研究者紹介システム

島 扶美
シマ フミ
大学院科学技術イノベーション研究科 科学技術イノベーション専攻
教授
医学
Last Updated :2021/07/25

研究者情報

所属

  • 【主配置】

    大学院科学技術イノベーション研究科 科学技術イノベーション専攻
  • 【配置】

    医学部 医学科, 大学院医学研究科 医科学専攻

学位

  • 博士(医学), 神戸大学

授業科目

ジャンル

  • 医療・健康 / 創薬

コメントテーマ

  • 分子標的がん治療薬
  • 創薬化学

研究活動

研究分野

  • ライフサイエンス / 分子生物学

受賞

  • 2011年06月 一般社団法人神緑会, 田中千賀子学術奨励賞, 女性研究者

    島 扶美

論文

  • 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

    2021年, Biochemical and Biophysical Research Communications, in press, 英語

    [査読有り]

    研究論文(学術雑誌)

  • 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 Y, Tsuda C, Araki M, Neya M, Shima F, Kataoka T

    2018年09月, Biochemistry, 57 (36), 5350 - 5358, 英語

    [査読有り]

    研究論文(学術雑誌)

  • YoshikawaY, TakanoO, KatoI, TakahashiY, ShimaF, KataokaT

    Metastasis stands as the major obstacle for the survival from cancers. Nonetheless most existing anti-cancer drugs inhibit only cell proliferation, and discovery of agents having both anti-proliferative and anti-metastatic properties would be more beneficial. We previously reported the discovery of small-molecule Ras inhibitors, represented by Kobe0065, that displayed anti-proliferative activity on xenografts of human colorectal cancer (CRC) cell line SW480 carrying the K-ras(G12V) gene. Here we show that treatment of cancer cells carrying the activated ras genes with Kobe0065 or a siRNA targeting Ras downregulates the expression of lysyl oxidase (LOX), which has been implicated in metastasis. LOX expression is enhanced by co-expression of Ras(G12V) through activation of phosphatidylinositol 3-kinase (PI3K)/Akt and concomitant accumulation of hypoxia-inducible factor (HIF)-1 alpha. Furthermore, Kobe0065 effectively inhibits not only migration and invasion of cancer cells carrying the activated ras genes but also lung metastasis of human CRC cell line SW620 carrying the K-ras(G12V) gene. Collectively, these results indicate that Kobe0065 prevents metastasis through inhibition of the Ras-P13K-Akt-HIF-1 alpha-LOX signaling and suggest that Ras inhibitors in general might exhibit both anti-proliferative and anti-metastatic properties toward cancer cells carrying the activated ras genes. (C) 2017 Elsevier B.V. All rights reserved.

    ELSEVIER IRELAND LTD, 2017年12月, Cancer Lett, 410, 82 - 91, 英語

    [査読有り]

    研究論文(学術雑誌)

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

    The state transitions of solvated H-Ras protein with GTP were theoretically analyzed through molecular dynamics (MD) simulations. To accelerate the structural changes associated with the locations of two switch regions (I and II), the Parallel Cascade Selection MD (PaCS-MD) method was employed in this study. The interconversions between the State 1 and State 2 were thus studied in atomic details, leading to a reasonable agreement with experimental observations and consequent scenarios concerning the transition mechanism that would be essential for the development of Ras inhibitors as anti-cancer agents. Furthermore, the state-transition-based local network entropy (SNE) was calculated for the transition process from State 1 to State 2, by which the temporal evolution of information entropy associated with the dynamical behavior of hydrogen bond network composed of hydration water molecules was described. The calculated results of SNE thus proved to provide a good indicator to detect the dynamical state transition of solvated Ras protein system (and probably more general systems) from a viewpoint of nonequilibrium statistical thermodynamics. (C) 2017 Elsevier Inc. All rights reserved.

    ELSEVIER SCIENCE INC, 2017年10月, JOURNAL OF MOLECULAR GRAPHICS & MODELLING, 77, 51 - 63, 英語

    [査読有り]

    研究論文(学術雑誌)

  • OkadaT, LeeAY, QinLX, AgaramN, MimaeT, ShenY, O''ConnorR, López-LagoMA, CraigA, MillerML, AgiusP, MolinelliE, SocciND, CragoAM, ShimaF, SanderC, SingerS

    Myxofibrosarcoma is a common mesenchymal malignancy with complex genomics and heterogeneous clinical outcomes. Through gene-expression profiling of 64 primary high-grade myxofibrosarcomas, we defined an expression signature associated with clinical outcome. The gene most significantly associated with disease-specific death and distant metastasis was ITGA10 (integrin-alpha 10). Functional studies revealed that myxofibrosarcoma cells strongly depended on integrin-alpha 10, whereas normal mesenchymal cells did not. Integrin-alpha 10 transmitted its tumor-specific signal via TRIO and RICTOR, two oncoproteins that are frequently co-overexpressed through gene amplification on chromosome 5p. TRIO and RICTOR activated RAC/PAK and AKT/mTOR to promote sarcoma cell survival. Inhibition of these proteins with EHop-016 (RAC inhibitor) and INK128 (mTOR inhibitor) had antitumor effects in tumor-derived cell lines and mouse xenografts, and combining the drugs enhanced the effects. Our results demonstrate the importance of integrin-alpha 10/TRIO/RICTOR signaling for driving myxofibrosarcoma progression and provide the basis for promising targeted treatment strategies for patients with high-risk disease. SIGNIFICANCE: Identifying the molecular pathogenesis for myxofibrosarcoma progression has proven challenging given the highly complex genomic alterations in this tumor type. We found that integrin-alpha 10 promotes tumor cell survival through activation of TRIO-RAC-RICTOR-mTOR signaling, and that inhibitors of RAC and mTOR have antitumor effects in vivo, thus identifying a potential treatment strategy for patients with high-risk myxofibrosarcoma. (C) 2016 AACR.

    AMER ASSOC CANCER RESEARCH, 2016年10月, Cancer Discov, 6 (10), 1148 - 1165, 英語

    [査読有り]

    研究論文(学術雑誌)

  • MatsumotoS, MiyanoN, BabaS, LiaoJ, KawamuraT, TsudaC, TakedaA, YamamotoM, KumasakaT, KataokaT, ShimaF

    Ras.GTP adopts two interconverting conformational states, state 1 and state 2, corresponding to inactive and active forms, respectively. However, analysis of the mechanism for state transition was hampered by the lack of the structural information on wild-type Ras state 1 despite its fundamental nature conserved in the Ras superfamily. Here we solve two new crystal structures of wild-type H-Ras, corresponding to state 1 and state 2. The state 2 structure seems to represent an intermediate of state transition and, intriguingly, the state 1 crystal is successfully derived from this state 2 crystal by regulating the surrounding humidity. Structural comparison enables us to infer the molecular mechanism for state transition, during which a wide range of hydrogen-bonding networks across Switch I, Switch II and the alpha 3-helix interdependently undergo gross rearrangements, where fluctuation of Tyr32, translocation of Gln61, loss of the functional water molecules and positional shift of GTP play major roles. The NMR-based hydrogen/deuterium exchange experiments also support this transition mechanism. Moreover, the unveiled structural features together with the results of the biochemical study provide a new insight into the physiological role of state 1 as a stable pool of Ras.GTP in the GDP/GTP cycle of Ras.

    NATURE PUBLISHING GROUP, 2016年05月, Sci Rep, 6, 25931, 英語

    [査読有り]

    研究論文(学術雑誌)

  • 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

    Mutational activation of the Ras oncogene products (H-Ras, K-Ras, and N-Ras) is frequently observed in human cancers, making them promising anticancer drug targets. Nonetheless, no effective strategy has been available for the development of Ras inhibitors, partly owing to the absence of well-defined surface pockets suitable for drug binding. Only recently, such pockets have been found in the crystal structures of a unique conformation of Ras center dot GTP. Here we report the successful development of small-molecule Ras inhibitors by an in silico screen targeting a pocket found in the crystal structure of M-Ras center dot GTP carrying an H-Ras-type substitution P40D. The selected compound Kobe0065 and its analog Kobe2602 exhibit inhibitory activity toward H-Ras center dot GTP-c-Raf-1 binding both in vivo and in vitro. They effectively inhibit both anchorage-dependent and -independent growth and induce apoptosis of H-ras(G12V)-transformed NIH 3T3 cells, which is accompanied by down-regulation of downstream molecules such as MEK/ERK, Akt, and RalA as well as an upstream molecule, Son of sevenless. Moreover, they exhibit antitumor activity on a xenograft of human colon carcinoma SW480 cells carrying the K-ras(G12V) gene by oral administration. The NMR structure of a complex of the compound with H-Ras center dot GTP(T35S), exclusively adopting the unique conformation, confirms its insertion into one of the surface pockets and provides a molecular basis for binding inhibition toward multiple Ras center dot GTP-interacting molecules. This study proves the effectiveness of our strategy for structure-based drug design to target Ras center dot GTP, and the resulting Kobe0065-family compounds may serve as a scaffold for the development of Ras inhibitors with higher potency and specificity.

    NATL ACAD SCIENCES, 2013年05月, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 110 (20), 8182 - 8187, 英語

    [査読有り]

    研究論文(学術雑誌)

  • Fumi Shima, Yoko Yoshikawa, Shigeyuki Matsumoto, Tohru Kataoka

    Ras proteins, particularly their active GTP-bound forms (Ras·GTP), were thought "undruggable" owing to the absence of apparent drug-accepting pockets in their crystal structures. Only recently, such pockets have been found in the crystal structures representing a novel Ras·GTP conformation. We have conducted an in silico docking screen targeting a pocket in the crystal structure of M-RasP40D·GTP and obtained Kobe0065, which, along with its analogue Kobe2602, inhibits binding of H-Ras·GTP to c-Raf-1. They inhibit the growth of H-rasG12V-transformed NIH3T3 cells, which are accompanied by downregulation of not only MEK/ERK but also Akt, RalA, and Sos, indicating the blockade of interaction with multiple effectors. Moreover, they exhibit antitumor activity on a xenograft of human colon carcinoma carrying K-rasG12V. The nuclear magnetic resonance structure of a complex of the compound with H-RasT35S·GTP confirms its insertion into the surface pocket. Thus, these compounds may serve as a novel scaffold for the development of Ras inhibitors with higher potency and specificity. © 2013 Elsevier Inc.

    2013年, Enzymes, 34, 1 - 23, 英語

    [査読有り]

    研究論文(学術雑誌)

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

    Shima F, Kataoka T

    2013年, SPring-8 Research Frontiers, 英語

    [査読有り][招待有り]

    研究論文(大学,研究機関等紀要)

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

    GTP-bound Ras adopts two interconverting conformations, "inactive" state 1 and "active" state 2. However, the tertiary structure of wild-type (WT) state 1 remains unsolved. Here we solve the state 1 crystal structures of H-Ras WT together with its oncogenic G12V and Q61L mutants. They assume open structures characterized by impaired interactions of both Thr-35 in switch I and Gly-60 in switch II with the gamma-phosphate of GTP and possess two surface pockets of mutually different shapes unseen in state 2, a potential target for selective inhibitor development. Furthermore, they provide a structural basis for the low GTPase activity of state 1. (c) 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

    ELSEVIER SCIENCE BV, 2012年06月, FEBS LETTERS, 586 (12), 1715 - 1718, 英語

    [査読有り]

    研究論文(学術雑誌)

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

    GTP-bound Ras adopts two interconverting conformations, "inactive" state 1 and "active" state 2. However, the tertiary structure of wild-type (WT) state 1 remains unsolved. Here we solve the state 1 crystal structures of H-Ras WT together with its oncogenic G12V and Q61L mutants. They assume open structures characterized by impaired interactions of both Thr-35 in switch I and Gly-60 in switch II with the gamma-phosphate of GTP and possess two surface pockets of mutually different shapes unseen in state 2, a potential target for selective inhibitor development. Furthermore, they provide a structural basis for the low GTPase activity of state 1. (c) 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

    ELSEVIER SCIENCE BV, 2012年06月, FEBS LETTERS, 586 (12), 1715 - 1718, 英語

    [査読有り]

    研究論文(学術雑誌)

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

    Ras small GTPases undergo dynamic equilibrium of two interconverting conformations, state 1 and state 2, in the GTP-bound forms, where state 2 is recognized by effectors, whereas physiological functions of state 1 have been unknown. Limited information, such as static crystal structures and (31)P NMR spectra, was available for the study of the conformational dynamics. Here we determine the solution structure and dynamics of state 1 by multidimensional heteronuclear NMR analysis of an H-RasT35S mutant in complex with guanosine 5'-(beta, gamma-imido)triphosphate (GppNHp). The state 1 structure shows that the switch I loop fluctuates extensively compared with that in state 2 or H-Ras-GDP. Also, backbone (1)H, (15)N signals for state 2 are identified, and their dynamics are studied by utilizing a complex with c-Raf-1. Furthermore, the signals for almost all the residues of H-Ras.GppNHp are identified by measurement at low temperature, and the signals for multiple residues are found split into two peaks corresponding to the signals for state 1 and state 2. Intriguingly, these residues are located not only in the switch regions and their neighbors but also in the rigidly structured regions, suggesting that global structural rearrangements occur during the state interconversion. The backbone dynamics of each state show that the switch loops in state 1 are dynamically mobile on the picosecond to nanosecond time scale, and these mobilities are significantly reduced in state 2. These results suggest that multiconformations existing in state 1 are mostly deselected upon the transition toward state 2 induced by the effector binding.

    AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2011年11月, JOURNAL OF BIOLOGICAL CHEMISTRY, 286 (45), 39644 - 39653, 英語

    [査読有り]

    研究論文(学術雑誌)

  • 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

    GTP-bound forms of Ras family small GTPases exhibit dynamic equilibrium between two interconverting conformations, "inactive" state 1 and "active" state 2. A great variation exists in their state distribution; H-Ras mainly adopts state 2, whereas M-Ras predominantly adopts state 1. Our previous studies based on comparison of crystal structures representing state 1 and state 2 revealed the importance of the hydrogen-bonding interactions of two flexible effector-interacting regions, switch I and switch II, with the gamma-phosphate of GTP in establishing state 2 conformation. However, failure to obtain both state structures from a single protein hampered further analysis of state transition mechanisms. Here, we succeed in solving two crystal structures corresponding to state 1 and state 2 from a single Ras polypeptide, M-RasD41E, carrying an H-Ras-type substitution in residue 41, immediately preceding switch I, in complex with guanosine 5'-(beta,gamma-imido)triphosphate. Comparison among the two structures and other state 1 and state 2 structures of H-Ras/M-Ras reveal two new structural features playing critical roles in state dynamics; interaction of residues 31/41 (H-Ras/M-Ras) with residues 29/39 and 30/40, which induces a conformational change of switch I favoring its interaction with the gamma-phosphate, and the hydrogen-bonding interaction of switch II with its neighboring alpha-helix, alpha 3-helix, which induces a conformational change of switch II favoring its interaction with the gamma-phosphate. The importance of the latter interaction is proved by mutational analyses of the residues involved in hydrogen bonding. These results define the two novel functional regions playing critical roles during state transition.

    AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2011年04月, JOURNAL OF BIOLOGICAL CHEMISTRY, 286 (17), 15403 - 15412, 英語

    [査読有り]

    研究論文(学術雑誌)

  • Mitsugu Araki, Fumi Shima, Yoko Yoshikawa, Shin Muraoka, Yuichi Ijiri, Yuka Nagahara, Tomoya Shirono, Tohru Kataoka, 田村 厚夫

    2011年01月, J. Biol. Chem, 286 (45), 39644 - 39653, 英語

    [査読有り]

    研究論文(学術雑誌)

  • 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

    Ras family small GTPases assume two interconverting conformations, "inactive" state 1 and "active" state 2, in their GTP-bound forms. Here, to clarify the mechanism of state transition, we have carried out x-ray crystal structure analyses of a series of mutant H-Ras and M-Ras in complex with guanosine 5'-(beta,gamma-imido) triphosphate (GppNHp), representing various intermediate states of the transition. Crystallization of H-RasT35S-GppNHp enables us to solve the first complete tertiary structure of H-Ras state 1 possessing two surface pockets unseen in the state 2 or H-Ras-GDP structure. Moreover, determination of the two distinct crystal structures of H-RasT35S-GppNHp, showing prominent polysterism in the switch I and switch II regions, reveals a pivotal role of the guanine nucleotide-mediated interaction between the two switch regions and its rearrangement by a nucleotide positional change in the state 2 to state 1 transition. Furthermore, the (31)P NMR spectra and crystal structures of the GppNHp-bound forms of M-Ras mutants, carrying various H-Ras-type amino acid substitutions, also reveal the existence of a surface pocket in state 1 and support a similar mechanism based on the nucleotide-mediated interaction and its rearrangement in the state 1 to state 2 transition. Intriguingly, the conformational changes accompanying the state transition mimic those that occurred upon GDP/GTP exchange, indicating a common mechanistic basis inherent in the high flexibility of the switch regions. Collectively, these results clarify the structural features distinguishing the two states and provide new insights into the molecular basis for the state transition of Ras protein.

    AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2010年07月, JOURNAL OF BIOLOGICAL CHEMISTRY, 285 (29), 22696 - 22705, 英語

    [査読有り]

    研究論文(学術雑誌)

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

    Bardet-Biedl syndrome (BBS) is a pleiotropically genetic disorder, whose etiology is linked to cilia. Mutations in the Arf/Arl-family GTPase Arl6 have been recently shown to be responsible for BBS type 3. Here we show that BBS mutations alter the guanine nucleotide-binding properties of Arl6. Specifically, substitution of 31st Threonine to Arginine selectively abrogates the GTP-binding ability of Arl6 without affecting GDP binding/dissociating properties. Furthermore, all the BBS Mutations in Arl6 result in low expression of the mutant proteins, Which can be restored by the inhibition of the proteasome. These findings implicate that Arl6 Mutants are destabilized and eliminated by the proteasome in cells, probably due to the altered nucleotide-binding properties. (C) 2009 Elsevier Inc. All rights reserved.

    ACADEMIC PRESS INC ELSEVIER SCIENCE, 2009年04月, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 381 (3), 439 - 442, 英語

    [査読有り]

    研究論文(学術雑誌)

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

    Previous P-31 NMR studies revealed that small GTPases H-Ras and K-Ras in complex with GTP assume two interconverting conformational states, state I and state 2. While state 2 corresponds to an active conformation, little is known about the function of state 1, an inactive conformation incapable of effector binding. To address the biochemical properties of state 1, we measured the P-31 NMR spectra of five Ras family small GTPases; H-Ras, M-Ras, Rap1A, Rap2A and Ra1A, and find that they exhibit distinctive state 2/state 1 populations with the ratios ranging from 0.072 for M-Ras to 16 for Rap2A. Further, we show that GTPases with higher populations of state I exhibit higher dissociation and association rate constants for GTP. These results imply that GTP loading to the nucleotide-free small GTPases preferentially yields state 1, which is subsequently converted to state 2, rendering the GTP-bound form functional. (c) 2008 Elsevier Inc. All rights reserved.

    ACADEMIC PRESS INC ELSEVIER SCIENCE, 2008年05月, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 369 (2), 327 - 332, 英語

    [査読有り]

    研究論文(学術雑誌)

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

    Although some members of Ras family small GTPases, including M-Ras, share the primary structure of their effector regions with Ras, they exhibit vastly different binding properties to Ras effectors such as c-Raf-1. We have solved the crystal structure of M-Ras in the GDP-bound and guanosine 5'-(beta, gamma-imido) triphosphate (Gpp(NH) p)-bound forms. The overall structure of M-Ras resembles those of H-Ras and Rap2A, except that M-Ras-Gpp( NH) p exhibits a distinctive switch I conformation, which is caused by impaired intramolecular interactions between Thr-45 (corresponding to Thr-35 of H-Ras) of the effector region and the gamma-phosphate of Gpp(NH) p. Previous P-31 NMR studies showed that H-Ras-Gpp( NH) p exists in two interconverting conformations, states 1 and 2. Whereas state 2 is a predominant form of H-Ras and corresponds to the "on" conformation found in the complex with effectors, state 1 is thought to represent the "off" conformation, whose tertiary structure remains unknown. P-31 NMR analysis shows that free M-Ras-Gpp(NH)p predominantly assumes the state 1 conformation, which undergoes conformational transition to state 2 upon association with c-Raf-1. These results indicate that the solved structure of M-Ras-Gpp(NH) p corresponds to the state 1 conformation. The predominance of state 1 in M-Ras is likely to account for its weak binding ability to the Ras effectors, suggesting the importance of the tertiary structure factor in small GTPase-effector interaction. Further, the first determination of the state 1 structure provides a molecular basis for developing novel anti-cancer drugs as compounds that hold Ras in the state 1 "off" conformation.

    AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2005年09月, JOURNAL OF BIOLOGICAL CHEMISTRY, 280 (35), 31267 - 31275, 英語

    [査読有り]

    研究論文(学術雑誌)

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

    F Shima, T Kataoka

    JAPANESE BIOCHEMICAL SOC, 2005年06月, SEIKAGAKU, 77 (6), 519 - 526, 日本語

    [査読有り]

    研究論文(学術雑誌)

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

    Genetic studies on Schizosaccharomyces pombe adenylyl cyclase (cyr1) have shown that its activity is positively regulated by a heterotrimetric G protein α subunit gpa2 and that the resulting increase in intracellular cAMP concentration causes inhibition of sexual development including mating and meiosis. However, molecular mechanism underlying this gpa2-dependent regulation of cyr1 remains to be clarified. Here, we show that gpa2 exhibits a direct and GTP-dependent binding to the Ras-associating domain (RAD) of cyr1, which is identified by a computer algorithm-based search of the cyr1 amino acid sequence. Overexpression of this RAD results in acceleration of the sexual development of fission yeast cells presumably by competitive sequestration of gpa2. Furthermore, cyr1 is activated in vitro by the addition of purified gpa2, which is converted to the active state by treatment with AlF4-. These results indicate a crucial role of the RAD as a direct binding site of gpa2 in activation of cyr1. Thus, RADs, which have been defined as a conserved motif shared among the Ras-family small G protein-associating domains, are for the first time shown to exhibit a functional association with a member of the heterotrimeric G proteins.

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

    [査読有り]

    研究論文(学術雑誌)

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

    Mammalian candidate effectors of the small GTPase Ras, such as RalGDS, afadin/AF-6, Rin1, and phospholipase Cc, have been shown to share structurally conserved modules termed Ras-associating (RA) domains at their Ras-binding sites. The Ras-binding domains of Raf-1 and phosphoinositide 3-kinase gamma (other Ras effectors) also share a similar tertiary structure with the RA domains. On the other hand, the primary Ras-binding site of Saccharomyces cerevisiae adenylyl cyclase, the best characterized Ras effector, has been mapped by mutational studies to the leucine-rich repeats (LRR) domain (amino acids 674-1300), whose structure apparently bears no resemblance to the RA domains. By a computer algorithm-based search we have unexpectedly found an RA domain in the N-terminal 81 amino acid residues (676-756) of the LRR domain. The purified RA-domain polypeptide exhibits an ability to bind directly to Ras in a GTP-dependent manner and to competitively inhibit Ras-dependent activation of adenylyl cyclase in vitro, with an affinity comparable with that of the whole LRR domain. The specificity of binding of the RA domain to various Ras effector region mutants is indistinguishable from that of the full-length adenylyl cyclase. The activated RAS2 (RAS2(Val-19))-dependent heat shock sensitivity of yeast cells is suppressed by overexpression of the RA domain polypeptide. Further, mutations of the RA domain abolish its Ras binding activity, and adenylyl cyclase molecules carrying these mutations are rendered unactivatable by Ras in vitro. This RA domain bears highest similarity to the Ras-binding domain of Raf-1 based on comparison of its primary and predicted secondary structures with those of other Ras effectors. These results indicate that the RA domain is a primary Ras-binding site for activation of adenylyl cyclase, implicating RA domains as universal modules for interaction of effectors with Ras, conserved from yeast to mammals.

    AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2002年02月, JOURNAL OF BIOLOGICAL CHEMISTRY, 277 (5), 3117 - 3123, 英語

    [査読有り]

    研究論文(学術雑誌)

  • 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

    Full activation of Raf-l requires the interaction of its CRD with Has. The serine/threonine-rich region, CR2, of Raf-l was implicated in Raf-l regulation, but the underlying mechanism was unclear. Here we show that CRD loses its Ras-binding activity when expressed in connection with CR2, suggesting that CR2 masks CRD. This masking effect is abolished by substitution of Asp or Ala for Ser-259, a growth factor- and TPA-induced phosphorylation site in CR2. Treatment of COS-7 cells expressing Ha-Ras(Val-12) and Raf-l with TPA enhances the Ha-Ras(Val-12)-dependent Raf-l kinase activity. In contrast, the Ha-Ras(Val-12)-dependent activities of the Raf-1(S259D) and Raf-1(S259A) mutants are comparable to that of wild-type Raf-l stimulated by both Ha-Ras(Val-12) and TPA and cannot be further stimulated by TPA treatment. These results suggest that the in vivo phosphorylation of Ser-259 may comprise a crucial step for Ras-dependent Raf-l activation by unmasking CRD and promoting its association with Ras. (C) 2000 Academic Press.

    ACADEMIC PRESS INC, 2000年05月, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 271 (3), 596 - 602, 英語

    [査読有り]

    研究論文(学術雑誌)

  • 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

    Ras proteins are conserved from yeasts to mammals and implicated in regulation of the actin cytoskeleton. The flightless-1 (fli-1) gene of Drosophila melanogaster and its homologs in Caenorhabditis elegans and humans encode proteins (FLI-1) comprising a fusion of a leucine-rich repeats (LRRs) domain and a gelsolin-like domain. This LRRs domain is highly homologous to those of three proteins involved in Ras-mediated signaling; Saccharomyces cerevisiae adenylyl cyclase, C. elegans SUR-8, and mammalian RSP-1. Here we report that the LRRs domain of C. elegans FLI-1 (Ce-FLI-1) associates directly with Has (K-d = 11 nM) and, when overexpressed, suppresses the heat shock sensitive phenotype of yeast cells bearing the activated RAS2 gene (RAS2(Val-19)). Further, the gelsolin-like domain of Ce-FLI-1 is shown to possess a Ca2+-independent G-actin-binding activity as well as F-actin-binding and -severing activities. FLI-1 may be involved in regulation of the actin cytoskeleton through Has. (C) 1999 Academic Press.

    ACADEMIC PRESS INC, 1999年04月, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 257 (1), 111 - 116, 英語

    [査読有り]

    研究論文(学術雑誌)

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

    In the budding yeast Saccharomyces cerevisiae, association with the 70- kDa cyclase-associated protein (CAP) is required for proper response of adenylyl cyclase to Ras proteins. We show here that a small segment comprising the N-terminal 36 amino acid residues of CAP is sufficient for association with adenylyl cyclase as well as for its function in the Ras- adenylyl cyclase pathway as assayed by the ability to confer RAS2(Val-19)- dependent heat shock sensitivity to yeast cells. The CAP-binding site of adenylyl cyclase was mapped to a segment of 119 amino acid residues near its C terminus. Both of these regions contained tandem repetitions of a heptad motif αXXαXXX (where α represents a hydrophobic amino acid and X represents any amino acid), suggesting a coiled-coil interaction. When mutants of CAP defective in associating with adenylyl cyclase were isolated by screening of a pool of randomly mutagenized CAP, they were found to carry substitution mutations in one of the key hydrophobic residues in the heptad repeats. Furthermore, mutations of the key hydrophobic residues in the heptad repeats of adenylyl cyclase also resulted in loss of association with CAP. These results indicate the coiled-coil mechanism as a basis of the CAP- adenylyl cyclase interaction.

    1998年10月23日, Journal of Biological Chemistry, 273 (43), 28019 - 28024, 英語

    [査読有り]

    研究論文(学術雑誌)

  • 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

    Mammalian Ras proteins regulate multiple effecters including Raf, Ral guanine nucleotide dissociation stimulator (RalGDS), and phosphoinositide 3-kinase. In the nematode Caenorhabditis elegans, LIN-45 Raf has been identified by genetic analyses as an effector of LET-60 Ras. To search for other effecters in C. elegans, we performed a yeast two-hybrid screening for LET-60-binding proteins. The screening identified two cDNA clones encoding a phosphoinositide-specific phospholipase C (PI-PLC) with a predicted molecular mass of 210 kDa, designated PLC210, PLC210 possesses two additional functional domains unseen in any known PI-PLCs. One is the C-terminal Ras-associating domain bearing a structural homology with those of RalGDS and AF-6. This domain, which could be narrowed down to 100 amino acid residues, associated in vitro with human Ha-Ras in a GTP-dependent manner and competed with yeast adenylyl cyclase for binding Ha-Ras. The binding was abolished by specific mutations within the effector region of Ha-Ras. The other functional domain is the N-terminal CDC25-like domain, which possesses a structural homology to guanine nucleotide exchange proteins for Ras. These results strongly suggest that PLC210 belongs to a novel class of PI-PLC, which is a putative effector of Ras.

    AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 1998年03月, JOURNAL OF BIOLOGICAL CHEMISTRY, 273 (11), 6218 - 6222, 英語

    [査読有り]

    研究論文(学術雑誌)

MISC

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

    Despite the importance of ras as driver genes in many cancers, clinically effective anti-cancer drugs targeting their products, Ras, have been unavailable so far, which was in part ascribable to the apparently 'undruggable' nature of their tertiary structures. Nonetheless, recent studies in academia and industry have identified novel surface pockets accepting small-molecule ligands in both their active GTP-bound and inactive GDP-bound forms (Ras center dot GTP and Ras center dot GDP, respectively), which has led to a surge of investigations into the discovery of Ras-specific inhibitors particularly by utilizing their structural information for structure-based drug design (SBDD). We have been developing Ras inhibitors by SBDD targeting a novel conformation of Ras center dot GTP called state 1, possessing 'druggable' surface pockets, which emerges from the conformational dynamics. In this article, we will survey Ras functions from the structural biological point of view and summarize the current status of the development of Ras inhibitors including our own.

    OXFORD UNIV PRESS, 2015年08月, JOURNAL OF BIOCHEMISTRY, 158 (2), 91 - 99, 英語

    [査読有り]

    書評論文,書評,文献紹介等

  • 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

    島扶美, 熊坂崇, 松本篤幸, 吉川陽子, 山本雅貴, 片岡徹

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

    [査読有り]

    記事・総説・解説・論説等(学術雑誌)

  • 【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

    島扶美, 片岡徹

    2005年06月, 生化学, 77巻, 6号, pp.519-526, 日本語

    記事・総説・解説・論説等(学術雑誌)

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

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

書籍等出版物

  • 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

    島 扶美, 松本篤幸, 吉川陽子, 片岡徹

    共著, がん分子標的治療, 2015年, 日本語

    一般書・啓蒙書

  • 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

    島 扶美

    共著, 日本生化学会, 2005年06月, 日本語

    学術書

講演・口頭発表等

  • 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

    第43回日本分子生物学会年会, 2020年12月03日, 英語

    ポスター発表

  • 微小結晶を利用したRas caged-GTP時分割測定の試み

    河村高志,槇野義輝*,長谷川和也,中根崇智,馬場清喜,南後恵理子,田中里枝,岩田想,島扶美*,熊坂崇

    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, 2020年01月

  • 新規がん治療薬創出に向けた構造生物学的アプローチ

    島扶美*、槇野義輝

    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, 2019年12月09日

    [招待有り]

  • Caged-GTPを用いたがん遺伝子産物RasのSACLA、Spring-8、NMRによるGTP加水分解過程の構造変化の解明

    槇野義輝, 河村高志, 松本篤幸, 南後恵理子, 岩田想, 熊坂崇, 島扶美

    第57回日本生物物理学会年会, 2019年09月, 日本語, 国内会議

    ポスター発表

  • 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, 2019年02月, 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

    [招待有り]

  • 光制御可能なcaged GTPを用いたがん遺伝子産物Ras蛋白質の構造変化の観測に基くGTP加水分解過程の速度論研究

    萩原睦, 槇野義輝, 松本篤幸, 河村高志, 森一郎, 南後恵理子, 熊坂崇, 島扶美

    第41回日本分子生物学会年会, 2018年11月, 日本分子生物学会年会, パシフィコ横浜

    ポスター発表

  • Caged-GTPを用いた時間依存的なNMR信号変化のモニタリングによるガン遺伝子産物RasのGTP加水分解過程における構造変化の解明

    萩原睦, 槇野義輝, 松本篤幸, 河村高志, 森一郎, 南後恵理子, 熊坂崇, 片岡徹, 島扶美

    第56回日本生物物理学会年会, 2018年09月15日, 日本生物物理学会, 岡山大学 津島キャンパス

  • B-Raf阻害剤耐性メラノーマに対するRas阻害剤の新規薬効と作用メカニズムの解析

    森元 智行, 吉川 陽子, 白川 慶徳, 森 一郎, 片岡 徹, 島 扶美

    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), 2017年12月, 日本語, 日本分子生物学会日本生化学会, 神戸, 国内会議

    ポスター発表

  • Ras阻害剤は、リシルオキシダーゼの発現抑制を通じてrasがん遺伝子を持つがん細胞に転移抑制活性を示す

    吉川陽子, 島扶美, 片岡徹

    第76回 日本癌学会学術総会, 2017年09月, 日本語, 日本癌学会, 横浜, 国際会議

    口頭発表(一般)

  • In silico discovery of small-molecule Ras inhibitors

    Fumi Shima

    University of Washington-Kobe University Joint Symposium on Cell Signaling, 2015年09月, 英語, University of Washington and Kobe University, Seattle, USA, 国際会議

    [招待有り]

    口頭発表(招待・特別)

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

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

    2015 Annual Meeting of the American Crystallographic Association, 2015年07月, 英語, American Crystallographic Association, Philadelphia, USA, 国際会議

    口頭発表(一般)

  • 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, 河村 高志, 松本 篤幸, 山本 雅貴, 片岡徹, 島扶美

    第15回日本蛋白質科学会年会, 2015年06月, 日本語, 日本蛋白質科学会, 徳島, 国内会議

    ポスター発表

  • 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

    松本 篤幸, 宮野 菜央, 馬場 清喜, Liao Jingling, 竹田 あずさ, 山本 雅貴, 熊坂 崇, 片岡 徹, 島 扶美

    第15回日本蛋白質科学会年会, 2015年06月, 日本語, 日本蛋白質科学会, 徳島, 国内会議

    ポスター発表

  • 創薬支援ネットワークの支援を受けて

    島 扶美

    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, 2015年01月, 日本語, 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, 国内会議

    [招待有り]

    口頭発表(招待・特別)

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

    Osamu Takano, Yoko Yoshikawa, Fumi Shima, Tohru Kataoka

    第72回日本癌学会学術総会, 2013年10月, 英語, 日本癌学会, 横浜, 国内会議

    ポスター発表

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

    松本 耕祐, 島 扶美, 村岡 真, 井尻 悠一, 市川 晋也, 荒木 望嗣, 熊坂 崇, 田村 厚夫, 片岡 徹

    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), 2010年12月, 日本語, 日本生化学会大会/日本分子生物学会, 神戸, 国内会議

    ポスター発表

  • 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, 島 扶美, 村岡 真, 井尻 悠一, 市川 晋也, 荒木 望嗣, 熊坂 崇, 田村 厚夫, 片岡 徹

    第33回日本分子生物学会年会, 2010年12月, 日本語, 日本分子生物学会, 神戸, 国内会議

    口頭発表(一般)

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

    片岡 徹, 島 扶美

    第69回日本癌学会学術総会, 2010年09月, 日本語, 日本癌学会, 大阪, 国内会議

    口頭発表(招待・特別)

  • GTP結合型Rasの構造遷移における分子メカニズムの解析

    島扶美, 村岡真, 廖静伶, 荒木望嗣, 片岡徹

    第32回日本分子生物学会年会, 2009年12月, 日本語, 日本分子生物学会, 横浜, 国内会議

    ポスター発表

  • 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

    村岡真, 島扶美, 廖静伶, 片岡徹

    第82回日本生化学会大会, 2009年10月, 日本語, 日本生化学会, 神戸, 国内会議

    ポスター発表

  • GTP結合型Rasの構造遷移メカニズムと創薬への応用

    島扶美

    「G蛋白質シグナル」研究班会議, 2009年09月, 日本語, 文部科学省特定領域研究, 千葉県・南房総市, 国内会議

    その他

  • Structural analysis of the novel state1 conformation of Ras protein

    Fumi Shima, Shin Muraoka, Tohru Kataoka

    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, 2009年07月, 日本語, 神戸大学/グローバルCOE, 淡路, 国内会議

    ポスター発表

  • GTP結合型Rasの立体構造多型性と創薬への応用

    島扶美

    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, 2009年01月, 日本語, 文部科学省特定領域研究, 神戸, 国内会議

    口頭発表(一般)

  • 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

    島扶美

    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, 2009年01月, 日本語, 文部科学省特定領域研究, 神戸, 国内会議

    口頭発表(一般)

  • 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

    島扶美

    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, 2009年01月, 日本語, 文部科学省特定領域研究, 神戸, 国内会議

    口頭発表(一般)

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

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

    Kobe University Global COE Program International Symposium on Integrative Membrane Biology, 2008年12月, 英語, グローバルCOE, 神戸, 国内会議

    ポスター発表

  • 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

    村岡真, 荒木望嗣, 吉川陽子, 廖静伶, 片岡徹, 島扶美

    特定研究領域「G蛋白質シグナル」研究班会議, 2008年09月, 日本語, 特定研究領域「G蛋白質シグナル」, 新潟, 国内会議

    ポスター発表

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

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

    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, 2008年07月, 日本語, グローバルCOE, 淡路, 国内会議

    ポスター発表

  • New strategy to develop Ras specific inhibitors

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

    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, 2008年07月, 日本語, グローバルCOE, 淡路, 国内会議

    ポスター発表

  • Conformational equilibrium of small GTPases and signal transduction

    島扶美, 廖静伶, 村岡真, 吉川陽子, 片岡徹

    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, 2007年12月, 日本語, 日本分子生物学会/日本生化学会, 横浜, 国内会議

    ポスター発表

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

    Fumi Shima

    2007InternationalSymposiumon“G-proteinSignaling”, 2007年07月, 英語, 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, 国際会議

    [招待有り]

    口頭発表(招待・特別)

  • Rasをターゲットにした抗癌剤のインシリコ創薬

    島扶美

    第66回神戸バイオサイエンス研究会, 2007年05月, 日本語, 神戸バイオサイエンス研究会, 神戸, 国内会議

    口頭発表(招待・特別)

  • GTP Dissociation Rate and Conformational Equilibrium in Various Small GTPases

    Fumi Shima, Shin Muraoka, Tohru kataoka

    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〜, 2006年12月, 英語, 日本分子生物学会, 名古屋, 国内会議

    ポスター発表

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

    Fumi Shima, Tohru kataoka

    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, 2006年08月, 日本語, 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, 国内会議

    ポスター発表

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

    Fumi Shima, Shin Muraoka, Tohru Kataoka

    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, 2006年06月, 英語, 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, 国際会議

    ポスター発表

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

    島 扶美, 叶 敏, 村岡 真, 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, 2006年01月, 英語, Keystone Symposia, キーストン, 国際会議

    ポスター発表

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

    叶 敏, 島 扶美, 村岡 真, 廖 静伶, 岡本 英嗣, 山本 雅貴, 田村 厚夫, 徳島 大介, 宮川 知也, 片岡 徹

    第28回日本分子生物学会年会, 2005年12月, 英語, 日本分子生物学会, 福岡, 国内会議

    ポスター発表

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

    廖 静伶, 島 扶美, 村岡 真, 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, 片岡 徹

    第64回日本癌学会学術総会, 2005年09月, 英語, 日本癌学会, 札幌, 国内会議

    その他

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

    村岡 真, 山本 雅貴, 八木 直人, 植木 龍夫, 叶 敏, 島 扶美, 廖 静伶, 岡本 英嗣, 田村 厚夫, 片岡 徹

    XX Congress of the International Union of Crystallography, 2005年08月, 英語, International Union of Crystallography, フィレンツェ, 国際会議

    ポスター発表

  • 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, 島 扶美, 村岡 真, 山本 雅貴, 植木 龍夫, 廖 静伶, 田村 尚, 片岡 徹

    第77回日本生化学会大会, 2004年10月, 英語, 日本生化学会, 神戸, 国内会議

    ポスター発表

  • 低分子量GTP結合蛋白質M-RasのX線構造解析

    叶 敏, 島 扶美, 村岡 真, 山本 雅貴, 八木 直人, 片岡 徹

    第26回日本分子生物学会年会, 2003年12月, 英語, 日本分子生物学会, 横浜, 国内会議

    ポスター発表

共同研究・競争的資金等の研究課題

  • caged-GTPを用いた低分子量G蛋白質のシグナル伝達過程の時分割構造解析

    島 扶美

    日本学術振興会, 科学研究費助成事業 新学術領域研究(研究領域提案型), 新学術領域研究(研究領域提案型), 神戸大学, 2020年10月 - 2022年03月

  • 新規Rasシグナル伝達阻害剤創出を目指した研究

    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, 2020年04月 - 2022年03月

  • がん治療薬の設計基盤となるSACLAによるRasの原子スケール動的構造解析

    島 扶美

    日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 神戸大学, 2019年04月 - 2022年03月

  • 新規PPI阻害作用機構に基づく抗がん剤の探索

    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, 神戸大学, 2019年12月 - 2021年03月, 研究代表者

    競争的資金

  • 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, 2019年04月 - 2020年03月, 研究代表者

    競争的資金

  • 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, 2014年07月 - 2019年03月, 研究代表者

    競争的資金

  • 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, 2018年04月 - 2018年12月, 研究代表者

    競争的資金

  • 片岡 徹

    科学研究費補助金/基盤研究(B), 2014年04月 - 2017年03月

    競争的資金

  • 島 扶美

    科学研究費補助金/基盤研究(B), 2014年04月 - 2017年03月, 研究代表者

    競争的資金

  • 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, 2011年04月 - 2016年03月

    競争的資金

  • 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, 2014年04月 - 2015年03月, 研究代表者

    競争的資金

  • 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, 2013年04月 - 2014年03月, 研究代表者

    競争的資金

  • 島 扶美

    学術研究助成基金助成金/基盤研究(C), 2011年04月 - 2014年03月, 研究代表者

    競争的資金

  • 片岡 徹

    科学研究費補助金/基盤研究(B), 2011年

    競争的資金

  • 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年, 研究代表者

    競争的資金

  • 島 扶美

    科学研究費補助金/基盤研究(C), 2008年04月 - 2010年03月, 研究代表者

    競争的資金

  • 島 扶美

    科学研究費補助金/特定領域研究, 2008年04月 - 2010年03月, 研究代表者

    競争的資金

  • 島 扶美

    科学研究費補助金/特定領域研究, 2006年04月 - 2008年03月, 研究代表者

    競争的資金

  • 片岡 徹

    科学研究費補助金/基盤研究(B), 2008年

    競争的資金

  • 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), 2004年04月 - 2006年03月, 研究代表者

    競争的資金

  • 片岡 徹

    科学研究費補助金/基盤研究(B), 2005年

    競争的資金

  • 片岡 徹

    科学研究費補助金/特定領域研究, 2005年

    競争的資金

  • 島 扶美

    科学研究費補助金/若手研究(B), 2002年04月 - 2004年03月, 研究代表者

    競争的資金

産業財産権

  • Ras機能阻害作用を有するチオキソチアゾリジン誘導体

    片岡 徹, 島 扶美

    特願2013-514037, 2012年05月09日, 大学長, 特許6014816, 2016年10月07日

    特許権

  • 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)

    片岡 徹, 島 扶美

    14/116152, 2012年05月09日, 大学長, US9056862, 2015年06月16日

    特許権

  • Ras機能阻害作用を有するチオキソチアゾリジン誘導体

    島 扶美

    特願WO 2012/153775 A1, 2011年05月10日, 特許WO 2012/153775 A1

    特許権

  • Ras 機能阻害剤のスクリーニング方法

    島 扶美

    特願WO/2012/108297 A1, 2011年02月07日, 特許WO/2012/108297 A1

    特許権

  • Ras部分ポリペプチド含有水溶液及びRas機能阻害剤のスクリーニング方法

    島 扶美

    特願WO2012108297A1, 2011年02月07日, 特許WO2012108297A1

    特許権