌 (22件)

[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.. 275・14. 10291-10299 (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.. 275・18. 13167-13170 (2000)
[文献書誌] Deguchi,M.: "PAPAIN-A novel multiple PSD-95/Dlg-A/zO-1 protein interacting with neural plakophihlin-related armadillo-repeat protein(NPRAP)/ δ-catenin and p0071."J.Biol.Chem.. 275・38. 29875-29880 (2000)
[文献書誌] Tachibana,K.: "Two cell adhesion molecules, Nectin and Cadherin, interact through their cytoplasmic domain-associated proteins."J.Cell Biol.. 150・5. 1161-1176 (2000)
[文献書誌] Takakura,A.: "Involvement of a small GTP-binding protein (G protein) regulator, small G protein GDP dissociation stimulator, in antiapoptotic cell survival signaling."Mol.Biol.Cell. 11・5. 1875-1886 (2000)
[文献書誌] Kodama,A.: "Involvement of an SHP-2-Rho small G protein pathway in hepatocyte growth factor/scatter factor-induced cell scattering."Mol.Biol.Cell. 11・8. 2565-2575 (2000)
[文献書誌] Ono,Y.: "Two actions of frabin : direct activation of Cdc42 and indirect activation of Rac."Oncogene. 19・27. 3050-3058 (2000)
[文献書誌] Kikyo,M.: "Cell-cell adhesion-mediated tyrosine phosphorylation of nectin-2δ, an immunoglobulin-like cell adhesion molecule at adherens junctions."Oncogene. 19・35. 4022-4028 (2000)
[文献書誌] Yao,I.: "Association of membrane-associated guanylate kinase-interacting protein (MAGUIN)-1 with Raf-1."Biochem.Biophys.Res.Commun.. 270・2. 538-542 (2000)
[文献書誌] Fujiwara,T.: "Rho small G protein-dependent binding of mDia to a Src homology 3 domain-containing IRSp 53/BAIAP2 ."Biochem.Biophys.Res.Commun.. 271・3. 626-629 (2000)
[文献書誌] Takaishi,K.: "Mechanisms of activation and action of mDial in the formation of parallel stress fibers in MDCK cells."Biochem.Biophys.Res.Commun.. 274・1. 68-72 (2000)
[文献書誌] Yasuda,T.: "Importance of spatial activation of Cdc42 small G proteins by frabin for its functions in MDCK cells."Genes Cells. 5・7. 583-591 (2000)
[文献書誌] Takaishi,K.: "Multiple downstream signaling rathways from ROCK, a target molecule of Rho small G protein, in reorganization of the actin cytoskeleton in Madin-Darby canine kidney cells."Genes Cells. 5・11. 929-936 (2000)
[文献書誌] Peng,Y.F.: "Ankycorbin : A novel actin cytoskeleton-associated protein."Genes Cells. 5・12. 925-932 (2000)
[文献書誌] Mino,A.: "Membrane-associated guanylate kinase with inverted orientation(HAGI)-1/brain angiogenesis inhibitor 1-associated protein(BAP1) as a scaffolding molecule for Rap small G protein GDP/GTP exchange protein at tight junctions"Genes Cells. 5・12. 1009-1016 (2000)
[文献書誌] Suzuki,T.: "Rho family GTPase Cdc42 is essential for the actin-based motility of Shigella in mammalian cells."J.Exp.Med.. 191・11. 1905-1920 (2000)
[文献書誌] Mammoto A.: "Stimulation of Rho GDI relaease by ERM proteins."Methods Enzymol.. 325. 91-101 (2000)
[文献書誌] Matozaki,T.: "Small G protein networks : Their crosstalks and signal cascades."Cellular Signalling. 12・8. 515-524 (2000)
[文献書誌] Ozaki-Kuroda,K.: "Dynamic localization and function of Bnilp at the sites of directed growth in yeast Saccharomyces cerevisiae."Mol.Cell.Biol.. 21・3. 827-839 (2001)
[文献書誌] Takai,Y.: "Small GTP-binding proteins."Physiol.Rev.. 81・1. 153-208 (2001)
[文献書誌] Sakisaka,T.: "Requirement of interaction of Nectin-1α/HveC with afadin for efficient cell-cell spread of herpes simplex virus type 1."J.Virol.. (in press). (2001)

2000 年度 実績報告書

細胞増殖のシグナリング機構

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] 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.. 275・14. 10291-10299 (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.. 275・18. 13167-13170 (2000)

[文献書誌] Deguchi,M.: "PAPAIN-A novel multiple PSD-95/Dlg-A/zO-1 protein interacting with neural plakophihlin-related armadillo-repeat protein(NPRAP)/ δ-catenin and p0071."J.Biol.Chem.. 275・38. 29875-29880 (2000)

[文献書誌] Tachibana,K.: "Two cell adhesion molecules, Nectin and Cadherin, interact through their cytoplasmic domain-associated proteins."J.Cell Biol.. 150・5. 1161-1176 (2000)

[文献書誌] Takakura,A.: "Involvement of a small GTP-binding protein (G protein) regulator, small G protein GDP dissociation stimulator, in antiapoptotic cell survival signaling."Mol.Biol.Cell. 11・5. 1875-1886 (2000)

[文献書誌] Kodama,A.: "Involvement of an SHP-2-Rho small G protein pathway in hepatocyte growth factor/scatter factor-induced cell scattering."Mol.Biol.Cell. 11・8. 2565-2575 (2000)

[文献書誌] Ono,Y.: "Two actions of frabin : direct activation of Cdc42 and indirect activation of Rac."Oncogene. 19・27. 3050-3058 (2000)

[文献書誌] Kikyo,M.: "Cell-cell adhesion-mediated tyrosine phosphorylation of nectin-2δ, an immunoglobulin-like cell adhesion molecule at adherens junctions."Oncogene. 19・35. 4022-4028 (2000)

[文献書誌] Yao,I.: "Association of membrane-associated guanylate kinase-interacting protein (MAGUIN)-1 with Raf-1."Biochem.Biophys.Res.Commun.. 270・2. 538-542 (2000)

[文献書誌] Fujiwara,T.: "Rho small G protein-dependent binding of mDia to a Src homology 3 domain-containing IRSp 53/BAIAP2 ."Biochem.Biophys.Res.Commun.. 271・3. 626-629 (2000)

[文献書誌] Takaishi,K.: "Mechanisms of activation and action of mDial in the formation of parallel stress fibers in MDCK cells."Biochem.Biophys.Res.Commun.. 274・1. 68-72 (2000)

[文献書誌] Yasuda,T.: "Importance of spatial activation of Cdc42 small G proteins by frabin for its functions in MDCK cells."Genes Cells. 5・7. 583-591 (2000)

[文献書誌] Takaishi,K.: "Multiple downstream signaling rathways from ROCK, a target molecule of Rho small G protein, in reorganization of the actin cytoskeleton in Madin-Darby canine kidney cells."Genes Cells. 5・11. 929-936 (2000)

[文献書誌] Peng,Y.F.: "Ankycorbin : A novel actin cytoskeleton-associated protein."Genes Cells. 5・12. 925-932 (2000)

[文献書誌] Mino,A.: "Membrane-associated guanylate kinase with inverted orientation(HAGI)-1/brain angiogenesis inhibitor 1-associated protein(BAP1) as a scaffolding molecule for Rap small G protein GDP/GTP exchange protein at tight junctions"Genes Cells. 5・12. 1009-1016 (2000)

[文献書誌] Suzuki,T.: "Rho family GTPase Cdc42 is essential for the actin-based motility of Shigella in mammalian cells."J.Exp.Med.. 191・11. 1905-1920 (2000)

[文献書誌] Mammoto A.: "Stimulation of Rho GDI relaease by ERM proteins."Methods Enzymol.. 325. 91-101 (2000)

[文献書誌] Matozaki,T.: "Small G protein networks : Their crosstalks and signal cascades."Cellular Signalling. 12・8. 515-524 (2000)

[文献書誌] Ozaki-Kuroda,K.: "Dynamic localization and function of Bnilp at the sites of directed growth in yeast Saccharomyces cerevisiae."Mol.Cell.Biol.. 21・3. 827-839 (2001)

[文献書誌] Takai,Y.: "Small GTP-binding proteins."Physiol.Rev.. 81・1. 153-208 (2001)

[文献書誌] Sakisaka,T.: "Requirement of interaction of Nectin-1α/HveC with afadin for efficient cell-cell spread of herpes simplex virus type 1."J.Virol.. (in press). (2001)

2000 年度実績報告書

高井義美大阪大学, 医学系研究科, 教授 (60093514)