2003 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	匂坂敏朗大阪大学, 医学系研究科, 助手 (80359843) 清水一也大阪大学, 医学系研究科, 助手 (50335353) 入江賢児大阪大学, 医学系研究科, 助教授 (90232628)
キーワード	細胞増殖 / 細胞接着 / 細胞運動 / Nectin-Afadin系 / Cadherin-Catenin系 / Cdc42 / Rac / がん
研究概要	細胞の運動・増殖・接着のそれぞれのシグナル系の間には、密接なクロストークが存在し、とりわけ細胞の接触阻害の破綻が、がんの増殖や浸潤・転移の機構へとつながる。私共は、接着分子ネクチンが、カドヘリンと協調してアドヘレンスジャンクション(AJ)の形成を制御すること、Cdc42とRac低分子量G蛋白質を活性化することを明らかにしている。一方、ネクチン様分子Necl-5が細胞の運動を制御していることも明らかにしている。本年度の研究では、ネクチンとネクチン様分子を介した細胞の運動・増殖・接着のシグナル系のクロストークに焦点をあてて解析し、以下の成果を得た。 (1)ネクチンによって活性化されたCdc42が、上皮細胞におけるAJとタイトジャンクションの形成を促進した。ネクチンによるCdc42の活性化には、c-Srcと、GDP/GTP交換因子FRGが関与していた。また、トランス結合をしていないネクチンは、カドヘリンによるRacの活性化とAJの形成を阻害した。一方、ネクチンは、極性タンパク質Par-3に直接結合し、その局在化に関与していた。以上の結果から、細胞間接着形成におけるネクチンとCdc42、Racの作用機構が解明され、ネクチンが細胞極性の形成にも関与していることが明らかになった。 (2)ネクチン様分子Necl-5が、インテグリンおよび増殖因子受容体と協調的に作用して細胞の運動・増殖を制御していた。Necl-5とネクチンの結合は、細胞間接着形成にも関与していた。Necl-5の発現はがん細胞で上昇していると報告されていることから、Necl-5が、ネクチンやインテグリン、増殖因子受容体と相互作用しながら、がん細胞の運動・増殖の異常に関与していると考えられる。このように、本年度の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。今後、本研究をさらに発展させることにより、細胞の運動・増殖・接着のシグナル系のクロストークの分子機構が解明されるだけでなく、永年不明であった細胞の運動・増殖の接触阻害の分子機構や、がん化によるその破壊機構の分子機構の解明にもつながることが期待される。

研究成果
(20件)

すべてその他

すべて文献書誌 (20件)

[文献書誌] Asada, M.: "ADIP, a novel afadin- and α-actinin-binding protein localized at cell-cell adherens junctions."J.Biol.Chem.. 278・6. 4103-4111 (2003)
[文献書誌] Takekuni, K.: "Direct binding of cell polarity protein PAR-3 to cell-cell adhesion molecule nectin at neuroepithelial cells of developing mouse."J.Biol.Chem.. 278・8. 5497-5500 (2003)
[文献書誌] Ikeda, W.: "Tage4/nectin-like molecule-5 heterophilically trans-interacts with cell adhesion molecule nectin-3 and enhances cell migration."J.Biol.Chem.. 278・30. 28167-28172 (2003)
[文献書誌] Shingai, T.: "Implications of nectin-like molecule-2/IGSF4/RA175/SglGSF/TSLC1/SynCAM1 in cell-cell adhesion and transmembrane protein localization in epithelial cells."J.Biol.Chem.. 278・37. 35421-35427 (2003)
[文献書誌] Fukuhara, A.: "Involvement of nectin-activated Cdc42 small G protein in organization of adherens and tight junctions in Madin-Darby canine kidney cells."J.Biol.Chem.. 278・51. 51885-51893 (2003)
[文献書誌] Tanaka, Y.: "Role of nectin in formation of E-cadherin-based adherens junctions in keratinocytes : Analysis with the N-cadherin dominant negative mutant."Mol.Biol.Cell. 14・4. 1597-1609 (2003)
[文献書誌] Katata, T.: "Involvement of nectin in the localization of IQGAP1 at the cell-cell adhesion sites through the actin cytoskeleton in Madin-Darby canine kidney cells."Oncogene. 22・14. 2097-2109 (2003)
[文献書誌] Yasumi, M.: "Role of each immunoglobulin-like loop of nectin for its cell-cell adhesion activity."Biochem.Biophys.Res.Commun.. 302・1. 61-66 (2003)
[文献書誌] Honda, T.: "Regulation by nectin of the velocity of the formation of adherens junctions and tight junctions."Biochem.Biophys.Res.Commun.. 306・1. 104-109 (2003)
[文献書誌] Honda, T.: "Antagonistic and agonistic effects of an extracellular fragment of nectin on formation of E-cadherin-based cell-cell adhesion."Genes Cells. 8・1. 51-63 (2003)
[文献書誌] Honda, T.: "Cdc42 and Rac small G proteins activated by trans-interactions of nectins are involved in activation of c-Jun N-terminal kinase, but not in association of nectins and cadherin to form adherents junctions, in fibroblasts."Genes Cells. 8・5. 481-491 (2003)
[文献書誌] Kawabe, H.: "A novel Rabconnectin-3-binding protein that directly binds a GDP/GTP exchange protein for Rab3A small G protein implicated in Ca^<2+>-dependent exocytosis of neurotransmitter."Genes Cells. 8・6. 537-546 (2003)
[文献書誌] Takai, Y.: "Nectins and nectin-like molecules : Roles in cell adhesion, migration, and polarization."Cancer Science. 94・8. 655-667 (2003)
[文献書誌] Takai, Y.: "Nectin and afadin : Novel organizers of intercellular junctions."J.CellSci.. 116・1. 17-27 (2003)
[文献書誌] Shimizu, K.: "Roles of the intercellular adhesion molecule nectin in intracellular signaling."J.Biochem.. 134・5. 631-636 (2003)
[文献書誌] Ikeda, W.: "Nectin-like molecule-5/Tage4 enhances cell migration in an integrin-dependent, nectin-3-independent manner."J.Biol.Chem.. in press. (2004)
[文献書誌] Hoshino, T.: "A novel role of nectins in inhibition of the E-cadherin-induced activation of Rac and formation of cell-cell adherens junctions."Mol.Biol.Cell. 15・3. 1077-1088 (2004)
[文献書誌] Yamamoto, Y.: "Direct binding of the human homologue of the drosophila disc large tumor suppressor gene to seven-pass transmembrane proteins, tumor endothelial marker 5 (TEM5) and a novel TEM5-like protein."Oncogene. in press. (2004)
[文献書誌] Okabe, N.: "Localization patterns of nectins and afadin for epithelial remodeling during mouse development."Dev.Dyn.. in press. (2004)
[文献書誌] Irie, K.: "Roles of nectins in cell adhesion, signaling, and polarization."Handbook of Experimental Pharmacology. in press. (2004)

2003 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] Asada, M.: "ADIP, a novel afadin- and α-actinin-binding protein localized at cell-cell adherens junctions."J.Biol.Chem.. 278・6. 4103-4111 (2003)

[文献書誌] Takekuni, K.: "Direct binding of cell polarity protein PAR-3 to cell-cell adhesion molecule nectin at neuroepithelial cells of developing mouse."J.Biol.Chem.. 278・8. 5497-5500 (2003)

[文献書誌] Ikeda, W.: "Tage4/nectin-like molecule-5 heterophilically trans-interacts with cell adhesion molecule nectin-3 and enhances cell migration."J.Biol.Chem.. 278・30. 28167-28172 (2003)

[文献書誌] Shingai, T.: "Implications of nectin-like molecule-2/IGSF4/RA175/SglGSF/TSLC1/SynCAM1 in cell-cell adhesion and transmembrane protein localization in epithelial cells."J.Biol.Chem.. 278・37. 35421-35427 (2003)

[文献書誌] Fukuhara, A.: "Involvement of nectin-activated Cdc42 small G protein in organization of adherens and tight junctions in Madin-Darby canine kidney cells."J.Biol.Chem.. 278・51. 51885-51893 (2003)

[文献書誌] Tanaka, Y.: "Role of nectin in formation of E-cadherin-based adherens junctions in keratinocytes : Analysis with the N-cadherin dominant negative mutant."Mol.Biol.Cell. 14・4. 1597-1609 (2003)

[文献書誌] Katata, T.: "Involvement of nectin in the localization of IQGAP1 at the cell-cell adhesion sites through the actin cytoskeleton in Madin-Darby canine kidney cells."Oncogene. 22・14. 2097-2109 (2003)

[文献書誌] Yasumi, M.: "Role of each immunoglobulin-like loop of nectin for its cell-cell adhesion activity."Biochem.Biophys.Res.Commun.. 302・1. 61-66 (2003)

[文献書誌] Honda, T.: "Regulation by nectin of the velocity of the formation of adherens junctions and tight junctions."Biochem.Biophys.Res.Commun.. 306・1. 104-109 (2003)

[文献書誌] Honda, T.: "Antagonistic and agonistic effects of an extracellular fragment of nectin on formation of E-cadherin-based cell-cell adhesion."Genes Cells. 8・1. 51-63 (2003)

[文献書誌] Honda, T.: "Cdc42 and Rac small G proteins activated by trans-interactions of nectins are involved in activation of c-Jun N-terminal kinase, but not in association of nectins and cadherin to form adherents junctions, in fibroblasts."Genes Cells. 8・5. 481-491 (2003)

[文献書誌] Kawabe, H.: "A novel Rabconnectin-3-binding protein that directly binds a GDP/GTP exchange protein for Rab3A small G protein implicated in Ca^<2+>-dependent exocytosis of neurotransmitter."Genes Cells. 8・6. 537-546 (2003)

[文献書誌] Takai, Y.: "Nectins and nectin-like molecules : Roles in cell adhesion, migration, and polarization."Cancer Science. 94・8. 655-667 (2003)

[文献書誌] Takai, Y.: "Nectin and afadin : Novel organizers of intercellular junctions."J.CellSci.. 116・1. 17-27 (2003)

[文献書誌] Shimizu, K.: "Roles of the intercellular adhesion molecule nectin in intracellular signaling."J.Biochem.. 134・5. 631-636 (2003)

[文献書誌] Ikeda, W.: "Nectin-like molecule-5/Tage4 enhances cell migration in an integrin-dependent, nectin-3-independent manner."J.Biol.Chem.. in press. (2004)

[文献書誌] Hoshino, T.: "A novel role of nectins in inhibition of the E-cadherin-induced activation of Rac and formation of cell-cell adherens junctions."Mol.Biol.Cell. 15・3. 1077-1088 (2004)

[文献書誌] Yamamoto, Y.: "Direct binding of the human homologue of the drosophila disc large tumor suppressor gene to seven-pass transmembrane proteins, tumor endothelial marker 5 (TEM5) and a novel TEM5-like protein."Oncogene. in press. (2004)

[文献書誌] Okabe, N.: "Localization patterns of nectins and afadin for epithelial remodeling during mouse development."Dev.Dyn.. in press. (2004)

[文献書誌] Irie, K.: "Roles of nectins in cell adhesion, signaling, and polarization."Handbook of Experimental Pharmacology. in press. (2004)

2003 年度実績報告書

高井義美大阪大学, 医学系研究科, 教授 (60093514)