Mechanism of cell growth regulation by small G proteins

• Project/Area Number: 17014061
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kobe University
• Principal Investigator: KATAOKA Tohru Kobe University, 大学院・医学研究科, 教授 (40144472)
• Co-Investigator(Kenkyū-buntansha): SHIMA Fumi 神戸大学, 大学院・医学研究科, 助教 (60335445) ; EDAMATSU Hironori 神戸大学, 大学院・医学研究科, 助教 (70335438)
• Project Period (FY): 2005 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥72,100,000 (Direct Cost: ¥72,100,000); Fiscal Year 2009: ¥14,400,000 (Direct Cost: ¥14,400,000); Fiscal Year 2008: ¥14,400,000 (Direct Cost: ¥14,400,000); Fiscal Year 2007: ¥14,500,000 (Direct Cost: ¥14,500,000); Fiscal Year 2006: ¥14,500,000 (Direct Cost: ¥14,500,000); Fiscal Year 2005: ¥14,300,000 (Direct Cost: ¥14,300,000)
• Keywords: 低分子量G蛋白質 / rasがん遺伝子 / rap1がん抑制遺伝子 / ホスホリパーゼC / 化学発がん / グアニンヌクレオチド交換因子 / X線結晶解析 / インシリコ創薬 / ボスホリパーゼC / rap1がん抑御遺伝子 / ras癌遺伝子 / rap1癌抑制遺伝子 / 化学発癌 / イン・シリコ創薬

Research Abstract

We found that phospholipase C・, an effector of the ras oncogene product (Ras), plays a crucial and universal role in tumor promotion through triggering inflammatory reactions, and analyzed the underlying action mechanisms. Furthermore, we elucidated the molecular mechanism for the conformational dynamics of the GTP-bound Ras. By using a new strategy based on this mechanism, we developed small molecule Ras inhibitors, which exhibit equivalent or even higher anti-tumor activities in animal models compared to the existing anti-cancer drugs, through an in silico approach.

Research Products

• [Journal Article] Structural basis for conformational dynamics of GTP-bound Ras protein. (2010)
  • Author(s): Shima, F., Ijiri, Y., Muraoka, S., Liao, J., Ye, M., Araki, M., Matsumoto, K., Yamamoto, N., Sugimoto, T., Yoshikawa, Y., Kumasaka, T., Yamamoto, M., Tamura, A., Kataoka, T.
  • Journal Title: J. Biol. Chem. (in press)
  • Peer Reviewed
• [Journal Article] Crucial role of the small GTPase Rac1 in insulin-stimulated translocation of glucose transporter 4 to the mouse skeletal muscle sarcolemma. (2010)
  • Author(s): U eda, S., Kitazawa, S., Ishida, K., Nishikawa, Y., Matsui, M., Matsumoto, H., Aoki, T., Nozaki, S., Takeda, T., Tamori, Y., Aiba, A., Kahn, C.R., Kataoka, T., Satoh, T.
  • Journal Title: FASEB J. (in press)
  • Peer Reviewed
• [Journal Article] Crucial role of phospholipase C・in induction of local skin inflammatory reactions in the elicitation stage of allergic contact hypersensitivity. (2010)
  • Author(s): Hu, L., Edamatsu, H., Takenaka, N., Ikuta, S., Kataoka, T.
  • Journal Title: J. Immunol. 184 Pages: 993-1002
  • Peer Reviewed
• [Journal Article] Crucial role of phospholipase CE in induction of local skin inflammatory reactions in the elicitation stave of allereic contact hypersensitivity (2010)
  • Author(s): Lizhi Hu, et al.
  • Journal Title: The Journal of Immunology 184巻・2号 Pages: 993-1002
  • Peer Reviewed
• [Journal Article] Crucial role of the small GTPase Rac1 in insulin-stimulated translocation of glucose transporter 4 to the mouse skeletal muscle sarcolemma (2010)
  • Author(s): Shuji Ueda, et al.
  • Journal Title: The FASEB Journal (未定)(印刷中)(掲載確定)
  • Peer Reviewed
• [Journal Article] Impaired vascular development in the yolk sac and allantois in mice lacking RA-GEF-1. (2009)
  • Author(s): Kanemura, H., Satoh, T., Bilasy, S.E., Ueda, S., Hirashima, M., Kataoka, T.
  • Journal Title: Biochem. Biophys. Res. Comm. 387 Pages: 754-759
  • Peer Reviewed
• [Journal Article] Regulation of mitotic spindle formation by the RhoA guanine nucleotide exchange factor ARHGEF10. (2009)
  • Author(s): Aoki, T., Ueda, S., Kataoka, T., Satoh, T.
  • Journal Title: BMC Cell Biol. 10 Pages: 56-56
  • Peer Reviewed
• [Journal Article] Phospholipase C・promotes intestinal tumorigenesis of ApcMin/+ mice through augmentation of inflammation and angiogenesis. (2009)
  • Author(s): Li, M., Edamatsu, H., Kitazawa, R., Kitazawa, R., Kataoka, T.
  • Journal Title: Carcinogenesis 30 Pages: 1424-1432
  • Peer Reviewed
• [Journal Article] Dorsal telencephalon- specific RA-GEF-1 knockout mice develop heterotropic cortical mass and commissural fiber defect (2009)
  • Author(s): Bilasy, S.E., Satoh, T., Ueda, S., Wei, P., Kanemura, H., Aiba, A., Terashima, T., Kataoka, T.
  • Journal Title: Eur. J. Neurosci. 29 Pages: 1994-2008
  • Peer Reviewed
• [Journal Article] Phospholipase Cε promotes intestinal tumorigenesis of APC^<Min/+> mice through augmentation of inflammation and angiogenesis (2009)
  • Author(s): Mingzhen Li, et al.
  • Journal Title: Carcinogenesis 30巻・8号 Pages: 1424-1432
  • Peer Reviewed
• [Journal Article] Dorsal telencephalon-specific RA-GEF-1 knockout mice develop heterotropic cortical mass and commissural fiber defect (2009)
  • Author(s): Shymaa E.Bilasy, et al.
  • Journal Title: European Journal of Neuroscience 29巻・10号 Pages: 1994-2009
  • Peer Reviewed
• [Journal Article] Biochemical characterization of missense mutations in the Arf/Arl-family small GTPase Ar16 causing Bardet-Biedl syndrome (2009)
  • Author(s): Tetsuo Kobayashi, et al.
  • Journal Title: Biochem.Biophys.Res.Commun. 381巻・3号 Pages: 439-442
  • Peer Reviewed
• [Journal Article] Regulation of mitotic spindle formation by the RhoA guanine nucleotide exchange factor ARHGEF10 (2009)
  • Author(s): Takuji Aoki, et al.
  • Journal Title: BMC Cell Biology 10巻・56号
  • Peer Reviewed
• [Journal Article] Impaired vascular development in the yolk sac and allantois in mice lacking RA-GEF-1 (2009)
  • Author(s): Hoshimi Kanemura, et al.
  • Journal Title: Biochem.Biophys.Res.Commun. 387巻・4号 Pages: 754-759
  • Peer Reviewed
• [Journal Article] Biochemical characterization of missense mutations in the Arf/Arl-family small GTPase Ar16 causing Bardet-Biedl syndrome (2009)
  • Author(s): Tetsuo Kobayashi., et.al.
  • Journal Title: Biochem. Biophys. Res. Commun (印刷中)
  • Peer Reviewed
• [Journal Article] Dorsal telencephalon-specific RA-GEF-1 knockout mice develop heterotopic cortical mass and commissural fiber defect (2009)
  • Author(s): Shymaa E. Bilasy, et.al.
  • Journal Title: Eur. J. Neurosci (印刷中)
  • Peer Reviewed
• [Journal Article] Activation of the small GTPase Rac1 by a specific nucleotide exchange factor suffices to induce glucose uptake into skeletal muscle cells (2008)
  • Author(s): Ueda, S., Kataoka, T., Satoh, T.
  • Journal Title: Biol. Cell 100 Pages: 645-657
  • Peer Reviewed
• [Journal Article] Two conformational states of Ras GTPase exhibit differential GTP-binding kinetics. (2008)
  • Author(s): Liao, J., Shima, F., Araki, M., Ye, M., Muraoka, S., Sugimoto, T., Kawamura, M., Yamamoto, N., Tamura, A., Kataoka, T.
  • Journal Title: Biochem. Biophys. Res. Comm. 369 Pages: 327-332
  • Peer Reviewed
• [Journal Article] Crucial role of phospholipase C・in skin inflammation induced by tumor-promoting phorbor ester. (2008)
  • Author(s): Ikuta, S., Edamatsu, H., Li, M., Hu, L., Kataoka, T.
  • Journal Title: Cancer Res. 68 Pages: 64-72
  • Peer Reviewed
• [Journal Article] Two conformational states of Ras GTPase exhibit differential GTP-binding kinetics (2008)
  • Author(s): Jingling Liao, et.al.
  • Journal Title: Biochem Biophys. Res. Commun 369巻・2号 Pages: 327-332
  • Peer Reviewed
• [Journal Article] Activation of the small GTPase Racl by a specific nucleotide exchange factor suffices to induce glucose uotake into skeletal muscle cells (2008)
  • Author(s): Shuji Ueda, et.al.
  • Journal Title: Biol. Cell 100巻・11号 Pages: 645-657
  • Peer Reviewed
• [Journal Article] Multiple roles of phosphoinositide-specific phospholipase C isozymes (2008)
  • Author(s): Pann-Ghill Suh, et.al.
  • Journal Title: BMB Reports 41巻・6号 Pages: 415-434
  • Peer Reviewed
• [Journal Article] Crucial role of phospholipase Cε in skin inflammation induced by tumor promoting phorbor ester (2008)
  • Author(s): Shuzo Ikuta, et. al.
  • Journal Title: Cancer Research 68巻・1号 Pages: 64-72
  • Peer Reviewed
• [Journal Article] Two conformational states of Ras GTPase exhibit differential GTP-binding kinetics (2008)
  • Author(s): Jingling Liao, et. al.
  • Journal Title: Biochem. Biophys. Res. Commun. 未定(印刷中)
  • Peer Reviewed
• [Journal Article] Defective vascular morphogenesis and mid-gestation embryonic death in mice lacking RA-GEF-1. (2007)
  • Author(s): Wei, P., Satoh, T., Edamatsu, H., Aiba, A., Setsu, T., Terashima, T., Kitazawa, S., Nakao, K., Yoshikawa, Y., Tamada, M., Kataoka, T.
  • Journal Title: Biochem. Biophys. Res. Comm. 363 Pages: 106-112
  • NAID: 120004107908
  • Peer Reviewed
• [Journal Article] Role of the guanine nucleotide exchange factor Ost in negative regulation of receptor endocytosis by the small GTPase Rac1. (2007)
  • Author(s): Ieguchi, K., Ueda, S., Kataoka, T., Satoh, T.
  • Journal Title: J. Biol. Chem. 282 Pages: 23296-23305
  • Peer Reviewed
• [Journal Article] The M-Ras-RA-GEF-2-Rap1 pathway mediates tumor necrosis factor-・-dependent regulation of integrin activation in splenocytes. (2007)
  • Author(s): Yoshikawa, Y., Satoh, T., Tamura, T., Wei, P., Bilasy, S.E., Edamatsu, H., Aiba, A., Katagiri, K., Kinashi, T., Nakao, K., Kataoka, T.
  • Journal Title: Mol. Biol. Cell 18 Pages: 2949-2959
  • Peer Reviewed
• [Journal Article] The M-Ras-RA-GEF-2-Rap1 pathway mediates tumor necrosis factor-α-dependent regulation of integrin actication in splenocytes (2007)
  • Author(s): Yoko Yoshikawa, et. al.
  • Journal Title: Molecular Biology of the Cell 18巻・8号 Pages: 2949-2959
  • Peer Reviewed
• [Journal Article] Role of the guanine nucleotide exchange factor Ost in negative regulation of receptor endocytosis by the small GTP ase Rac1 (2007)
  • Author(s): Katsuaki Ieguchi, et. al.
  • Journal Title: The Journal of Biolohical Chemistry 282巻・32号 Pages: 23296-23305
  • Peer Reviewed
• [Journal Article] Defective vascular morphpgenesis and mid-gestation embryonic death in mice lacking RA-GEF-1 (2007)
  • Author(s): Ping Wei, et. al.
  • Journal Title: Biochem. Biophys. Res. Commun. 363巻・1号 Pages: 106-112
  • Peer Reviewed
• [Journal Article] Phospholipase C・guanine nucleotide exchange factor activity and activation of Rap1. (2006)
  • Author(s): Satoh, T., Edamatsu, H., Kataoka, T.
  • Journal Title: Methods Enzymol. 407 Pages: 281-290
• [Journal Article] Ras and Rap1 activation of PLC・lipase activity. (2006)
  • Author(s): Edamatsu, H., Satoh, T., Kataoka, T.
  • Journal Title: Methods Enzymol. 407 Pages: 99-107
• [Journal Article] Ras and Rap1 activation of PLC_ε lipase activity (2006)
  • Author(s): Hironori Edamatsu, et al.
  • Journal Title: Methods in Enzymology 407巻 Pages: 99-107
• [Journal Article] Phospholipase C_ε guanine nucleotide exchange factor activity and activation of Rap1 (2006)
  • Author(s): Takaya Satoh, et al.
  • Journal Title: Methods in Enzymology 407巻 Pages: 281-290
• [Journal Article] Dynamic polymorphism of Ras observed by single molecule FRET is the basis for molecular recognition (2006)
  • Author(s): Yoshiyuki Arai, et al.
  • Journal Title: Biochemical and Biophysical Research Communications 343巻3号 Pages: 809-815
• [Journal Article] Phospholipase Cε guanine nucleotide exchange factor activity and activation of Rap1 (2006)
  • Author(s): Takaya Satoh, et al.
  • Journal Title: Methods in Enzymology 407巻(印刷中)
• [Journal Article] Ras and Rapt activation of PLCε lipase activity (2006)
  • Author(s): Hironori Edamatsu, et al.
  • Journal Title: Methods in Enzymology 407巻(印刷中)
• [Journal Article] Crystal structure of M-Ras reveals a GTP-bound "off" state conformation of Ras family small GTPases. (2005)
  • Author(s): Ye, M., Shima, F., Muraoka, S., Liao, J., Okamoto, H., Yamamoto, M., Tamura, A., Yagi, N., Ueki, T., Kataoka, T.
  • Journal Title: J. Biol. Chem. 280 Pages: 31267-31275
  • Peer Reviewed
• [Journal Article] エフェクター活性化過程に必須であるRasの翻訳後修飾-Ras-エフェクター相互作用の高次構造解析 (2005)
  • Author(s): 島扶美、片岡徹
  • Journal Title: 生化学 77 Pages: 519-526
  • NAID: 10016452222
• [Journal Article] Congenital semilunar valvulogenesis defect in mice deficient in phospholipase C・ (2005)
  • Author(s): Tadano, M., Edamatsu, H., Minamisawa, S., Yokoyama, U., Ishikawa, Y., Suzuki, N., Wu, D., Masago-Toda, M., Yamawaki-Kataoka, Y., Setsu, T., Terashima, T., Maeda, S., Satoh, T., Kataoka, T.
  • Journal Title: Mol. Cell. Biol. 25 Pages: 2191-2199
  • Peer Reviewed
• [Journal Article] Crystal structure of M-Ras reveals a GTP-bound "off" state conformation of Ras family small GTPases (2005)
  • Author(s): Min Ye, et al.
  • Journal Title: The Journal of Biological Chemistry 280巻・35号 Pages: 31267-31275
• [Journal Article] エフェクター活性化過程に必須であるRasの翻訳後修飾 (2005)
  • Author(s): 島 扶美, et al.
  • Journal Title: 生化学 77巻・6号 Pages: 519-526
• [Presentation] Role of phospholipase C・in T cell-derived cytokine-induced activation of dermal fibroblasts and epidermal keratinocytes. (2009)
  • Author(s): 胡立志, ら
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2009-12-09
• [Presentation] GTP結合型Rasの構造遷移における分子メカニズムの解析 (2009)
  • Author(s): 井尻悠一, ら
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2009-12-09
• [Presentation] 、Keratinocyte-specific overexpression of phospholipase C・induces psoriasis-like chronic dermatitis through activation of IL-23/TH17 axis (2009)
  • Author(s): 竹中延之, ら
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2009-12-09
• [Presentation] Keratinocyte-specific overexpression of phospholipase Cε induces psoriasis-like chronic dermatitis through activation of IL-23/TH17 axis (2009)
  • Author(s): Nobuyuki Takenaka, et al.
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2009-12-09
• [Presentation] Role of phospholipase Cε in T cell-derived cytokine-induced activation, of dermal fibroblasts and epidermal keratinocytes (2009)
  • Author(s): Lizhi Hu, et al.
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2009-12-09
• [Presentation] 出芽酵母の低分子量Gタンパク質Ras2のX線結晶構造解析 (2009)
  • Author(s): 村岡真, ら
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸国際会議場(兵庫県)
  • Year and Date: 2009-10-24
• [Presentation] ホスホリパーゼc・は炎症と血管形成の増大を通してApcMinマウスの腸腫瘍形成を促進する (2009)
  • Author(s): 枝松裕紀, ら
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸国際会議場(兵庫県)
  • Year and Date: 2009-10-24
• [Presentation] マウス胎生期の血管形成におけるRA-GEF-1の機能解析 (2009)
  • Author(s): 金村星余, ら
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸国際会議場(兵庫県)
  • Year and Date: 2009-10-24
• [Presentation] ホスホリパーゼCεは炎症と血管形成の増大を通してApcMinマウスの腸腫瘍形成を促進する (2009)
  • Author(s): Hironori Edainatsu, et al.
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸国際会議場(兵庫県)
  • Year and Date: 2009-10-24
• [Presentation] ホスホリパーゼCεの癌と炎症への関与に関する遺伝子改変マウスを用いた解析 (2009)
  • Author(s): Hironori Edamatsu, et al.
  • Organizer: 神戸大学グローバルCOEプログラム「統合的膜生物学の国際教育研究拠点」 第3回ワークショップ
  • Place of Presentation: 淡路夢舞台国際会議場(兵庫県)
  • Year and Date: 2009-07-07
• [Presentation] Roles of Ras/Rap effectors in biomembrane functions and their therapeutic applications. (2008)
  • Author(s): Kataoka, T.
  • Organizer: International Symposium on Integrative Membrane Biology
  • Place of Presentation: 神戸国際会議場(兵庫県)
  • Year and Date: 2008-12-18
• [Presentation] Roles of Ras/Rap effectors in biomembrane functions and their therapeutic applications (2008)
  • Author(s): Tohru Kataoka
  • Organizer: International Symposium on Integrative Membrane Biology
  • Place of Presentation: 兵庫県神戸市
  • Year and Date: 2008-12-18
• [Presentation] 接触性皮膚炎発症におけるボスホリパーゼCεの重要な機能 (2008)
  • Author(s): Lizhi Hu, et.al.
  • Organizer: 第31回日本分子生物学会年会・第81回日本生化学会合同大会(BMB2008)
  • Place of Presentation: 兵庫県神戸市
  • Year and Date: 2008-12-10
• [Presentation] 角化細胞特異的ボスホリパーゼCε過剰発現マウスは乾癬様慢性皮膚炎を発症する (2008)
  • Author(s): Nobuyuki Takenaka, et.al.
  • Organizer: 第31回日本分子生物学会年会・第81回日本生化学会合同大会(BMB2008)
  • Place of Presentation: 兵庫県神戸市
  • Year and Date: 2008-12-10
• [Presentation] PLCεによる小腸腺腫における腫瘍細胞の増殖と生存の制御 (2008)
  • Author(s): Mingzhen Li, et.al.
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 愛知県名古屋市
  • Year and Date: 2008-10-29
• [Presentation] Universal roles of phospholipase CE in de novo carcinogenesis and inflammation (2008)
  • Author(s): Tohru Kataoka
  • Organizer: International Workshop of Kobe Univ. Global CC E Program "New Frontier of Membrane Biology"
  • Place of Presentation: 兵庫県淡路市
  • Year and Date: 2008-07-02
• [Presentation] Universal roles of phospholipase C・in de novo carcinogenesis and inflammation. (2008)
  • Author(s): Kataoka, T.
  • Organizer: Pohang Conference on Cellular Signaling
  • Place of Presentation: Pohang(韓国)
  • Year and Date: 2008-02-21
• [Presentation] Universal roles of phospholipase Cε in de novo carcinogenesis and inflammation (2008)
  • Author(s): 片岡 徹
  • Organizer: Pohang Conference on Cellular Singaling
  • Place of Presentation: Phang, Korea
  • Year and Date: 2008-02-21
• [Presentation] Rasを分子標的とした抗がん剤のインシリコ創薬 (2007)
  • Author(s): 片岡徹
  • Organizer: 第69回日本血液学会/第49回日本臨床血液学会合同総会シンポジウム「シグナル伝達研究と分子標的療法」
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2007-10-12
• [Presentation] Rasを分子標的とした抗がん剤のインシリコ創薬 (2007)
  • Author(s): 片岡 徹
  • Organizer: 第69回日本血液学会/第49回日本臨床血液学会合同総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-12
• [Presentation] Rasファミリー低分子量Gタンパク質の高次構造遷移:その機能と創薬への展開 (2006)
  • Author(s): 片岡徹
  • Organizer: 21世紀COE合同シンポジウム「シグナル伝達と構造生物学の接点」
  • Place of Presentation: 先端技術支援センター(兵庫県)
  • Year and Date: 2006-12-09
• [Presentation] Specific inhibitors of Ras oncoprotein identified by a new strategy. (2006)
  • Author(s): Kataoka, T.
  • Organizer: International Symposium on TOR-Signaling Mechanisms in the Cell Growth Regulation.
  • Place of Presentation: 神戸大学(兵庫県)
  • Year and Date: 2006-11-30
• [Presentation] New strategies for development of anti-cancer drugs targeting the Ras pathway (2006)
  • Author(s): Kataoka, T.
  • Organizer: International Symposium of Kobe University 21st Century COE Program on Signal Transduction
  • Place of Presentation: 神戸国際会議場(兵庫県)
  • Year and Date: 2006-02-09
• [Patent(Industrial Property Rights)] 変異型Rasポリペプチドの結晶 (2009)
  • Inventor(s): 片岡徹、島扶美、田村厚夫、熊坂崇
  • Industrial Property Rights Holder: 神戸大学、高輝度光科学研究センター
  • Industrial Property Number: 2009-165717
  • Filing Date: 2009-07-14
• [Patent(Industrial Property Rights)] ホスホリパーゼC・を分子標的とした新規抗炎症薬のスクリーニング方法、および尋常性乾癬様の慢性皮膚炎モデル動物 (2007)
  • Inventor(s): 片岡徹、枝松裕紀、竹中延之権利者:神戸大学
  • Industrial Property Rights Holder: 神戸大学
  • Industrial Property Number: 2007-285792
  • Filing Date: 2007-11-02
• [Patent(Industrial Property Rights)] ホスホリパーゼCεを分子標的とした新規抗炎症薬のスクリーニング方法および尋常性乾癬様の慢性皮膚炎モデル動物 (2007)
  • Inventor(s): 片岡徹、枝松裕紀、竹中延之
  • Industrial Property Rights Holder: 神戸大学
  • Industrial Property Number: 2007-285792
  • Filing Date: 2007-11-02