Mechanism of cell growth regulation by small G proteins

2009 Fiscal Year Final Research Report

• 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
• 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

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] 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
  • 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] 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] 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
  • 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] 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] 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
• [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
• [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] 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] 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] 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] 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: 特許権・特願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: 特許権・特願2007-285792
  • Filing Date: 2007-11-02