Research activity information

• Jun. 2011 一般社団法人神緑会, 田中千賀子学術奨励賞, 女性研究者

  Shima Fumi

• SARS-CoV-2 papain-like protease inhibits ISGylation of the viral nucleocapsid protein to evade host anti-viral immunity

  Aulia Fitri Rhamadianti, Takayuki Abe, Tomohisa Tanaka, Chikako Ono, Hisashi Katayama, Yoshiteru Makino, Lin Deng, Chieko Matsui, Kohji Moriishi, Fumi Shima, Yoshiharu Matsuura, Ikuo Shoji

  ABSTRACT A severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes mild-to-severe respiratory symptoms, including acute respiratory distress. Despite remarkable efforts to investigate the virological and pathological impacts of SARS-CoV-2, many of the characteristics of SARS-CoV-2 infection still remain unknown. The interferon-inducible ubiquitin-like protein ISG15 is covalently conjugated to several viral proteins to suppress their functions. It was reported that SARS-CoV-2 utilizes its papain-like protease (PLpro) to impede ISG15 conjugation, ISGylation. However, the role of ISGylation in SARS-CoV-2 infection remains unclear. We aimed to elucidate the role of ISGylation in SARS-CoV-2 replication. We observed that the SARS-CoV-2 nucleocapsid protein is a target protein for the HERC5 E3 ligase-mediated ISGylation in cultured cells. Site-directed mutagenesis reveals that the residue K374 within the C-terminal spacer B-N3 (SB/N3) domain is required for nucleocapsid-ISGylation, alongside conserved lysine residue in MERS-CoV (K372) and SARS-CoV (K375). We also observed that the nucleocapsid-ISGylation results in the disruption of nucleocapsid oligomerization, thereby inhibiting viral replication. Knockdown of ISG15 mRNA enhanced SARS-CoV-2 replication in the SARS-CoV-2 reporter replicon cells, while exogenous expression of ISGylation components partially hampered SARS-CoV-2 replication. Taken together, these results suggest that SARS-CoV-2 PLpro inhibits ISGylation of the nucleocapsid protein to promote viral replication by evading ISGylation-mediated disruption of the nucleocapsid oligomerization. IMPORTANCE ISG15 is an interferon-inducible ubiquitin-like protein that is covalently conjugated to the viral protein via specific Lys residues and suppresses viral functions and viral propagation in many viruses. However, the role of ISGylation in SARS-CoV-2 infection remains largely unclear. Here, we demonstrated that the SARS-CoV-2 nucleocapsid protein is a target protein for the HERC5 E3 ligase-mediated ISGylation. We also found that the residue K374 within the C-terminal spacer B-N3 (SB/N3) domain is required for nucleocapsid-ISGylation. We obtained evidence suggesting that nucleocapsid-ISGylation results in the disruption of nucleocapsid-oligomerization, thereby suppressing SARS-CoV-2 replication. We discovered that SARS-CoV-2 papain-like protease inhibits ISG15 conjugation of nucleocapsid protein via its de-conjugating enzyme activity. The present study may contribute to gaining new insight into the roles of ISGylation-mediated anti-viral function in SARS-CoV-2 infection and may lead to the development of more potent and selective inhibitors targeted to SARS-CoV-2 nucleocapsid protein.

  American Society for Microbiology, Sep. 2024, Journal of Virology, 98(9) (9), English

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Small-molecule RAS/RAF Binding Inhibitors Allosterically Disrupt RAF Conformation and Exert Efficacy Against a Broad Spectrum of RAS-driven Cancers

  Fumi Shima, Yoko Yoshikawa, Yoshiteru Makino, Hirokazu Kubota, Takashi Kawamura, Shigeyuki Matsumoto, Hitomi Yuki, Akira Shibaike, Megumi Okamura, Tomoyo Okada, Manabu Horikawa, Kazumasa Horie, Michiyo Koyanagi-Aoi, Takashi Aoi, Tohru Kataoka, Teruki Honma, Takashi Kumasaka, Hiroo Koyama

  Jan. 2024


• Oncogenic mutations Q61L and Q61H confer active form-like structural features to the inactive state (state 1) conformation of H-Ras protein

  Shigeyuki Matsumoto, Haruka Taniguchi-Tamura, Mitsugu Araki, Takashi Kawamura, Ryo Miyamoto, Chiemi Tsuda, Fumi Shima, Takashi Kumasaka, Yasushi Okuno, Tohru Kataoka

  GTP-bound forms of Ras proteins (Ras•GTP) assume two interconverting conformations, "inactive" state 1 and "active" state 2. Our previous study on the crystal structure of the state 1 conformation of H-Ras in complex with guanosine 5'-(β, γ-imido)triphosphate (GppNHp) indicated that state 1 is stabilized by intramolecular hydrogen-bonding interactions formed by Gln61. Since Ras are constitutively activated by substitution mutations of Gln61, here we determine crystal structures of the state 1 conformation of H-Ras•GppNHp carrying representative mutations Q61L and Q61H to observe the effect of the mutations. The results show that these mutations alter the mode of hydrogen-bonding interactions of the residue 61 with Switch II residues and induce conformational destabilization of the neighboring regions. In particular, Q61L mutation results in acquirement of state 2-like structural features. Moreover, the mutations are likely to impair an intramolecular structural communication between Switch I and Switch II. Molecular dynamics simulations starting from these structures support the above observations. These findings may give a new insight into the molecular mechanism underlying the aberrant activation of the Gln61 mutants.

  Elsevier BV, Aug. 2021, Biochemical and Biophysical Research Communications, 565, 85 - 90, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Molecular Basis for Allosteric Inhibition of GTP-Bound H-Ras Protein by a Small-Molecule Compound Carrying a Naphthalene Ring.

  Matsumoto S, Hiraga T, Hayashi Y, Yoshikawa Yoko, Tsuda C, Araki M, Neya M, SHIMA FUMI, Kataoka Tohru

  Sep. 2018, Biochemistry, 57(36) (36), 5350 - 5358, English

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Ras inhibitors display an anti-metastatic effect by downregulation of lysyl oxidase through inhibition of the Ras-PI3K-Akt-HIF-1 alpha pathway

  Yoko Yoshikawa, Osamu Takano, Ichiro Kato, Yoshihisa Takahashi, Fumi Shima, Tohru Kataoka

  Dec. 2017, CANCER LETTERS, 410, 82 - 91, English

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Structural transition of solvated H-Ras/GTP revealed by molecular dynamics simulation and local network entropy

  Shota Matsunaga, Yuta Hano, Yuta Saito, Kazuhiro J. Fujimoto, Takashi Kumasaka, Shigeyuki Matsumoto, Tohru Kataoka, Fumi Shima, Shigenori Tanaka

  Oct. 2017, JOURNAL OF MOLECULAR GRAPHICS & MODELLING, 77, 51 - 63, English

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Integrin-alpha 10 Dependency Identifies RAC and RICTOR as Therapeutic Targets in High-Grade Myxofibrosarcoma

  Tomoyo Okada, Ann Y. Lee, Li-Xuan Qin, Narasimhan Agaram, Takahiro Mimae, Yawei Shen, Rachael O'Connor, Miguel A. Lopez-Lago, Amanda Craig, Martin L. Miller, Phaedra Agius, Evan Molinelli, Nicholas D. Socci, Aimee M. Crago, Fumi Shima, Chris Sander, Samuel Singer

  Oct. 2016, CANCER DISCOVERY, 6(10) (10), 1148 - 1165, English

  [Refereed]

  Scientific journal


• Molecular Mechanism for Conformational Dynamics of Ras.GTP Elucidated from In-Situ Structural Transition in Crystal

  Shigeyuki Matsumoto, Nao Miyano, Seiki Baba, Jingling Liao, Takashi Kawamura, Chiemi Tsuda, Azusa Takeda, Masaki Yamamoto, Takashi Kumasaka, Tohru Kataoka, Fumi Shima

  May 2016, SCIENTIFIC REPORTS, 6, 25931, English

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction

  Fumi Shima, Yoko Yoshikawa, Min Ye, Mitsugu Araki, Shigeyuki Matsumoto, Jingling Liao, Lizhi Hu, Takeshi Sugimoto, Yuichi Ijiri, Azusa Takeda, Yuko Nishiyama, Chie Sato, Shin Muraoka, Atsuo Tamura, Tsutomu Osoda, Ken-ichiro Tsuda, Tomoya Miyakawa, Hiroaki Fukunishi, Jiro Shimada, Takashi Kumasaka, Masaki Yamamoto, Tohru Kataoka

  May 2013, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 110(20) (20), 8182 - 8187, English

  [Refereed]

  Scientific journal


• Discovery of Small-Molecule Ras Inhibitors that Display Antitumor Activity by Interfering with Ras·GTP-Effector Interaction

  Fumi Shima, Yoko Yoshikawa, Shigeyuki Matsumoto, Tohru Kataoka

  2013, Enzymes, 34, 1 - 23, English

  [Refereed]

  Scientific journal


• Structure-based drug design of small-molecule Ras inhibitors having anti-tumor activity

  Shima Fumi, Kataoka T

  2013, SPring-8 Research Frontiers, English

  [Refereed][Invited]

  Research institution


• Crystal structures of the state 1 conformations of the GTP-bound H-Ras protein and its oncogenic G12V and Q61L mutants

  Shin Muraoka, Fumi Shima, Mitsugu Araki, Tomoko Inoue, Akiko Yoshimoto, Yuichi Ijiri, Nobuaki Seki, Atsuo Tamura, Takashi Kumasaka, Masaki Yamamoto, Tohru Kataoka

  Jun. 2012, FEBS LETTERS, 586(12) (12), 1715 - 1718, English

  [Refereed]

  Scientific journal


• Solution Structure of the State 1 Conformer of GTP-bound H-Ras Protein and Distinct Dynamic Properties between the State 1 and State 2 Conformers

  Mitsugu Araki, Fumi Shima, Yoko Yoshikawa, Shin Muraoka, Yuichi Ijiri, Yuka Nagahara, Tomoya Shirono, Tohru Kataoka, Atsuo Tamura

  Nov. 2011, JOURNAL OF BIOLOGICAL CHEMISTRY, 286(45) (45), 39644 - 39653, English

  [Refereed]

  Scientific journal


• Critical Roles of Interactions among Switch I-preceding Residues and between Switch II and Its Neighboring alpha-Helix in Conformational Dynamics of the GTP-bound Ras Family Small GTPases

  Kousuke Matsumoto, Fumi Shima, Shin Muraoka, Mitsugu Araki, Lizhi Hu, Yuichi Ijiri, Rina Hirai, Jingling Liao, Takashi Yoshioka, Takashi Kumasaka, Masaki Yamamoto, Atsuo Tamura, Tohru Kataoka

  Apr. 2011, JOURNAL OF BIOLOGICAL CHEMISTRY, 286(17) (17), 15403 - 15412, English

  [Refereed]

  Scientific journal


• Structural Basis for Conformational Dynamics of GTP-bound Ras Protein

  Fumi Shima, Yuichi Ijiri, Shin Muraoka, Jingling Liao, Min Ye, Mitsugu Araki, Kousuke Matsumoto, Naoki Yamamoto, Takeshi Sugimoto, Yoko Yoshikawa, Takashi Kumasaka, Masaki Yamamoto, Atsuo Tamura, Tohru Kataoka

  Jul. 2010, JOURNAL OF BIOLOGICAL CHEMISTRY, 285(29) (29), 22696 - 22705, English

  [Refereed]

  Scientific journal


• Biochemical characterization of missense mutations in the Arf/Arl-family small GTPase Arl6 causing Bardet-Biedl syndrome

  Tetsuo Kobayashi, Yuji Hori, Nami Ueda, Hiroaki Kajiho, Shin Muraoka, Fumi Shima, Tohru Kataoka, Kenji Kontani, Toshiaki Katada

  Apr. 2009, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 381(3) (3), 439 - 442, English

  [Refereed]

  Scientific journal


• Two conformational states of Ras GTPase exhibit differential GTP-binding kinetics

  Jingling Liao, Fumi Shima, Mitsugu Araki, Min Ye, Shin Muraoka, Takeshi Sugimoto, Mei Kawamura, Naoki Yamamoto, Atsuo Tamura, Tohru Kataoka

  May 2008, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 369(2) (2), 327 - 332, English

  [Refereed]

  Scientific journal


• Crystal structure of M-Ras reveals a GTP-bound "off" state conformation of Ras family small GTPases

  M Ye, F Shima, S Muraoka, JL Liao, H Okamoto, M Yamamoto, A Tamura, N Yagi, T Ueki, T Kataoka

  Sep. 2005, JOURNAL OF BIOLOGICAL CHEMISTRY, 280(35) (35), 31267 - 31275, English

  [Refereed]

  Scientific journal


• Critical role of posttranslational modification of Ras proteins in effector activation

  F Shima, T Kataoka

  Jun. 2005, SEIKAGAKU, 77(6) (6), 519 - 526, Japanese

  [Refereed]

  Scientific journal


• Direct activation of fission yeast adenylyl cyclase by heterotrimeric G protein gpa2

  Hideki Ogihara, Fumi Shima, Kana Naito, Tsuyoshi Asato, Ken-Ichi Kariya, Tohru Kataoka

  2004, Kobe Journal of Medical Sciences, 50(3-4) (3-4), 111 - 121, English

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Critical function of the ras-associating domain as a primary ras-binding site for regulation of Saccharomyces cerevisiae adenylyl cyclase

  M Kido, F Shima, T Satoh, T Asato, K Kariya, T Kataoka

  Feb. 2002, JOURNAL OF BIOLOGICAL CHEMISTRY, 277(5) (5), 3117 - 3123, English

  [Refereed]

  Scientific journal


• Role of Raf-1 conserved region 2 in regulation of Ras-dependent Raf-1 activation

  H Sendoh, CD Hu, DM Wu, CH Song, Y Yamawaki-Kataoka, J Kotani, T Okada, F Shima, K Kariya, T Kataoka

  May 2000, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 271(3) (3), 596 - 602, English

  [Refereed]

  Scientific journal


• Association of yeast adenylyl cyclase with cyclase-associated protein CAP forms a second Ras-binding site which mediates its Ras-dependent activation

  Fumi Shima, Tomoyo Okada, Masahiro Kido, Hiroyoshi Sen, Yasuhiro Tanaka, Masako Tamada, Chang-Deng Hu, Yuriko Yamawaki-Kataoka, Ken-Ichi Kariya, Tohru Kataoka

  American Society for Microbiology, 2000, Molecular and Cellular Biology, 20(1) (1), 26 - 33, English

  Scientific journal


• Characterization of a novel Ras-binding protein Ce-FLI-1 comprising leucine-rich repeats and gelsolin-like domains

  M Goshima, K Kariya, Y Yamawaki-Kataoka, T Okada, M Shibatohge, F Shima, E Fujimoto, T Kataoka

  Apr. 1999, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 257(1) (1), 111 - 116, English

  [Refereed]

  Scientific journal


• Coiled-coil interaction of N-terminal 36 residues of cyclase-associated protein with adenylyl cyclase is sufficient for its function in Saccharomyces cerevisiae Ras pathway

  Yoshimitsu Nishida, Fumi Shima, Hiroyoshi Sen, Yasuhiro Tanaka, Chie Yanagihara, Yuriko Yamawaki-Kataoka, Ken-Ichi Kariya, Tohru Kataoka

  Oct. 1998, Journal of Biological Chemistry, 273(43) (43), 28019 - 28024, English

  [Refereed]

  Scientific journal


• Identification of PLC210, a Caenorhabditis elegans phospholipase C, as a putative effector of Ras

  M Shibatohge, K Kariya, YH Liao, CD Hu, Y Watari, M Goshima, F Shima, T Kataoka

  Mar. 1998, JOURNAL OF BIOLOGICAL CHEMISTRY, 273(11) (11), 6218 - 6222, English

  [Refereed]

  Scientific journal


• Effect of association with adenylyl cyclase-associated protein on the interaction of yeast adenylyl cyclase with Ras protein

  Fumi Shima, Yuriko Yamawaki-Kataoka, Chie Yanagihara, Masako Tamada, Tomoyo Okada, Ken-Ichi Kariya, Tohru Kataoka

  American Society for Microbiology, 1997, Molecular and Cellular Biology, 17(3) (3), 1057 - 1064, English

  Scientific journal


• Differential structural requirements for interaction of Ras protein with its distinct downstream effectors

  K Akasaka, M Tamada, F Wang, K Kariya, F Shima, A Kikuchi, M Yamamoto, M Shirouzu, S Yokoyama, T Kataoka

  Mar. 1996, JOURNAL OF BIOLOGICAL CHEMISTRY, 271(10) (10), 5353 - 5360, English

  [Refereed]

  Scientific journal

• Novel Insights into the Structural Perturbation Induced by the Oncogenic Mutations, Q61L and Q61H, in Ras State 1

  Shigeyuki Matsumoto, Haruka Taniguchi-Tamura, Mitsugu Araki, Takashi Kawamura, Ryo Miyamoto, Chiemi Tsuda, Yasushi Okuno, Fumi Shima, Takashi Kumasaka, Tohru Kataoka

  Feb. 2020, BIOPHYSICAL JOURNAL, 118(3) (3), 42A - 42A, English

  Summary international conference


• SACLA,SPring-8並びにNMRを用いた低分子量Gタンパク質RasのGTP加水分解過程における動的構造解析

  佐伯茉帆, 槇野義輝, 松本篤幸, 河村高志, 南後恵理子, 熊坂崇, 島扶美

  2020, 日本分子生物学会年会プログラム・要旨集(Web), 43rd


• Current status of the development of Ras inhibitors

  Fumi Shima, Shigeyuki Matsumoto, Yoko Yoshikawa, Takashi Kawamura, Masayuki Isa, Tohru Kataokat

  Aug. 2015, JOURNAL OF BIOCHEMISTRY, 158(2) (2), 91 - 99, English

  [Refereed]

  Book review


• rasがん遺伝子産物の新規立体構造情報を利用した分子標的がん治療薬の開発

  Shima Fumi, 熊坂崇, Matsumoto Shigeyuki, Yoshikawa Yoko, 山本雅貴, Kataoka Tohru

  日本放射光学会, 2014, 日本放射光学会誌 放射光, 27(1) (1), 3 - 9, Japanese

  [Refereed]

  Introduction scientific journal


• 【タンパク質修飾による機能変化】 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

  SHIMA, Fumi, KATAOKA, Toru

  Jun. 2005, 生化学, 77巻, 6号, pp.519-526, Japanese

  Introduction scientific journal


• シクラーゼ結合蛋白質CAPは, Ras蛋白質の翻訳後修飾の出芽酵母アデニル酸シクラーゼ活性化促進効果に必須である.

  島 扶美, 片岡 有里子, 柳原 千枝, 玉田 昌子, 岡田 知代, 苅谷 研一, 片岡 徹

  01 Aug. 1996, 日本分子生物学会年会プログラム・講演要旨集, 19, 314 - 314, Japanese


• Differential structural requirements for interaction of Ras protein with its distinct downstream effectors.

  AKASAKA K, TAMADA M, WANG F, KARIYA K, SHIMA F, KIKUCHI A, YAMAMOTO M, YOKOYAMA S, KATAOKA T

  1996, J. Biol. Chem., 271(10) (10), 5353 - 5360

• ras がん遺伝子産物 Ras を分子標的としたがん治療薬開発の現状

  SHIMA FUMI, Matsumoto Shigeyuki, Yoshikawa Yoko, Kataoka Tohru

  Joint work, がん分子標的治療, 2015, Japanese

  General book


• 生化学 / エフェクター活性化過程に必須であるRasの翻訳後修飾

  SHIMA FUMI

  Joint work, 日本生化学会, Jun. 2005, Japanese

  Scholarly book

• Recognition mechanism of conformational states in RAS by GTPase-acting protein,GAP

  WakakoSakisaka, YoshiteruMakino TaisukeHorikawa, YokoYoshikawa, TakashiKawamura ErikoNngo TakashiKumasaka FumiShima

  第46回日本分子生物学会年会, Dec. 2023, Japanese

  Poster presentation


• Inactivation mechanism og RASelucidated by photoreactive GTP

  HorikawaTaisuke, YoshiteruMakino WakakoSakisaka, YokoYoshikawa, TakashiKawamura ErikoNango, TakashiKumasaka FumiShima

  The 96th Annual Meeting of the Japanese Biochemical Society, Oct. 2023, Japanese

  Oral presentation


• RAS-signaling inhibitors that allosterically disrupt effector conformation and inhibit growth of RAS-driven cancers

  YokoYoshikawa, YoshiteruMakino HirokazuKubota ShigeyukiaMatsumoto, HitomiYuki, TerukiHonma HirooKoyama FumiShima

  THE 82ND ANNUAL MEETING OF THE JAPANESE CANCER ASSOCIATION, Sep. 2023, Japanese

  Oral presentation


• 低分子量Gタンパク質H-Rasのフリーズトラップ結晶構造解析によるGTPase活性分子メカニズムの追跡

  河村高志, 槇野義輝, 長谷川和也, 吉川陽子, 島扶美, 熊坂崇

  第95回日本生化学会大会, Nov. 2022, Japanese

  Poster presentation


• SACLA/SPring-8/NMRを駆使した低分子量G蛋白質Rasの不活性化機構におけるアロステリック構造変化の解明

  槇野義輝, 河村高志, 吉川陽子, 南後恵理子, 熊坂崇, 島扶美

  第95回日本生化学会大会, Nov. 2022, Japanese

  Poster presentation


• SACLA/SPring-8/NMRを用いたRasのアロステリック構造変化の解明

  槇野義輝, 島扶美

  第5回徳島大学統合的がん創薬研究クラスター・合同オンラインミーティング, Mar. 2022, Japanese


• Confoemational changes neighboring the GTP-binding site of small GTPase Ras upon GTP hydrolysis process.

  Maho Saeki, Yoshiteru Makino, Takashi Kawamura, Eriko Nango, Takashi Kumasaka, Fumi Shima

  第94回日本生化学会大会, Nov. 2021

  Poster presentation


• Visualization of enzyme-catalyezed reaction of oncogene product Ras utilizing its photo-reactive substrate

  Fumi Shima, Yoshiteru Makino, Eriko Nango, Takashi Kumasaka

  第94回日本生化学会大会, Nov. 2021, Japanese

  Invited oral presentation


• Analysis of conformational dynamics of small G-proten Ras on GTP hydrolysis process by SACLA,Spring-8 and NMR

  Maho Saeki, Yoshiteru Makino, Shigeyuki Matsumoto, Takashi Kawamura, Eriko Nango, Takashi Kumasaka, Fumi Shima

  第43回日本分子生物学会年会, Dec. 2020, English

  Poster presentation


• -

  Takashi Kawamura , Yoshiteru Makino* , Kazuya Hasegawa , Takanori Nakane , Seiki Baba , Eriko Nango , Rie Tanaka , So Iwata , Takashi Kumasaka and Fumi Shima*

  第33回日本放射光学会年会・放射光科学合同シンポジウム, Jan. 2020


• -

  Fumi Shima* , Yoshiteru Makino

  第3回徳島大学統合的がん創薬研究クラスター合同ミーティング, Dec. 2019

  [Invited]


• Structural changes on GTP hydrolysis of oncogene product Ras revealed by SACLA, Spring-8 and NMR using photo-controllable caged-GTP

  Yoshiteru Makino, Takashi Kawamura, Shigeyuki Matsumoto, Eriko Nango, So Iwata, Takashi Kumasaka, Fumi Shima

  第57回日本生物物理学会年会, Sep. 2019, Japanese, Domestic conference

  Poster presentation


• 構造生物学に基づくがん治療薬の創出研究

  島扶美

  第2回徳島大学統合的がん創薬研究クラスター合同ミーティング, Feb. 2019, 徳島大学統合的がん創薬研究クラスター, 淡路夢舞台 国際会議場

  [Invited]


• Conformational dynamics of small GTPase Ras on GTP hydrolysis process revealed by SACLA, Spring-8 and NMR

  Chika Hagihara, Yoshiteru Makino, Shigeyuki Matsumoto, Takashi Kawamura, Ichiro Mori, Eriko Nango, Takashi Kumasaka, Fumi Shima

  第41回日本分子生物学会年会, Nov. 2018, 日本分子生物学会年会, パシフィコ横浜

  Poster presentation


• Conformational changes on GTP hydrolysis of oncogene product Ras revealed by monitoring of time-dependent NMR signal using caged-GTP

  Chika Hagihara, Yoshiteru Makino, Shigeyuki Matsumoto, Takashi Kawamura, Ichiro Mori, Eriko Nango, Takashi Kumasaka, Tohru Kataoka, Fumi Shima

  第56回日本生物物理学会年会, Sep. 2018, 日本生物物理学会, 岡山大学 津島キャンパス


• Novel effect of Ras inhibitor and its application to cancer therapy

  森元 智行, Yoshikawa Yoko, 白川 慶徳, 森 一郎, Kataoka Tohru, Shima Fumi

  2017年度生命科学系学会合同年次大会(第40回日本分子生物学会年会 第90回日本生化学会大会）, Dec. 2017, Japanese, 日本分子生物学会日本生化学会, 神戸, Domestic conference

  Poster presentation


• Ras inhibitors display anti-metastatic effect toward ras-transformed cancer cells via downregulation of lysyl oxidase

  Yoshikawa Yoko, Shima Fumi, Kataoka Tohru

  第76回 日本癌学会学術総会, Sep. 2017, Japanese, 日本癌学会, 横浜, International conference

  Oral presentation


• In silico discovery of small-molecule Ras inhibitors

  Shima Fumi

  University of Washington-Kobe University Joint Symposium on Cell Signaling, Sep. 2015, English, University of Washington and Kobe University, Seattle, USA, International conference

  [Invited]

  Invited oral presentation


• Crystal Mounting Method using Humid Air and Hydrophilic Glue Coating For Ambient and Cryogenic Experiments

  Takashi Kumasaka, Masaki Yamamoto, Kataoka Tohru, Shima Fumi, Matsumoto Shigeyuki, Kawamura Takashi, Nobuo Kamiya, Yasufumi Umena, Naoto Yagi, Seiki Baba

  2015 Annual Meeting of the American Crystallographic Association, Jul. 2015, English, American Crystallographic Association, Philadelphia, USA, International conference

  Oral presentation


• 試料雰囲気湿度調整によるRasタンパク質の結晶内構造転移

  熊坂 崇, 馬場 清喜, 宮野 菜央, Kawamura Takashi, Matsumoto Shigeyuki, 山本 雅貴, Kataoka Tohru, Shima Fumi

  第15回日本蛋白質科学会年会, Jun. 2015, Japanese, 日本蛋白質科学会, 徳島, Domestic conference

  Poster presentation


• GTP結合型H-RasのState 1結晶構造情報に基づく立体構造遷移機構の解明

  Matsumoto Shigeyuki, 宮野 菜央, 馬場 清喜, Liao Jingling, 竹田 あずさ, 山本 雅貴, 熊坂 崇, Kataoka Tohru, Shima Fumi

  第15回日本蛋白質科学会年会, Jun. 2015, Japanese, 日本蛋白質科学会, 徳島, Domestic conference

  Poster presentation


• 創薬支援ネットワークの支援を受けて

  Shima Fumi

  創薬支援ネットワーク・シンポジウム「オールジャパンの創薬支援」創薬立国日本に向けて, Jan. 2015, Japanese, 創薬支援ネットワーク・医薬基盤研究所 創薬支援戦略室, 大阪, Domestic conference

  [Invited]

  Invited oral presentation


• Analysis of the mechanism underlying the anti-metastatic action of Ras inhibitors by using a lung metastatic model mouse

  Osamu Takano, Yoshikawa Yoko, Shima Fumi, Kataoka Tohru

  第72回日本癌学会学術総会, Oct. 2013, English, 日本癌学会, 横浜, Domestic conference

  Poster presentation


• Molecular mechanism of conformational transition of GTP-bound Ras revealed by the crystal structure analysis of M-Ras mutants

  松本 耕祐, Shima Fumi, 村岡 真, 井尻 悠一, 市川 晋也, 荒木 望嗣, 熊坂 崇, 田村 厚夫, Kataoka Tohru

  BMB2010 （第33回日本分子生物学会年回・第83回日本生化学会大会合同大会）, Dec. 2010, Japanese, 日本生化学会大会/日本分子生物学会, 神戸, Domestic conference

  Poster presentation


• GTP結合型M-Ras変異体の二種類の結晶構造から考察される立体構造遷移メカニズム

  松本 耕祐, Shima Fumi, 村岡 真, 井尻 悠一, 市川 晋也, 荒木 望嗣, 熊坂 崇, 田村 厚夫, Kataoka Tohru

  第33回日本分子生物学会年会, Dec. 2010, Japanese, 日本分子生物学会, 神戸, Domestic conference

  Oral presentation


• New strategy for development of anti-cancer drugs targeting the ras oncogene products

  Kataoka Tohru, Shima Fumi

  第69回日本癌学会学術総会, Sep. 2010, Japanese, 日本癌学会, 大阪, Domestic conference

  Invited oral 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

  Shima Fumi, Muraoka Shin, Ryo Seirei, Araki Mitsugu, Kataoka Tohru

  第32回日本分子生物学会年会, Dec. 2009, Japanese, 日本分子生物学会, 横浜, Domestic conference

  Poster presentation


• X-ray crystal structure analysis of the budding yeast small GTPase Ras2

  Muraoka Shin, Shima Fumi, Ryo Seirei, Kataoka Tohru

  第82回日本生化学会大会, Oct. 2009, Japanese, 日本生化学会, 神戸, Domestic conference

  Poster presentation


• GTP結合型Ｒａｓの構造遷移メカニズムと創薬への応用

  Shima Fumi

  「Ｇ蛋白質シグナル」研究班会議, Sep. 2009, Japanese, 文部科学省特定領域研究, 千葉県・南房総市, Domestic conference

  Others


• Structural analysis of the novel state1 conformation of Ras protein

  Shima Fumi, Muraoka Shin, Kataoka Tohru

  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, Jul. 2009, Japanese, 神戸大学/グローバルCOE, 淡路, Domestic conference

  Poster presentation


• ＧＴＰ結合型Ｒａｓの立体構造多型性と創薬への応用

  Shima Fumi

  G蛋白質特定領域・膜輸送複合体特定領域合同若手ワークショップ 2009, Jan. 2009, Japanese, 文部科学省特定領域研究, 神戸, Domestic conference

  Oral presentation


• ＧＴＰ結合型M-Ｒａｓの構造遷移におけるH-Ras型アミノ酸置換の影響

  Shima Fumi

  G蛋白質特定領域・膜輸送複合体特定領域合同若手ワークショップ 2009, Jan. 2009, Japanese, 文部科学省特定領域研究, 神戸, Domestic conference

  Oral presentation


• ＧＴＰ結合型H-Ｒａｓの立体構造多型性とエフェクター新規認識機構

  Shima Fumi

  G蛋白質特定領域・膜輸送複合体特定領域合同若手ワークショップ 2009, Jan. 2009, Japanese, 文部科学省特定領域研究, 神戸, Domestic conference

  Oral presentation


• Screening for Ras specific inhibitors based on the conformational equilibrium of Ras in complex with GTP

  Shima Fumi, Muraoka Shin, Sugimoto Takeshi, Yoshikawa Yoko, Kataoka Tohru

  Kobe University Global COE Program International Symposium on Integrative Membrane Biology, Dec. 2008, English, グローバルCOE, 神戸, Domestic conference

  Poster presentation


• GTP結合型H-Rasの高次構造多型性とエフェクターの新規認識機構

  Muraoka Shin, Araki Mitsugu, Yoshikawa Yoko, Ryo Seirei, Kataoka Tohru, Shima Fumi

  特定研究領域「Ｇ蛋白質シグナル」研究班会議, Sep. 2008, Japanese, 特定研究領域「Ｇ蛋白質シグナル」, 新潟, Domestic conference

  Poster presentation


• New strategy to develop Ras specific inhibitors based on conformational equilibrium of Ras oncoprotein.

  Shima Fumi, Muraoka Shin, Sugimoto Takeshi, Yoshikawa Yoko, Kataoka Tohru

  第3回グローバルCOE研究討論会 兼グローバルCOE第2回ワークショップ, Jul. 2008, Japanese, グローバルCOE, 淡路, Domestic conference

  Poster presentation


• New strategy to develop Ras specific inhibitors

  Shima Fumi, Yoshikawa Yoko, Muraoka Shin, Sugimoto Takeshi, Kataoka Tohru

  第3回グローバルCOE研究討論会 兼グローバルCOE第2回ワークショップ, Jul. 2008, Japanese, グローバルCOE, 淡路, Domestic conference

  Poster presentation


• Conformational equilibrium of small GTPases and signal transduction

  Shima Fumi, Ryo Seirei, Muraoka Shin, Yoshikawa Yoko, Kataoka Tohru

  BMB2007第30回日本分子生物学会年会、第80回日本生化学会大会合同大会, Dec. 2007, Japanese, 日本分子生物学会/日本生化学会, 横浜, Domestic conference

  Poster presentation


• New strategy to develop Ras specific inhibitors based on conformational equilibrium of Ras oncoprotein

  Shima Fumi

  2007InternationalSymposiumon“G-proteinSignaling”, Jul. 2007, English, The Japanese Grant-in-Aid for Scientific Research on Priority Areas: “G-protein signal” 文部科学省特定領域研究「Ｇ蛋白質シグナル」, 東京, International conference

  [Invited]

  Invited oral presentation


• Rasをターゲットにした抗癌剤のインシリコ創薬

  Shima Fumi

  第６６回神戸バイオサイエンス研究会, May 2007, Japanese, 神戸バイオサイエンス研究会, 神戸, Domestic conference

  Invited oral presentation


• GTP Dissociation Rate and Conformational Equilibrium in Various Small GTPases

  SHIMA FUMI, MURAOKA SHIN, KATAOKA TOHRU

  日本分子生物学会2006フォーラム「分子生物学の未来」〜コンファレンス&サイエンティフィック・エキジビション〜, Dec. 2006, English, 日本分子生物学会, 名古屋, Domestic conference

  Poster presentation


• Signal transduction and conformational equilibrium in various small GTP-binding proteins

  SHIMA FUMI, KATAOKA TOHRU

  神戸大学21世紀COEプログラム「蛋白質のシグナル伝達機能」 平成18年度第1回研究発表会・若手ポスター発表会, Aug. 2006, Japanese, 神戸大学21世紀COEプログラム「蛋白質のシグナル伝達機能」, 神戸, Domestic conference

  Poster presentation


• Allostery in effector recognition by Ras family small GTPases: conformational transition in the GTP-bound form

  SHIMA FUMI, MURAOKA SHIN, KATAOKA TOHRU

  20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FAOMBM Congress,第79回日本生化学会大会、第29回日本分子生物学会年会, Jun. 2006, English, The International Union of Biochemistry and Molecular Biology／The The Federation of Asian and Oceanian Biochemists and Molecular Biologists ／日本生化学会／日本分子生物学会, 京都, International conference

  Poster presentation


• Crystal structure of M-Ras reveals a GTP-bound "off" state conformation of Ras family small GTPases

  SHIMA, Fumi, 叶 敏, MURAOKA, Shin, 廖 静伶, 岡本 英嗣, 山本 雅貴, 田村 厚夫, 徳島 大介, 宮川 知也

  Keystone Symposia, Frontiers in Structural Biology, Jan. 2006, English, Keystone Symposia, キーストン, International conference

  Poster presentation


• Crystal structure of M-Ras reveals a GTP-bound "off" state conformation of Ras family small GTPases

  叶 敏, SHIMA, Fumi, MURAOKA, Shin, 廖 静伶, 岡本 英嗣, 山本 雅貴, 田村 厚夫, 徳島 大介, 宮川 知也, KATAOKA, Toru

  第28回日本分子生物学会年会, Dec. 2005, English, 日本分子生物学会, 福岡, Domestic conference

  Poster presentation


• Crystal structure of M-Ras reveals a GTP-bound "off" state conformation of Ras family small GTPase

  廖 静伶, SHIMA, Fumi, MURAOKA, Shin, 叶 敏, 岡本 英嗣, 山本 雅貴, 田村 厚夫, 八木 直人, 徳島 大介, 宮川 知也, KATAOKA, Toru

  第64回日本癌学会学術総会, Sep. 2005, English, 日本癌学会, 札幌, Domestic conference

  Others


• Crystal Structure of the small G protein M-Ras and its implications

  MURAOKA, Shin, 山本 雅貴, 八木 直人, 植木 龍夫, 叶 敏, SHIMA, Fumi, 廖 静伶, 岡本 英嗣, 田村 厚夫, KATAOKA, Toru

  XX Congress of the International Union of Crystallography, Aug. 2005, English, International Union of Crystallography, フィレンツェ, International conference

  Poster presentation


• M-Rasの特異的高次構造とGTPase活性及びｴﾌｪｸﾀｰ認識機

  叶 敏, SHIMA, Fumi, MURAOKA, Shin, 山本 雅貴, 植木 龍夫, 廖 静伶, TAMURA, Takashi, KATAOKA, Toru

  第77回日本生化学会大会, Oct. 2004, English, 日本生化学会, 神戸, Domestic conference

  Poster presentation


• 低分子量GTP結合蛋白質M-RasのX線構造解析

  叶 敏, SHIMA, Fumi, MURAOKA, Shin, 山本 雅貴, 八木 直人, KATAOKA, Toru

  第26回日本分子生物学会年会, Dec. 2003, English, 日本分子生物学会, 横浜, Domestic conference

  Poster presentation

• Development of Novel PPI inhibitors as anti-cancer drugs

  島 扶美

  国立研究開発法人日本医療研究開発機構, AMED創薬支援ネットワーク委託実験調査, Kobe University, Apr. 2024 - Mar. 2025, Principal investigator


• 新規白血病治療薬の開発

  大阪大学医学部付属病院未来医療開発部, 「橋渡し研究推進による」未来医療創出」, 神戸大学, Sep. 2023 - Mar. 2024


• Rasシグナルの網羅的阻害を示す革新的がん治療薬の創出を目指した研究

  国立研究開発法人科学技術振興機構, 研究成果展開事業 社会還元加速プログラムSTART大学・エコシステム推進型 大学推進型, 神戸大学, May 2023 - Mar. 2024, Principal investigator


• Development of Novel PPI inhibitors as anti-cancer drugs

  島 扶美

  国立研究開発法人 日本医療研究開発機構, AMED創薬支援ネットワーク委託実験調査（スクリーニング）, Kobe University, Apr. 2022 - Mar. 2024, Principal investigator


• Elucidation of cancer signal transduction mechanism using photo-controllable Ras on an atomic scale

  島 扶美

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area), Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area), Kobe University, Apr. 2022 - Mar. 2024


• Rasシグナルの網羅的阻害を基軸とした革新的がん治療薬の開発

  島扶美

  国立研究開発法人科学技術振興機構, 産学が連携した研究開発成果の展開 研究成果展開事業 大学発新産業創出プログラム(START) 大学推進型, 神戸大学, Apr. 2022 - Mar. 2023, Principal investigator

  本事業の目的は、神戸大学および大阪工業大学において、5年後までに外部資金の間接経費や寄附金を原資とする継続的なGAPファンドやシード投資ファンドを運営・発展させ、継続的な起業活動支援を可能にすることである。 神戸大学と大阪工業大学に所属する研究者の技術シーズに基づく起業活動支援を通じて技術シーズやビジネスモデルのブラッシュアップを行うとともに、「大学発新産業創出プログラム(START)」の申請やベンチャーキャピタル(VC)へ橋渡しする。同時にさらなる技術シーズの創出につなげることで内閣府事業「スタートアップ・エコシステム拠点都市注)」の「グローバル拠点都市」に採択された「京阪神連携によるスタートアップ・エコシステム拠点形成」に貢献する。 具体的には、神戸大学と大阪工業大学が共同でGAPファンドプログラム、起業活動支援プログラムを構築し、試作品製作、追加データ取得などにより、STARTやVCでの評価や投資判断ができるレベルまでビジネスモデルをブラッシュアップする。


• Development of novel leukemia therapeutics

  島 扶美

  国立研究開発法人日本医療研究開発機構, Translational Research Program, Kobe University, Apr. 2022 - Mar. 2023


• Time-resolved structural analysis of small GTPase Ras signaling transduction by utilizing caged-GTP-coupled Ras protein

  Time-resolved structural analysis of small, GTPase Ras signaling, ransduction by utilizing, caged-GTP-coupled Ras protein

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area), Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area), Kobe University, Oct. 2020 - Mar. 2022

  ① NPEcagedGTP・Ras複合体微結晶に加え、光制御下でのcage離脱速度がより速いpHPcagedGTP を用いたSFXを実施しポケット開閉運動初期のデータ収集を行ために、pHPcagedGTPの合成経路の探索を外注（ナード社）において行った。 cagedATP合成に関する文献と同一、もしくは類似のルート、およびいくつかのルーとを探索したが合成の難易度が比較的高いことが明らかになった。中間体の合成方法は見出されたが、中間体からcagedGTPへの縮合反応が上手く進まない状況にある。現在、グアノシンならびにグアノシンモノリン酸をグアノシン側のパーツとしてして用いた新たな合成ルートを検討している。課題採択ならびに研究開始時期が2020年度下期だったこともあり、pHPcagedGTPの入手には至っていない。 ② NPEcaged-GTP型H-Rasの光照射HSQC_NMR測定とアミノ酸残基ごとのkinetics解析により、GTPの加水分解反応（GDP生成反応）において、２つのSwitch領域の構造変化に先駆けて、当該領域に隣接するα３ヘリックスとP-loopの構造変化が起こることが確認できた。また、GTPの加水分解過程においてRasはState 1構造を経由した後GDP型になることが明らかになった。 ③ GTP加水分解反応に際してState 2構造を経由するかどうかについては、構造変化の速度が溶液中と比較して緩やかになることが予想される、NPEcagedGTP型H-Ras微結晶を用いた光照射・固体31P_ NMR測定が必要と考えらえたため、当該測定を実施したこところ、cage離脱後State 1からState 2を経てGDP型への構造変化を示唆する実験データが得られた。 以上の研究成果を2020.12の第43回日本分子生物学会にて発表した（Saeki et al.）。


• Development of novel Ras-signaling inhibitors

  島 扶美

  国立研究開発法人日本医療研究開発機構, 橋渡し研究戦略的推進プログラム「異分野融合型研究の推進による自立循環型新規医療創出基盤の確立」, 神戸大学, Apr. 2020 - Mar. 2022


• Atomic-scale dynamic structural analysis of Ras by SACLA, which provide promising information on designing cancer therapeutic agents

  Shima Fumi

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C), Grant-in-Aid for Scientific Research (C), Kobe University, Apr. 2019 - Mar. 2022

  Small GTPase Ras functions as a molecular switch by cycling between GTP-bound active and GDP-bound inactive forms in cell signaling pathways. Despite its importance as a cancer driver gene product, dedicated efforts to directly target Ras for decades still have not yielded therapeutic efficacy, due to limited structural information on natural GTP-bound Ras and its ‘undruggable’ nature of drug-binding site, i.e., structural dynamics hampering stable drug-binding, that is intriguingly linked to its GTP hydrolysis activity. Here to elucidate structural dynamics of natural GTP-bound Ras, we performed time-dependent structural analysis of photo-controllable caged-GTP-bound Ras on GTP hydrolysis process by SACLA, SPring-8 and NMR. Photo-irradiation to caged-GTP-bound Ras yielded natural GTP-bound Ras, leading to GTP hydrolysis for production of Ras-GDP. These results provide new insight into the structural dynamics of Ras, realizing novel strategies for development of Ras inhibitors.


• Development of Novel PPI inhibitors as anti-cancer drugs

  島 扶美

  国立研究開発法人 日本医療研究開発機構, AMED創薬支援ネットワーク委託実験調査（標的検証・後期）, 神戸大学, Dec. 2019 - Mar. 2021, Principal investigator

  Competitive research funding


• 抗がん剤の設計基盤となるX線自由電子レーザーによるRasの時分割構造解析

  島 扶美

  公益財団法人ひょうご科学技術協会, 平成31年度学術研究助成, Apr. 2019 - Mar. 2020, Principal investigator

  Competitive research funding


• Ras/Rafシグナル伝達を阻害する新規抗がん剤の研究

  島 扶美

  国立研究開発法人 日本医療研究開発機構, AMED創薬支援ネットワーク委託実験調査, Jul. 2014 - Mar. 2019, Principal investigator

  Competitive research funding


• がん転移治療抗体薬開発のためのインテグリンα10の立体構造解析

  島 扶美

  神戸大学医学部第二内科同門会, 神戸大学医学部第二内科同門会助成金, Apr. 2018 - Dec. 2018, Principal investigator

  Competitive research funding


• 低分子量G蛋白質Rasの翻訳後脂質修飾の役割の構造科学的研究

  片岡 徹

  科学研究費補助金／基盤研究(B), Apr. 2014 - Mar. 2017

  Competitive research funding


• 創薬への応用に向けたrasがん遺伝子産物の構造ダイナミクスの分子機構の解明

  島 扶美

  科学研究費補助金／基盤研究(B), Apr. 2014 - Mar. 2017, Principal investigator

  Competitive research funding


• rasがん遺伝子産物の新規立体構造情報に基づくがん分子標的治療薬の開発

  片岡 徹

  厚生労働科研研究費補助金, Apr. 2011 - Mar. 2016

  Competitive research funding


• 新規Ras機能阻害物質Kobe0065ファミリー化合物のがん転移抑制メカニズムの解析

  島 扶美

  高松宮妃癌研究基金研究助成金, Apr. 2014 - Mar. 2015, Principal investigator

  Competitive research funding


• rasがん遺伝子産物の立体構造情報を基盤としたがん分子標的治療薬の理論設計

  島 扶美

  公益財団法人ひょうご科学技術協会, 学術研究助成金, Apr. 2013 - Mar. 2014, Principal investigator

  Competitive research funding


• Ｒａｓ－Ｒａｆ結合阻害活性を有する抗がん剤の創製

  島 扶美

  学術研究助成基金助成金／基盤研究(C), Apr. 2011 - Mar. 2014, Principal investigator

  Competitive research funding


• ホスホリパーゼＣεの炎症・発癌促進機能に関わる新規シグナル伝達系の解明

  片岡 徹

  科学研究費補助金／基盤研究(B), 2011

  Competitive research funding


• A-STEP「Ras/Rafシグナル伝達を阻害する新規抗がん剤の開発」

  島 扶美

  研究成果最適展開支援プログラム フィージビリティスタディステージ 探索タイプ 拠点型, 2011, Principal investigator

  Competitive research funding


• Ｒａｓの新規高次構造を標的とした抗癌剤の開発

  島 扶美

  科学研究費補助金／基盤研究(C), Apr. 2008 - Mar. 2010, Principal investigator

  Competitive research funding


• 低分子量Ｇ蛋白質の高次構造多型性のシグナル伝達における意義

  島 扶美

  科学研究費補助金／特定領域研究, Apr. 2008 - Mar. 2010, Principal investigator

  Competitive research funding


• 低分子量Ｇ蛋白質の高次構造多型性のシグナル伝達における意義

  島 扶美

  科学研究費補助金／特定領域研究, Apr. 2006 - Mar. 2008, Principal investigator

  Competitive research funding


• 低分子量Ｇ蛋白質のクロストークを仲介するＲａｐ１活性化因子の機能解析

  片岡 徹

  科学研究費補助金／基盤研究(B), 2008

  Competitive research funding


• Ｒａｓ／Ｒａｐ結合（ＲＡ）ドメインによるＧＴＰ結合蛋白質認識機構の解明

  島 扶美

  科学研究費補助金／若手研究(B), Apr. 2004 - Mar. 2006, Principal investigator

  Competitive research funding


• Ｒａｓ／Ｒａｐ標的蛋白質ホスホリパーゼＣεの生体内機能の解明

  片岡 徹

  科学研究費補助金／基盤研究(B), 2005

  Competitive research funding


• 低分子量Ｇ蛋白質による細胞増殖の制御機構

  片岡 徹

  科学研究費補助金／特定領域研究, 2005

  Competitive research funding


• Ｒａｓ／Ｒａｐ結合（ＲＡ）ドメインによるＧＴＰ結合蛋白質認識機構の解明

  島 扶美

  科学研究費補助金／若手研究(B), Apr. 2002 - Mar. 2004, Principal investigator

  Competitive research funding


• Analysis of the Regulatory Mechanism and Function of a Novel Class of Phospholipase C, PLCε

  KATAOKA Tohru, SATOH Takaya, SHIMA Fumi, EDAMATSU Hironori

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), Kobe University, 2003 - 2004

  1, We constructed phospholipase C_ε(PLC_ε) knockout mice and showed that the hearts of these mice develop ventricular dilation, which is caused by a volume overload resulting from marked regurgitation and mild stenosis of the semilunar (aortic and pulmonic) valves. We analysed the mechanism of the congenital semilunar valvulogenesis defect causing these phenotypes and concluded that the abnormal thickening and morphology of the semilunar valve leaflets in PLC_ε knockout mice were caused by aberrant cellular proliferation in valve remodeling at the late stages of semilunar valvulogenesis. By analogy with the phenotypes of mice carrying an attenuated epidermal growth factor (EGF) receptor or deficient in heparin-binding EGF, we speculated a crucial role of PLC_ε, as a Ras effector downstream of the EGF receptor, in inhibition of valvular cell proliferation. In fact, we observed increased phosphorylation of Smad1/5/8, which induce valvular cell proliferation downstream of the BMP receptor, in PLC_ε knockout mice. 2, By applying the two stage skin chemical carcinogenesis protocol using DMBA as an initiator and a phorbor ester TPA as a promoter to PLC_ε knockout mice, we showed that PLC_ε plays a crucial role in ras oncogene-induced development of benign tumors as well as in their malignant progression. We further analysed the mechanism of action of PLC_ε. PLC_ε knockout mice showed marked reduction in proliferation of basal layer cells and epidermal hyperplasia induced by TPA, suggesting a crucial role of PLC_ε in downstream signaling from TPA. 3, We disrupted the PLC_ε gene in a model organism Caenorhabditis elegans and observed a sterile phenotype, caused by abnormal contraction of sphincter muscles of the spermatheca. 4, By using BaF3 cells expressing a PDGF receptor mutant lacking the PLC_γ-binding sites, we showed the importance of PH and RA domains by establishing an assay system for Ca^<2+> increase induced by PDGF-dependent PLC_ε activation.


• Analysis of the Function of a Novel Class of Mammalian Phospholipase C, PLCε

  KATAOKA Tohru, EDAMATSU Hironori, SHIMA Fumi, SATOH Takaya

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), Kobe University, 2001 - 2002

  We have clarified the regulation mechanism of a novel class of phospholipase C, PLCε, and established PLDε as an effector of small GTPases Ras and Pap1. Also, a physiological function of PlCε has been elucidated. 1. The CDC25 homology domain of PLCε acts as a guanine nucleotide exchange factor for Rap1, thereby amplifying Rap1-dependent signaling. Stimulation of cells by platelet-derived growth factor (PDGF), induces two phase activation of PLCε through activation of Ras and Rap1. The rapid and initial phase of this activation is mediated by Ras at the plasma membrane, whereas Rap1 is responsible for the prolonged activation at the Golgi apparatus. The CDC25 homology domain is crucial for the prolonged activation of PCLε by Rap1. The Ras/Rap1-dependent activation of PLCε prevents BaF3 cells from undergoing apoptosis and sustains their proliferation. 2. Analysis of the spatial and temporal expression patterns of PLCε indicates that in mouse embryos a specific induction of PLCε expression is observed during the course of differentiation of the neural stem cells into the neuronal lineage. In adult, PLCε is expressed abundantly in the heart. The PLCε gene-knockout mice, created by gene targeting, are found to exhibit a phenotype characterized by a market cardiomegaly as well as by overexpression of the heart failure markers as early as 4 weeks of age. Thus, PLCε may play a crucial function in intracellular signaling of the cardiomyocytes by linking the Ras pathway with the Ca^<2+>-calcineurin-NFAT pathway. 3. We have isolated a Caenorhabditis elegans mutant worm lacking the PLCε gene. It exhibits a sterile phenotype due to a disorder in transporting the eggs to the uterus, which is presumably caused by defective relaxation of the sphincters of the spermatheca. It is interesting that both the mammals and the nematodes exhibit a similar phenotype carrying a defect in rhythmic muscular contraction.

• RasRaf binding inhibitors

  Fumi Shima, Yoko, Yoshikawa, Yoshiteru Makino, Hirokazu kubota, Hitomi Yuki, Takashi Kumasaka, Takashi Kawamura

  特願2021-125013, 30 Jul. 2021, Kobe University

  Patent right


• Ras機能阻害作用を有するチオキソチアゾリジン誘導体

  KATAOKA TOHRU, SHIMA FUMI

  特願2013-514037, 09 May 2012, 大学長, 特許6014816, 07 Oct. 2016

  Patent right


• Ras機能阻害作用を有するチオキソチアゾリジン誘導体（アメリカ）

  KATAOKA TOHRU, SHIMA FUMI

  14/116152, 09 May 2012, 大学長, US9056862, 16 Jun. 2015

  Patent right


• THIOXOTHIAZOLIDINE DERIVATIVE HAVING RAS FUNCTION INHIBITORY EFFECT

  SHIMA Fumi

  特願WO 2012/153775 A1, 10 May 2011, 特許WO 2012/153775 A1

  Patent right


• AQUEOUS SOLUTION CONTAING PARTIAL RaS POLYPEPTIDE AND METHOD FOR SCREENING INHIBITOR OF RAS FUNCTION

  SHIMA Fumi

  特願WO/2012/108297 A1, 07 Feb. 2011, 特許WO/2012/108297 A1

  Patent right


• Aqueous Solution Containing Partial Ras Polypeptid and Method for Screening Inhibitor of Ras Function

  SHIMA Fumi

  特願WO2012108297A1, 07 Feb. 2011, 特許WO2012108297A1

  Patent right