System-level analysis of signal transduction mechanisms by high-resolution proteomics

• Project Area: Integrative understanding of biological signaling networks based on mathematical science
• Project/Area Number: 16H06578
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Complex systems
• Research Institution: The University of Tokyo
• Principal Investigator: Oyama Masaaki 東京大学, 医科学研究所, 准教授 (30422398)
• Co-Investigator(Kenkyū-buntansha): 秦 裕子 東京大学, 医科学研究所, 技術専門員 (80401256)
• Project Period (FY): 2016-06-30 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥44,330,000 (Direct Cost: ¥34,100,000、Indirect Cost: ¥10,230,000); Fiscal Year 2020: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000); Fiscal Year 2019: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000); Fiscal Year 2018: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000); Fiscal Year 2017: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000); Fiscal Year 2016: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
• Keywords: プロテオーム / シグナル伝達 / 癌

Outline of Final Research Achievements

In this study, we established an analytical platform to perform global ubiquitination and acetylation proteome analyses of human cancer cells using high-resolution nanoflow liquid chromatography-tandem mass spectrometry (nanoLC-MS/MS) system. We also developed a bioinformatical platform named 'Post Translational Modification mapper (PTMapper)' to reconstruct regulatory protein-protein interaction relations at the protein modification level towards systematic network analysis based on PTM-oriented quantitative activation data,

Academic Significance and Societal Importance of the Research Achievements

シグナル伝達系は細胞の運命決定を担う最も重要な生命制御システムの一つであり、リン酸化やユビキチン化・アセチル化をはじめとする多様なタンパク質翻訳後修飾による複雑かつ精細な相互作用ネットワークがその動的な駆動力として機能している。本研究によってシグナル伝達制御を担う主要翻訳後修飾に関する大規模同定・定量分析プラットフォームが確立され、被修飾部位ごとの詳細な活性変動を基盤とする次世代の数理モデル・統計モデル解析研究に資するプロテオーム情報基盤を構築することができた。

Research Products

• [Journal Article] Comparative whole-genome and proteomics analyses of the next seed bank and the original master seed bank of MucoRice-CTB 51A line, a rice-based oral cholera vaccine (2021)
  • Author(s): Sasou Ai、Yuki Yoshikazu、Honma Ayaka、Sugiura Kotomi、Kashima Koji、Kozuka-Hata Hiroko、Nojima Masanori、Oyama Masaaki、Kurokawa Shiho、Maruyama Shinichi、Kuroda Masaharu、Tanoue Shinjiro、Takamatsu Narushi、Fujihashi Kohtaro、Goto Eiji、Kiyono Hiroshi
  • Journal Title: BMC Genomics Volume: 22 Issue: 1 Pages: 59-59
  • DOI: 10.1186/s12864-020-07355-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CADM1 suppresses c-Src activation by binding with Cbp on membrane lipid rafts and intervenes colon carcinogenesis (2020)
  • Author(s): Tsuboi Yumi、Oyama Masaaki、Kozuka-Hata Hiroko、Ito Akihiko、Matsubara Daisuke、Murakami Yoshinori
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 529 Issue: 3 Pages: 854-860
  • DOI: 10.1016/j.bbrc.2020.05.103
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prohibitin-1 Contributes to Cell-to-Cell Transmission of Herpes Simplex Virus 1 via the MAPK/ERK Signaling Pathway (2020)
  • Author(s): Watanabe Mizuki、Arii Jun、Takeshima Kosuke、Fukui Ayano、Shimojima Masayuki、Kozuka-Hata Hiroko、Oyama Masaaki、Minamitani Takeharu、Yasui Teruhito、Kubota Yuji、Takekawa Mutsuhiro、Kosugi Isao、Maruzuru Yuhei、Koyanagi Naoto、Kato Akihisa、Mori Yasuko、Kawaguchi Yasushi
  • Journal Title: Journal of Virology Volume: 95 Issue: 3
  • DOI: 10.1128/jvi.01413-20
  • Peer Reviewed / Open Access
• [Journal Article] Osmostress enhances activating phosphorylation of Hog1 MAP kinase by mono-phosphorylated Pbs2 MAP2K. (2020)
  • Author(s): Tatebayashi K, Yamamoto K, Tomida T, Nishimura A, Takayama T, Oyama M, Kozuka-Hata H, Adachi-Akahane S, Tokunaga Y, Saito H
  • Journal Title: EMBO J Volume: 39 Issue: 5
  • DOI: 10.15252/embj.2019103444
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] System-Wide Analysis of Protein Acetylation and Ubiquitination Reveals a Diversified Regulation in Human Cancer Cells (2020)
  • Author(s): Kozuka-Hata Hiroko、Kitamura Aya、Hiroki Tomoko、Aizawa Aiko、Tsumoto Kouhei、Inoue Jun-ichiro、Oyama Masaaki
  • Journal Title: Biomolecules Volume: 10 Issue: 3 Pages: 411-411
  • DOI: 10.3390/biom10030411
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Widespread Family of Heat-Resistant Obscure (Hero) Proteins Protect Against Protein Instability and Aggregation (2020)
  • Author(s): Tsuboyama K, Osaki T, Matsuura-Suzuki E, Kozuka-Hata H, Okada Y, Oyama M, Ikeuchi Y, Iwasaki S, Tomari Y
  • Journal Title: PLOS Biology Volume: 18 Issue: 3 Pages: 3000632-3000632
  • DOI: 10.1371/journal.pbio.3000632
  • Peer Reviewed / Open Access
• [Journal Article] Discovery of a Vertebrate-Specific Factor that Processes Flagellar Glycolytic Enolase during Motile Ciliogenesis (2020)
  • Author(s): Narita Keishi、Nagatomo Hiroaki、Kozuka-Hata Hiroko、Oyama Masaaki、Takeda Sen
  • Journal Title: iScience Volume: 23 Issue: 4 Pages: 100992-100992
  • DOI: 10.1016/j.isci.2020.100992
  • URL: https://pure.teikyo.jp/en/publications/ca2c94fe-eb98-437a-b0ce-41a7ee9865be
  • Peer Reviewed / Open Access
• [Journal Article] A High-Resolution Map of SBP1 Interactomes in Plasmodium falciparum-infected Erythrocytes (2019)
  • Author(s): Takano R, Kozuka-Hata H, Kondoh D, Bochimoto H, Oyama M, Kato K
  • Journal Title: iScience Volume: 19 Pages: 703-714
  • DOI: 10.1016/j.isci.2019.07.035
  • Peer Reviewed / Open Access
• [Journal Article] CD73 complexes with emmprin to regulate MMP-2 production from co-cultured sarcoma cells and fibroblasts (2019)
  • Author(s): Aoki M, Koga K, Miyazaki M, Hamasaki M, Koshikawa N, Oyama M, Kozuka-Hata H, Seiki M, Toole BP, Nabeshima K
  • Journal Title: BMC Cancer Volume: 19 Issue: 1 Pages: 912-912
  • DOI: 10.1186/s12885-019-6127-x
  • Peer Reviewed / Open Access
• [Journal Article] A novel ASXL1?OGT axis plays roles in H3K4 methylation and tumor suppression in myeloid malignancies (2018)
  • Author(s): Inoue D, Fujino T, Sheridan P, Zhang YZ, Nagase R, Horikawa S, Li Z, Matsui H, Kanai A, Saika M, Yamaguchi R, Kozuka-Hata H, Kawabata KC, Yokoyama A, Goyama S, Inaba T, Imoto S, Miyano S, Xu M, Yang FC, Oyama M, Kitamura T.
  • Journal Title: Leukemia Volume: 印刷中 Issue: 6 Pages: 1327-1337
  • DOI: 10.1038/s41375-018-0083-3
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Regulation of Herpes Simplex Virus 2 Protein Kinase UL13 by Phosphorylation and Its Role in Viral Pathogenesis. (2018)
  • Author(s): Koyanagi N, Kato A, Takeshima K, Maruzuru Y, Kozuka-Hata H, Oyama M, Arii J, Kawaguchi Y.
  • Journal Title: J Virol. Volume: 92 Issue: 17
  • DOI: 10.1128/jvi.00807-18
  • Peer Reviewed / Open Access
• [Journal Article] Roles of the Phosphorylation of Herpes Simplex Virus 1 UL51 at a Specific Site in Viral Replication and Pathogenicity. (2018)
  • Author(s): Kato A, Oda S, Watanabe M, Oyama M, Kozuka-Hata H, Koyanagi N, Maruzuru Y, Arii J, Kawaguchi Y.
  • Journal Title: J Virol. Volume: 92 Issue: 18
  • DOI: 10.1128/jvi.01035-18
  • Peer Reviewed / Open Access
• [Journal Article] Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis (2018)
  • Author(s): Asada S, Goyama S, Inoue D, Shikata S, Takeda R, Fukushima T, Yonezawa T, Fujino T, Hayashi Y, Kawabata KC, Fukuyama T, Tanaka Y, Yokoyama A, Yamazaki S, Kozuka-Hata H, Oyama M, Kojima S, Kawazu M, Mano H, Kitamura T
  • Journal Title: Nat Commun Volume: 9 Issue: 1 Pages: 2733-2733
  • DOI: 10.1038/s41467-018-05085-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] N-terminal acetylation by NatB is required for the shutoff activity of influenza A virus PA-X. (2018)
  • Author(s): Oishi K, Yamayoshi S, Kozuka-Hata H, Oyama M, Kawaoka Y.
  • Journal Title: Cell Rep Volume: 24 Issue: 4 Pages: 851-860
  • DOI: 10.1016/j.celrep.2018.06.078
  • Peer Reviewed / Open Access
• [Journal Article] Identification of Proteolytic Cleavage Sites of EphA2 by Membrane Type 1 Matrix Metalloproteinase on the Surface of Cancer Cells (2018)
  • Author(s): Kikuchi K, Kozuka-Hata H, Oyama M, Seiki M, Koshikawa N
  • Journal Title: Methods Mol Biol Volume: 1731 Pages: 29-37
  • DOI: 10.1007/978-1-4939-7595-2_3
  • ISBN: 9781493975945, 9781493975952
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Shotgun proteomics deciphered age/division of labor-related functional specification of three honeybee (Apis mellifera L.) exocrine glands (2018)
  • Author(s): Fujita T, Kozuka-Hata H, Hori Y, Takeuchi J, Kubo T, Oyama M
  • Journal Title: PLoS One Volume: 13 Issue: 2 Pages: e0191344-e0191344
  • DOI: 10.1371/journal.pone.0191344
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive Identification of Nuclear and Cytoplasmic TNRC6A-Associating Proteins (2017)
  • Author(s): Suzawa M, Noguchi K, Nishi K, Kozuka-Hata H, Oyama M, Ui-Tei K
  • Journal Title: J Mol Biol Volume: 429 Issue: 21 Pages: 3319-3333
  • DOI: 10.1016/j.jmb.2017.04.017
  • Peer Reviewed / Open Access
• [Journal Article] Lysosomal targeting of SIDT2 via multiple YxxΦ motifs is required for SIDT2 function in the process of RNautophagy (2017)
  • Author(s): Contu Viorica Raluca、Hase Katsunori、Kozuka-Hata Hiroko、Oyama Masaaki、Fujiwara Yuuki、Kabuta Chihana、Takahashi Masayuki、Hakuno Fumihiko、Takahashi Shin-Ichiro、Wada Keiji、Kabuta Tomohiro
  • Journal Title: Journal of Cell Science Volume: 130 Issue: 17 Pages: 2843-2853
  • DOI: 10.1242/jcs.202481
  • Peer Reviewed / Open Access
• [Journal Article] TLR7 mediated viral recognition results in focal type I interferon secretion by dendritic cells (2017)
  • Author(s): Saitoh SI, Abe F, Kanno A, Tanimura N, Mori Saitoh Y, Fukui R, Shibata T, Sato K, Ichinohe T, Hayashi M, Kubota K, Kozuka-Hata H, Oyama M, Kikko Y, Katada T, Kontani K and Miyake K
  • Journal Title: Nat Commun Volume: 8 Issue: 1 Pages: 1592-1592
  • DOI: 10.1038/s41467-017-01687-x
  • Peer Reviewed / Open Access
• [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
• [Presentation] Integrative network analysis of cancer cell signaling by high-resolution proteomics (2020)
  • Author(s): Masaaki Oyama, Hiroko Kozuka-Hata
  • Organizer: JSPS Core-to-Core Program
  • Int'l Joint Research / Invited
• [Presentation] 高精度翻訳後修飾プロテオミクスによるシグナルネットワーク解析 (2020)
  • Author(s): 尾山 大明、秦 裕子
  • Organizer: 第71回日本電気泳動学会総会
  • Invited
• [Presentation] High-resolution proteomic analysis of EGF-regulated ubiquitination dynamics in human cancer cells (2020)
  • Author(s): Hiroko Kozuka-Hata, Tomoko Hiroki, Aya Kitamura, Aiko Aizawa, Naoaki Miyamura, Kouhei Tsumoto, Jun-ichiro Inoue, Masaaki Oyama
  • Organizer: 第43回日本分子生物学会年会
  • Invited
• [Presentation] ヒトがん細胞におけるEGF刺激依存的プロテオームダイナミクスの高深度動態解析 (2020)
  • Author(s): 秦 裕子、廣木 朋子、北村 亜矢、相澤 愛子、宮村 尚明、津本 浩平、井上 純一郎、尾山 大明
  • Organizer: 第16回日本臨床プロテオゲノミクス研究会
• [Presentation] 翻訳後修飾プロテオミクスによるがん化シグナルネットワーク解析 (2019)
  • Author(s): 秦 裕子、北村 亜矢、廣木 朋子、相澤 愛子、津本 浩平、井上 純一郎、尾山 大明
  • Organizer: 第15回日本臨床プロテオゲノミクス研究会
• [Presentation] リシンアセチル化及びユビキチン化が規定する細胞応答ネットワークの時系列プロテオーム解析 (2019)
  • Author(s): 秦 裕子、北村 亜矢、廣木 朋子、相澤 愛子、宮村 尚明、小嶋 由希子、津本 浩平、井上 純一郎、 尾山 大明
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] Pulsed SILAC法を用いた癌細胞内タンパク質ターンオーバーのプロテオーム解析 (2019)
  • Author(s): 尾山 大明、秦 裕子
  • Organizer: 数理腫瘍学研究会
• [Presentation] Proteome-wide analysis of lysine acetylation and ubiquitination reveals critical signaling regulation in cancer cells (2019)
  • Author(s): 秦 裕子
  • Organizer: 第2回ユビキチン研究会
• [Presentation] Integrative analysis of cancer cell signaling networks by post-translational modification-directed proteomics (2019)
  • Author(s): Masaaki Oyama
  • Organizer: 1st International symposium on interdisciplinary approaches to integrative understanding of biological signaling networks
  • Int'l Joint Research
• [Presentation] Proteome-wide analysis of lysine acetylation and ubiquitination reveals critical signaling regulation in cancer cells (2019)
  • Author(s): Hiroko Kozuka-Hata
  • Organizer: 1st International symposium on interdisciplinary approaches to integrative understanding of biological signaling networks
  • Int'l Joint Research
• [Presentation] Integrative network analysis of phosphorylation-dependent signaling dynamics in cancer cells (2019)
  • Author(s): Masaaki Oyama
  • Organizer: Core to Core meeting
  • Int'l Joint Research
• [Presentation] System-wide analysis of lysine modification sites based on large-scale cellular proteome data (2019)
  • Author(s): Hiroko Kozuka-Hata
  • Organizer: Core to Core meeting
  • Int'l Joint Research
• [Presentation] Systematic discovery of cancer biomarkers by integrative post-translational modification-directed proteomics (2018)
  • Author(s): Masaaki Oyama and Hiroko Kozuka-Hata
  • Organizer: Mass Spectrometry and Proteomics 2018 (MSP2018)
  • Int'l Joint Research / Invited
• [Presentation] 大規模ユビキチン化及びアセチル化プロテオーム解析によるシグナル伝達制御機構の解明 (2018)
  • Author(s): 小塚（秦） 裕子、北村 亜矢、廣木 朋子、相澤 愛子、津本 浩平、井上 純一郎、尾山 大明
  • Organizer: 第41回日本分子生物学会年会
• [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 (2018)
  • Author(s): 尾山 大明、秦 裕子
  • Organizer: 数理腫瘍学研究会
• [Presentation] Comprehensive network analysis of cancer cell signaling through systematic integration of post-translational modification dynamics (2017)
  • Author(s): Masaaki Oyama and Hiroko Kozuka-Hata
  • Organizer: 12th International Symposium of the Institute Network
  • Int'l Joint Research
• [Presentation] 大規模細胞プロテオームデータを用いた包括的ユビキチン結合モチーフ解析 (2017)
  • Author(s): 小塚（秦） 裕子、廣木 朋子、北村 亜矢、市倉 慎也、津本 浩平、井上 純一郎、尾山 大明
  • Organizer: 2017年度生命科学系学会合同年次大会（ConBio2017）
• [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
• [Book] in silico創薬におけるスクリーニングの高速化・高精度化技術 (2018)
  • Author(s): 尾山 大明、秦 裕子
  • Total Pages: 540
  • Publisher: 技術情報協会
  • ISBN: 9784861046889
• [Book] Applications of RNA-Seq and Omics Strategies - From Microorganisms to Human Health (2017)
  • Author(s): Hiroko Kozuka‐Hata and Masaaki Oyama
  • Total Pages: 318
  • Publisher: IntechOpen
  • ISBN: 9789535135043
• [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
• [Remarks] 東京大学医科学研究所附属疾患プロテオミクスラボラトリー
  • URL: https://www.ims.u-tokyo.ac.jp/mpl/top.html
• [Remarks] 東京大学大学院新領域創成科学研究科メディカル情報生命専攻疾患蛋白質工学分野
  • URL: http://www.cbms.k.u-tokyo.ac.jp/lab/oyama.html