Quantitative phosphoproteomic analysis of mTOR signaling perturbation in glioblastoma stem cells

• Project/Area Number: 26505001
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: オミクス計測科学
• Research Institution: The University of Tokyo
• Principal Investigator: KOZUKA-HATA Hiroko 東京大学, 医科学研究所, 技術専門員 (80401256)
• Co-Investigator(Kenkyū-buntansha): 尾山 大明 東京大学, 医科学研究所, 准教授 (30422398)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2016: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: プロテオミクス / 膠芽腫幹細胞 / mTORシグナル / リン酸化 / SILAC / mTOR シグナル

Outline of Final Research Achievements

Glioblastoma is the most malignant brain tumor with poor prognosis and shows high resistance to the conventional treatment such as chemotherapy or radiation. In this study, we performed global quantitative proteome and phosphoproteome analyses of EGF-dependent mTOR signaling in patient-derived gliblastoma stem cells through perturbation by mTOR specific inhibitor, Torin1.
As a result of integrated statistical and mathematical analyses of these large-scale data, it was strongly suggested that DNA damage checkpoint might be involved in the maintenance of stemness properties in the glioblastoma stem cells.

Research Products

• [Journal Article] Differential analyses of major allergen proteins in wild-type rice and rice producing a fragment of anti-rotavirus antibody. (2016)
  • Author(s): Yuki Y, Kurokawa S, Kozuka-Hata H, Tokuhara D, Mejima M, Kuroda M, Oyama M, Nishimaki-Mogami T, Teshima R, Kiyono H.
  • Journal Title: Regul Toxicol Pharmacol Volume: 76 Pages: 128-136
  • DOI: 10.1016/j.yrtph.2016.01.023
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] USP7 and TDP-43: Pleiotropic regulation of Cryptochrome protein stability paces the oscillation of the mammalian circadian clock. (2016)
  • Author(s): Arisa Hirano, Tomoki Nakagawa, Hikari Yoshitane, Masaaki Oyama, Hiroko Kozuka-Hata, Darin Lanjakornsiripoan, and Yoshitaka Fukada
  • Journal Title: PLOS ONE Volume: 11 Issue: 4 Pages: e0154263-e0154263
  • DOI: 10.1371/journal.pone.0154263
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Quantitative phosphoproteomics-based molecular network description for high-resolution kinase-substrate interactome analysis. (2016)
  • Author(s): Narushima, Y., Kozuka-Hata, H., Tsumoto, K., Inoue, J. and Oyama, M.
  • Journal Title: Bioinformatics Volume: 印刷中 Issue: 14 Pages: 2083-2088
  • DOI: 10.1093/bioinformatics/btw164
  • Peer Reviewed / Open Access
• [Journal Article] Extremotolerant tardigrade genome and improved radiotolerance of human cultured cells by tardigrade-unique protein. (2016)
  • Author(s): Hashimoto T, Horikawa DD, Saito Y, Kuwahara H, Kozuka-Hata H, Shin-I T, Minakuchi Y, Ohishi K, Motoyama A, Aizu T, Enomoto A, Kondo K, Tanaka S, Hara Y, Koshikawa S, Sagara H, Miura T, Yokobori S, Miyagawa K, Suzuki Y, Kubo T, Oyama M, Kohara Y, Fujiyama A, Arakawa K, Katayama T, Toyoda A and Kunieda T
  • Journal Title: Nature Communications Volume: 7 Issue: 1 Pages: 12808-12808
  • DOI: 10.1038/ncomms12808
  • NAID: 120005971035
  • Peer Reviewed / Open Access
• [Journal Article] Ubiquitin-specific protease 9X in host cells interacts with herpes simplex virus 1 ICP0 (2016)
  • Author(s): Sato Y, Kato A, Arii J, Koyanagi N, Kozuka-Hata H, Oyama M, Kawaguchi Y.
  • Journal Title: Journal of Veterinary Medical Science Volume: 78 Issue: 3 Pages: 405-410
  • DOI: 10.1292/jvms.15-0598
  • NAID: 130005140885
  • ISSN: 0916-7250, 1347-7439
  • Peer Reviewed / Open Access
• [Journal Article] Integrative Network Analysis Combined with Quantitative Phosphoproteomics Reveals TGFBR2 as a Novel Regulator of Glioblastoma Stem Cell Properties (2016)
  • Author(s): Narushima Y, Kozuka-Hata H, Koyama-Nasu R, Tsumoto K, Inoue J, Akiyama T & Oyama M.
  • Journal Title: Molecular and Cellular Proteomics Volume: 15 Issue: 3 Pages: 1017-1031
  • DOI: 10.1074/mcp.m115.049999
  • Peer Reviewed / Open Access
• [Journal Article] Ubiquitin-Specific Protease 9X in Host Cells Interacts with Herpes Simplex Virus 1 ICP0. (2016)
  • Author(s): Y. Sato, A. Kato, J. Arii, N. Koyanagi, H. Kozuka-Hata, M. Oyama and Y. Kawaguchi.
  • Journal Title: The Journal of Veterinary Medical Science Volume: 2016 Issue: 6 Pages: 405-10
  • DOI: 10.1128/jvi.03043-15
  • NAID: 130005140885
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Long noncoding RNA UPAT promotes colon tumorigenesis by inhibiting degradation of UHRF1. (2016)
  • Author(s): Taniue K, Kurimoto A, Sugimasa H, Nasu E, Takeda Y, Iwasaki K, Nagashima T, Okada-Hatakeyama M, Oyama M, Kozuka-Hata H, Hiyoshi M, Kitayama J, Negishi L, Kawasaki Y, Akiyama T.
  • Journal Title: Proceedings of the National Academy of Sciences U S A. Volume: 113 Issue: 5 Pages: 1273-8
  • DOI: 10.1073/pnas.1500992113
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Scaffold Protein Ahk1, Which Associates with Hkr1, Sho1, Ste11, and Pbs2, Inhibits Cross Talk Signaling from the Hkr1 Osmosensor to the Kss1 Mitogen-Activated Protein Kinase. (2016)
  • Author(s): Nishimura A, Yamamoto K, Oyama M, Kozuka-Hata H, Saito H, Tatebayashi K.
  • Journal Title: Mol Cell Biol Volume: 36 Issue: 7 Pages: 1109-1123
  • DOI: 10.1128/mcb.01017-15
  • Peer Reviewed
• [Journal Article] Quantitative phosphoproteomics-based molecular network description for high-resolution kinase-substrate interactome analysis. (2016)
  • Author(s): Narushima Y, Kozuka-Hata H, Tsumoto K, Inoue J, Oyama M.
  • Journal Title: Bioinformatics Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Phosphoproteomics-based network analysis of cancer cell signaling systems. (2015)
  • Author(s): Kozuka-Hata H and Oyama M.
  • Journal Title: Springer Volume: - Pages: 3-15
  • DOI: 10.1007/978-4-431-55561-2_1
  • ISBN: 9784431555605, 9784431555612
  • Peer Reviewed
• [Journal Article] Interactome Analysis of Herpes Simplex Virus 1 Envelope Glycoprotein H. (2015)
  • Author(s): Y. Hirohata, A. Kato, M. Oyama, H. Kozuka-Hata, N. Koyanagi, J. Arii and Y. Kawaguchi.
  • Journal Title: Microbiology and Immunology Volume: 印刷中 Issue: 6 Pages: 331-7
  • DOI: 10.1111/1348-0421.12255
  • NAID: 40020510068
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Function of the Herpes Simplex Virus 1 Small Capsid Protein VP26 is Regulated by Phosphorylation at a Specific Site. (2015)
  • Author(s): R. Kobayashi, A. Kato, S. Oda, N. Koyanagi, M. Oyama, H. Kozuka-Hata, J. Arii, and Y. Kawaguchi.
  • Journal Title: Journal of Virology Volume: 89 Issue: 11 Pages: 6141-7
  • DOI: 10.1128/jvi.00547-15
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The stability of epigenetic factor ASXL1 is regulated through ubiquitination and USP7-mediated deubiquitination. (2015)
  • Author(s): Inoue, D., Nishimura, K., Kozuka-Hata, H., Oyama, M. and Kitamura, T.
  • Journal Title: Leukemia Volume: in press Issue: 11 Pages: 2257-2260
  • DOI: 10.1038/leu.2015.90
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Herpes simplex virus 1 recruits CD98 heavy chain and β1 integrin to the nuclear membrane for viral de-envelopment. (2015)
  • Author(s): Y. Hirohata, J. Arii, Z. Liu, K. Shindo, M. Oyama, H. Kozuka-Hata, H. Sagara, A. Kato, and Y. Kawaguchi.
  • Journal Title: Journal of Virology Volume: 89 Issue: 15 Pages: 7799-812
  • DOI: 10.1128/jvi.00741-15
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Role of Host Cell p32 in Herpes Simplex Virus 1 De-Envelopment during Viral Nuclear Egress. (2015)
  • Author(s): Liu Z, Kato A, Oyama M, Kozuka-Hata H, Arii J, Kawaguchi Y.
  • Journal Title: J Virol Volume: 89 Issue: 17 Pages: 8982-8998
  • DOI: 10.1128/jvi.01220-15
  • Peer Reviewed / Open Access
• [Journal Article] Role for Protein Kinase CK2 on Cell Proliferation: Assessing CK2 Complex Components in the Nucleus During the Cell Cycle Progression (2015)
  • Author(s): Kato-Homma M, Shibata T, Suzuki T, Ogura M, Kozuka-Hata H, Oyama M, Homma Y.
  • Journal Title: Springer Volume: 12 Pages: 197-226
  • Peer Reviewed / Open Access
• [Journal Article] Interactome Analysis of Herpes Simplex Virus 1 Envelope Glycoprotein H. (2015)
  • Author(s): Hirohata Y, Kato A, Oyama M, Kozuka-Hata H, Koyanagi N, Arii J, Kawaguchi Y.
  • Journal Title: Microbiol. Immunol. Volume: -
  • NAID: 40020510068
  • Peer Reviewed
• [Journal Article] The Function of the Herpes Simplex Virus 1 Small Capsid Protein VP26 is Regulated by Phosphorylation at a Specific Site. (2015)
  • Author(s): Kobayashi R, Kato A, Oda S, Koyanagi N, Oyama M, Kozuka-Hata H, Arii J, Kawaguchi Y.
  • Journal Title: J Virol. Volume: -
  • Peer Reviewed
• [Journal Article] Phosphoproteomics-based Network Analysis of Cancer Cell Signaling Systems (2015)
  • Author(s): Kozuka-Hata H, Oyama M
  • Journal Title: Springer Volume: -
  • Peer Reviewed / Open Access
• [Journal Article] Role of herpes simplex virus 1 immediate early protein ICP22 in viral nuclear egress. (2014)
  • Author(s): Maruzuru Y, Shindo K, Liu Z, Oyama M, Kozuka-Hata H, Arii J, Kato A, Kawaguchi Y.
  • Journal Title: J. Virol. Volume: 88 Pages: 7445-7454
  • Peer Reviewed
• [Journal Article] The UL12 protein of herpes simplex virus 1 is regulated by tyrosine phosphorylation. (2014)
  • Author(s): Fujii H, Kato A, Mugitani M, Kashima Y, Oyama M, Kozuka-Hata H, Arii J, Kawaguchi Y.
  • Journal Title: J. Virol. Volume: 88 Pages: 10624-10634
  • Peer Reviewed
• [Journal Article] 5-Hydroxymethylcytosine plays a critical role in glioblastomagenesis by recruiting the CHTOP-methylosome complex. (2014)
  • Author(s): Takai H, Masuda K, Sato T, Sakaguchi Y, Suzuki T, Suzuki T, Koyama-Nasu R, Nasu-Nishimura Y, Katou Y, Ogawa H, Morishita Y, Kozuka-Hata H, Oyama M, Todo T, Ino Y, Mukasa A, Saito N, Toyoshima C, Shirahige K, Akiyama T.
  • Journal Title: Cell Rep. Volume: 9 Pages: 48-60
  • Peer Reviewed
• [Journal Article] Direct interaction of Plk4 with STIL ensures formation of a single procentriole per parental centriole. (2014)
  • Author(s): Ohta M, Ashikawa T, Nozaki Y, Kozuka-Hata H, Goto H, Inagaki M, Oyama M, Kitagawa D.
  • Journal Title: Nat. Commun. Volume: 5 Pages: 5267-5267
  • Peer Reviewed
• [Journal Article] Influenza virus-host interactome screen as a platform for antiviral drug development. (2014)
  • Author(s): Watanabe T, Kawakami E, Shoemaker JE, Lopes TJ, Matsuoka Y, Tomita Y, Kozuka-Hata H, Gorai T, Kuwahara T, Takeda E, Nagata A, Takano R, Kiso M, Yamashita M, Sakai-Tagawa Y, Katsura H, Nonaka N, Fujii H, Fujii K, Sugita Y, Noda T, Goto H, Fukuyama S, Watanabe S, Neumann G, Oyama M, Kitano H, Kawaoka Y.
  • Journal Title: Cell Host Microbe Volume: 16 Pages: 795-805
  • Peer Reviewed
• [Presentation] 高精度プロテオミクスによるシグナル伝達制御機構の数理ネットワーク解析 (2017)
  • Author(s): 尾山 大明
  • Organizer: 新学術領域「数理シグナル」 第一回公開シンポジウム「数理シグナル」学術領域の創出
  • Place of Presentation: 東京大学医科学研究所附属病院棟8階 大会議室
  • Invited
• [Presentation] 大規模翻訳後修飾情報に基づくインタラクトーム解析 (2017)
  • Author(s): 尾山 大明
  • Organizer: 新学術領域「数理シグナル」 第一回公開シンポジウム「数理シグナル」学術領域の創出
  • Place of Presentation: 東京大学医科学研究所白金ホール
• [Presentation] 膠芽腫幹細胞情報伝達系の数理システム解析 (2017)
  • Author(s): 秦 裕子
  • Organizer: 新学術領域「数理シグナル」 第一回公開シンポジウム「数理シグナル」学術領域の創出
  • Place of Presentation: 東京大学医科学研究所白金ホール
• [Presentation] 高深度定量リン酸化プロテオミクスと大規模インタラクトーム情報を基盤とする膠芽腫幹細胞情報伝達系の統合ネ ットワーク解析 (2016)
  • Author(s): 秦 裕子、成島 悠太、廣木 朋子、那須 亮、津本 浩平、井上 純一郎、秋山 徹、尾山 大明
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30
• [Presentation] Phosphoproteomics-based Network Analysis of Cancer Cell Signaling Regulation (2016)
  • Author(s): Masaaki Oyama
  • Organizer: The 8th Asia Oceania Human Proteome Organization (AOHUPO) Congress
  • Place of Presentation: Fleur De Chine Hotel, Sun Moon Lake, Taiwan
  • Year and Date: 2016-09-22
  • Int'l Joint Research / Invited
• [Presentation] mTOR 阻害剤を用いた膠芽腫幹細胞プロテオーム及びリン酸化プロテオームに関する統合摂動解析 (2015)
  • Author(s): 秦 裕子, 廣木 朋子, 那須 亮, 津本 浩平, 井上 純一郎, 秋山 徹, 尾山 大明
  • Organizer: BMB2015
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-01
• [Presentation] 高精度定量リン酸化プロテオミクスに基づく統合ネットワーク解析による膠芽腫幹細胞分化制御因子の同定 (2015)
  • Author(s): 成島 悠太, 秦 裕子, 那須 亮, 津本 浩平, 井上 純一郎, 秋山 徹, 尾山 大明
  • Organizer: BMB2015
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-01
• [Presentation] IPA Advanced Analytics を活用した患者由来膠芽腫幹細胞における 蛋白質制御ネットワークの解明 (2015)
  • Author(s): 秦 裕子
  • Organizer: Ingenuity ユーザーミーティング
  • Place of Presentation: 大手町サンケイプラザ
  • Year and Date: 2015-10-02
  • Invited
• [Presentation] Sophisticated proteomics technologies for identifying protein-protein interaction sites using cross-linking / high-resolution mass spectrometry (2015)
  • Author(s): Hiroko Kozuka-Hata
  • Organizer: 2nd International Symposium on Protein Modifications in Pathogenic Dysregulation of Signaling
  • Place of Presentation: 東京大学医科学研究所
  • Year and Date: 2015-01-23 – 2015-01-24
• [Presentation] High-resolution phosphoproteomics defines regulation of cancer cell signaling (2015)
  • Author(s): Masaaki Oyama
  • Organizer: 2nd International Symposium on Protein Modifications in Pathogenic Dysregulation of Signaling
  • Place of Presentation: 東京大学医科学研究所
  • Year and Date: 2015-01-23 – 2015-01-24
  • Invited
• [Book] 実験医学増刊 生命科学で使える はじめての数理モデルとシミュレーション (2017)
  • Author(s): 尾山 大明、秦 裕子
  • Total Pages: 239
  • Publisher: 羊土社