Analysis of the function of Rap1-activating factors which mediate the cross-talks between different species of small G proteins

2010 Fiscal Year Final Research Report

• Project/Area Number: 20390080
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• 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): SATOH Takaya 神戸大学, 大学院・医学研究科, 准教授 (20251655) ; SHIMA FUMI 神戸大学, 大学院・医学研究科, 講師 (60335445) ; EDAMATSU Hironori 神戸大学, 大学院・医学研究科, 助教 (70335438)
• Co-Investigator(Renkei-kenkyūsha): HIRASHIMA Masanori 神戸大学, 大学院・医学研究科, 准教授 (40383757)
• Project Period (FY): 2008 – 2010
• Keywords: 低分子量G蛋白質 / Rap1 / グアニンヌクレオチド交換因子 / ノックアウトマウス / 血管形成 / 神経細胞移動 / 帯状異所性灰白質症 / 精子形成異常

Research Abstract

RA-GEF-1, RA-GEF-2, and phospholipase Cε? (PLCε) are specific activators (guanine nucleotide exchange factors) for Rap1, which mediate cross-talks between different species of small G proteins. We have elucidated crucial functions of RA-GEF-1 in fetal blood vessel formation and neuronal migration, of RA-GEF-2 in sperm formation, and of PLCε in inflammation and carcinogenesis through generation and phenotypic characterization of whole body and conditional knockout mice of the respective genes.

Research Products

• [Journal Article] Critical roles of interactions among switch I-preceding residues and between switch II and its neighboring ?-helix on conformational dynamics of the GTP-bound Ras family small GTPases. (2011)
  • Author(s): Matsumoto, K., Shima, F., Muraoka, S., Araki, M., Hu, L., Ijiri, Y., Hirai, R., Liao, J., Yoshioka, T., Kumasaka, T., Yamamoto, M., Tamura, A., Kataoka, T.
  • Journal Title: J.Biol.Chem. 286 Pages: 15403-15412
  • Peer Reviewed
• [Journal Article] Phospholipase C?has a crucial role in ultraviolet B-induced neutrophil-associated skin inflammation by regulating the expression of CXCL1/KC. (2011)
  • Author(s): Oka, M., Edamatsu, H., Kunisada, M., Hu, L., Takenaka, N., Sakaguchi, M., Kataoka, T., Nishigori, C.
  • Journal Title: Lab.Invest. 91 Pages: 711-718
  • Peer Reviewed
• [Journal Article] Overexpression of phospholipase C?in keratinocytes upregulates cytokine expression and causes dermatitis with acanthosis and T-cell infiltration. (2011)
  • Author(s): Takenaka, N., Edamatsu, H., Suzuki, N., Saito, H., Inoue, Y., Oka, M., Hu, L., Kataoka, T.
  • Journal Title: Eur.J.Immunol. 41 Pages: 202-213
  • Peer Reviewed
• [Journal Article] Enhancement of ultraviolet B-induced skin tumor development in phospholipase C?-knockout mice is associated with decreased cell death. (2010)
  • Author(s): Oka, M., Edamatsu, H., Kunisada, Hu, L., Takenaka, N., M., Dien, S., Kitazawa, R., Kataoka, T., Nishigori, C.
  • Journal Title: Carcinogenesis 31 Pages: 1897-1902
  • Peer Reviewed
• [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. 285 Pages: 22696-22705
  • 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): Ueda, 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. 24 Pages: 2254-2261
  • 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] Phospholipase C?promotes intestinal tumorigenesis of Apc^<Min/+> 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] 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] Multiple roles of phosphoinositide- specific phospholipase C isozymes. (2008)
  • Author(s): Suh, PG., Park, JI., Manzoli, L., Cocco, L., Peak, JC., Katan, M., Fukami, K., Kataoka, T., Yun, S., Ryu, SH.
  • Journal Title: BMB Rep. 41 Pages: 415-434
  • Peer Reviewed
• [Presentation] 大脳皮質の交連線維形成におけるグアニンヌクレオチド交換因子RA-GEF-1の機能 (2011)
  • Author(s): 寺島俊雄, ら
  • Organizer: 第88回日本生理学会・第116回日本解剖学会合同大会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2011-03-28
• [Presentation] The Rap1 guanine nucleotide exchange factor RA-GEF-1 is essential for the proper development of the mouse dorsal telencephalon. (2011)
  • Author(s): Bilasy, S.E., ら
  • Organizer: 31st Annual Meeting of the Australian Neuroscience Society
  • Place of Presentation: Auckland (New Zealand)
  • Year and Date: 2011-02-03
• [Presentation] The Rap1 guanine nucleotide exchange factor RA-GEF-1 is essential for the proper development of the mouse cerebral cortex. (2010)
  • Author(s): Bilasy, S.E., ら
  • Organizer: 第33回日本分子生物学会年会・日本生化学会大会合同大会(BMB2010)
  • Place of Presentation: 神戸国際会議場(兵庫県)
  • Year and Date: 2010-12-10
• [Presentation] rasがん遺伝子産物を標的とした新規抗がん剤の開発 (2010)
  • Author(s): 片岡徹
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪国際会議場(大阪府)
  • Year and Date: 2010-09-23
• [Presentation] The Rap1 guanine nucleotide exchange factor RA-GEF-1 is essential for the proper development of the mouse cerebral cortex. (2010)
  • Author(s): Bilasy, S.E., ら
  • Organizer: 第33回日本神経科学大会
  • Place of Presentation: 神戸国際会議場(兵庫県)
  • Year and Date: 2010-09-04
• [Presentation] Acanthosis accompanied by aberrant infiltration of IL-22-producing T cells in the transgenic mice overexpressing phospholipase C?in the epidermis. (2010)
  • Author(s): 枝松裕紀, ら
  • Organizer: 第14回国際免疫学会議(15th International Congress of Immunology)
  • Place of Presentation: 神戸国際会議場(兵庫県)
  • Year and Date: 2010-08-25
• [Presentation] ホスホリパーゼC?の炎症応答・発癌における重要な役割と創薬標的としての可能性 (2010)
  • Author(s): 枝松裕紀, ら
  • Organizer: 第31回日本炎症・再生医学会
  • Place of Presentation: 京王プラザホテル(東京都)
  • Year and Date: 2010-08-05
• [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] 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] 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] 背側終脳特異的RA-GEF-1ノックアウトマウスは大脳皮質ヘテロトピアと交連線維系の欠損を示す (2009)
  • Author(s): 寺島俊雄, ら
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2009-09-16
• [Presentation] Roles of Ras/Rap effectors in biomembrane functions and their therapeutic applications. (2008)
  • Author(s): 片岡徹
  • 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] 接触性皮膚炎発症におけるホスホリパーゼC?の重要な機能 (2008)
  • Author(s): 胡立志, ら
  • Organizer: 第31回日本分子生物学会年会・日本生化学会大会合同大会(BMB2008)
  • Place of Presentation: 神戸国際会議場(兵庫県)
  • Year and Date: 2008-12-10
• [Presentation] 角化細胞特異的ホスホリパーゼC?過剰発現マウスは乾癬様慢性皮膚炎を発症する (2008)
  • Author(s): 竹中延之, ら
  • Organizer: 第31回日本分子生物学会年会・日本生化学会大会合同大会(BMB2008)
  • Place of Presentation: 神戸国際会議場(兵庫県)
  • Year and Date: 2008-12-10
• [Presentation] The Rap1 guanine nucleotide exchange factor RA-GEF-1 is essential for mouse brain development. (2008)
  • Author(s): Bilasy, S.E., ら
  • Organizer: 第31回日本分子生物学会年会・日本生化学会大会合同大会(BMB2008)
  • Place of Presentation: 神戸国際会議場(兵庫県)
  • Year and Date: 2008-12-09
• [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): 李明珍, ら
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2008-10-29
• [Remarks] ホームページ等
  • URL: http://www.med.kobe-u.ac.jp/molbiol/index.html
• [Patent(Industrial Property Rights)] Ras機能阻害剤のスクリーニング方法 (2011)
  • Inventor(s): 片岡徹、島扶美、田村厚夫、荒木望嗣
  • Industrial Property Rights Holder: 神戸大学
  • Industrial Property Number: 特許権, 特願2011-023695
  • Filing Date: 2011-02-07
• [Patent(Industrial Property Rights)] 変異型Rasポリペプチドの結晶 (2010)
  • 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: PCT出願PCT/JP2010/61821
  • Filing Date: 2010-07-13
• [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