2001 Fiscal Year Annual Research Report

細胞増殖のシグナリング機構

Research Project

Project/Area Number	12215079
Research Institution	Osaka University
Principal Investigator	高井義美大阪大学, 医学研究科, 教授 (60093514)
Co-Investigator(Kenkyū-buntansha)	清水一也大阪大学, 医学研究科, 助手 (50335353) 萬代研二大阪大学, 医学研究科, 助手 (50322186) 中西宏之大阪大学, 医学研究科, 助教授 (80314318) 三好淳大阪府立成人病センター, 研究所, 部長(研究職) (80166214)
Keywords	細胞増殖 / 細胞接着 / 細胞運動 / Nectin-Afadin / Frabin-Cdc42 / Cadherin-Catenin系 / Gab-1 / Rab11
Research Abstract	細胞増殖のシグナル系と細胞の接着・運動のシグナル系との間には密接なクロストークが存在し、細胞の接着阻害の破綻が、がん細胞の増殖、浸潤、転移へとつながる。これまでに私共は、新しい細胞間接着機構Nectin-Afadin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。本年度は、Nectin-Afadin系、Frabin、Cdc42/Racを介した細胞の接着と運動のシグナル系を詳細に解析し、これらのシグナル系がどのようにして細胞増殖のシグナル系を制御しているかを検討し、以下の成果を得た。 (1)Nectin-Afadin系の機能と作用機構: Nectin-Afadin系がCadherin-Catenin系に加え、タイトジャンクションの構成分子であるZO-1やJAMも細胞間接着部位にリクルートすることを明らかにした。また、ヒト印環細胞がん由来のHSC-39細胞を用いて、Nectin-Afadin系が、がん細胞における細胞間接着能の低下に関与することを示した。 (2)Frabin-Cdc42系による細胞運動の制御機構: Frabinが、特定のアクチンフィラメント結合タンパク質を認識し、直接的にアクチン細胞骨格に作用するとともに、その近傍でCdc42を活性化することにより、フィロボディアの形成を制御することを明らかにした。 (3)細胞増殖のシグナル系と細胞間接着のシグナル系の相互制御機構: Nectin-Afadin系がmLin-7を介して何らかの細胞増殖因子受容体の局在に関与することを示唆する結果を得た。また、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。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。

Research Products
(24 results)

All Other

All Publications (24 results)

[Publications] Shinohara, M.: "Roles of cell-cell adhesion-dependent tyrosine phosphorylation of Gab-1"J.Biol.Chem.. 276・22. 48350-48355 (2001)
[Publications] Saka, A.: "Complementing yeast rho1 mutation groups with distinct functional defects"J.Biol.Chem.. 276・49. 46165-46171 (2001)
[Publications] Kawabe, H.: "Pilt, a novel peripheral membrane protein at tight junctions in epithelial cells"J.Biol.Chem.. 276・51. 48350-48355 (2001)
[Publications] Ozaki-Kuroda, K.: "Dynamic localization and function of Bni1p at the sites of directed growth in Saccharomyces cerevisiae"Mol.Cell.Biol.. 21・3. 827-839 (2001)
[Publications] Tanaka, M.: "Role of Rab3 GDP/GTP exchange protein in synaptic vesicle trafficking at the mouse neuromuscular junction"Mol.Biol.Cell. 12・5. 1421-1430 (2001)
[Publications] Yokoyama, S.: "α-Catenin-independent recruitment of ZO-1 to nectin-based cell-cell adhesion sites through afadin"Mol.Biol.Cell. 12・6. 1595-1609 (2001)
[Publications] Ikeda, W.: "Cooperation of Cdc42 small G protein-activating and actin filament-binding activities of frabin in microspike formation"Oncogene. 20・27. 3457-3463 (2001)
[Publications] Ikeda, W.: "Identification of splicing variants of frabin with partly different functions and tissue distribution"Biochem.Biophys.Res.Commun.. 286・5. 1066-1072 (2001)
[Publications] Sakisaka, T.: "Requirement of interaction of nectin-1α/HveC with afadin for efficient cell-cell spread of herpes simplex virus type 1"J.Virol.. 75・10. 4734-4743 (2001)
[Publications] Suzuki, N.: "A putative GDP-GTP exchange factor is required for development of the excretory cell in Caenorhabditis elegans"EMBO Report. 2・6. 530-535 (2001)
[Publications] Kodama, A.: "Regulation of Ras and Rho small G proteins by SHP-2"Genes Cells. 6・10. 869-876 (2001)
[Publications] Hamada, K.: "Crystallization and preliminary crystallographic studies of RhoGDI in complex with the radixin FERM domain"Acta Biological Crystallography. 57・6. 889-890 (2001)
[Publications] Takai, Y.: "Small GTP-binding proteins"In Physiological Reviews. 81. 153-208 (2001)
[Publications] Nakanishi, H.: "Purification and properties of Rab3 GDP/GTP exchange protein"In Methods Enzymol.. 329. 59-67 (2001)
[Publications] Nagano, F.: "Purification and properties of Rab3 GTPase activating protein"In Methods Enzymol.. 329. 67-75 (2001)
[Publications] Shirataki, H.: "Rabphilin-3 : a target molecule for Rab3 small G proteins"In Methods Enzymol.. 329. 75-82 (2001)
[Publications] Orita, S.: "Doc2αas modulator of Ca^<2+>-dependent exocytosis"In Methods Enzymol.. 329. 86-90 (2001)
[Publications] Nishimura, M.: "JEAP, a novel component of tight junctions in exocrine cells"J.Biol.Chem.. 277・7. 5583-5587 (2002)
[Publications] Mizoguchi, A.: "Nectin : An adhesion molecule involved in formation of synapses"J.Cell Biol.. 156・3. 555-565 (2002)
[Publications] Nagano, F.: "Rabconnectin-3, a novel protein that binds both GDP/GTP exchange protein and GTPase-activating protein for Rab3 small G protein family"J.Biol.Chem.. (in press). (2002)
[Publications] Satoh, K.: "Identification of activity-regulated proteins in the postsynaptic density fraction"Genes Cells. (in press). (2002)
[Publications] Kim, Y.: "Association of frabin with specific actin and membrane structures"Genes Cells. (in press). (2002)
[Publications] Peng, Y.F.: "Restoration of E-Cadherin-based cell-cell adhesion by overexpression of nectin in HSC-39 cells, a human signet ring cell gastric cancer cell line"Oncogene. (in press). (2002)
[Publications] Yamamoto, Y.: "Localization of mLim-7 at nectin-based cell-cell junctions"Oncogene. (in press). (2002)

2001 Fiscal Year Annual Research Report

細胞増殖のシグナリング機構

Principal Investigator

高井 義美 大阪大学, 医学研究科, 教授 (60093514)

Research Products

[Publications] Shinohara, M.: "Roles of cell-cell adhesion-dependent tyrosine phosphorylation of Gab-1"J.Biol.Chem.. 276・22. 48350-48355 (2001)

[Publications] Saka, A.: "Complementing yeast rho1 mutation groups with distinct functional defects"J.Biol.Chem.. 276・49. 46165-46171 (2001)

[Publications] Kawabe, H.: "Pilt, a novel peripheral membrane protein at tight junctions in epithelial cells"J.Biol.Chem.. 276・51. 48350-48355 (2001)

[Publications] Ozaki-Kuroda, K.: "Dynamic localization and function of Bni1p at the sites of directed growth in Saccharomyces cerevisiae"Mol.Cell.Biol.. 21・3. 827-839 (2001)

[Publications] Tanaka, M.: "Role of Rab3 GDP/GTP exchange protein in synaptic vesicle trafficking at the mouse neuromuscular junction"Mol.Biol.Cell. 12・5. 1421-1430 (2001)

[Publications] Yokoyama, S.: "α-Catenin-independent recruitment of ZO-1 to nectin-based cell-cell adhesion sites through afadin"Mol.Biol.Cell. 12・6. 1595-1609 (2001)

[Publications] Ikeda, W.: "Cooperation of Cdc42 small G protein-activating and actin filament-binding activities of frabin in microspike formation"Oncogene. 20・27. 3457-3463 (2001)

[Publications] Ikeda, W.: "Identification of splicing variants of frabin with partly different functions and tissue distribution"Biochem.Biophys.Res.Commun.. 286・5. 1066-1072 (2001)

[Publications] Sakisaka, T.: "Requirement of interaction of nectin-1α/HveC with afadin for efficient cell-cell spread of herpes simplex virus type 1"J.Virol.. 75・10. 4734-4743 (2001)

[Publications] Suzuki, N.: "A putative GDP-GTP exchange factor is required for development of the excretory cell in Caenorhabditis elegans"EMBO Report. 2・6. 530-535 (2001)

[Publications] Kodama, A.: "Regulation of Ras and Rho small G proteins by SHP-2"Genes Cells. 6・10. 869-876 (2001)

[Publications] Hamada, K.: "Crystallization and preliminary crystallographic studies of RhoGDI in complex with the radixin FERM domain"Acta Biological Crystallography. 57・6. 889-890 (2001)

[Publications] Takai, Y.: "Small GTP-binding proteins"In Physiological Reviews. 81. 153-208 (2001)

[Publications] Nakanishi, H.: "Purification and properties of Rab3 GDP/GTP exchange protein"In Methods Enzymol.. 329. 59-67 (2001)

[Publications] Nagano, F.: "Purification and properties of Rab3 GTPase activating protein"In Methods Enzymol.. 329. 67-75 (2001)

[Publications] Shirataki, H.: "Rabphilin-3 : a target molecule for Rab3 small G proteins"In Methods Enzymol.. 329. 75-82 (2001)

[Publications] Orita, S.: "Doc2αas modulator of Ca^<2+>-dependent exocytosis"In Methods Enzymol.. 329. 86-90 (2001)

[Publications] Nishimura, M.: "JEAP, a novel component of tight junctions in exocrine cells"J.Biol.Chem.. 277・7. 5583-5587 (2002)

[Publications] Mizoguchi, A.: "Nectin : An adhesion molecule involved in formation of synapses"J.Cell Biol.. 156・3. 555-565 (2002)

[Publications] Nagano, F.: "Rabconnectin-3, a novel protein that binds both GDP/GTP exchange protein and GTPase-activating protein for Rab3 small G protein family"J.Biol.Chem.. (in press). (2002)

[Publications] Satoh, K.: "Identification of activity-regulated proteins in the postsynaptic density fraction"Genes Cells. (in press). (2002)

[Publications] Kim, Y.: "Association of frabin with specific actin and membrane structures"Genes Cells. (in press). (2002)

[Publications] Peng, Y.F.: "Restoration of E-Cadherin-based cell-cell adhesion by overexpression of nectin in HSC-39 cells, a human signet ring cell gastric cancer cell line"Oncogene. (in press). (2002)

[Publications] Yamamoto, Y.: "Localization of mLim-7 at nectin-based cell-cell junctions"Oncogene. (in press). (2002)

高井義美大阪大学, 医学研究科, 教授 (60093514)