Regulation of the TGF-beta signaling by peptide aptamers

• Project/Area Number: 17K19581
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Miyazono Kenichi 東京大学, 大学院農学生命科学研究科(農学部), 特任准教授 (90554486)
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: がん / TGF-β / ペプチドアプタマー / ペプチド工学 / シグナル伝達 / 制御 / 蛋白質

Outline of Final Research Achievements

SMAD2/3 are hub proteins that regulate TGF-beta signaling in cell. In this study, we have designed and developed peptide aptamers that bind strongly to SMAD2/3. The peptide aptamers, which are produced by the tandem linkage of SMAD2/3 cofactors, are expected to regulate the function of TGF-beta signaling in cell by the competition with SMAD2/3 cofactors. Among SMAD2/3 cofactors, SMAD2/3 binding domains of SARA, FOXH1 and SKI were fused in tandem, and their SMAD2/3 binding abilities were evaluated by surface plasmon resonance assay. One of the peptide aptamers binds strongly to SMAD2/3 with dissociation constants of nanomolar order. In addition, we have determined the crystal structures of SMAD2/3-cofactor complexes and presented the results as papers.

Academic Significance and Societal Importance of the Research Achievements

TGF-βシグナル伝達の異常は、がんの悪性化や線維症の発症など重篤な疾病と関連している。これらの疾病の治療において、TGF-βシグナル伝達系は有望な創薬ターゲットと考えられているが、その制御はシグナルの上流部分を対象とすることがほとんどであった。本研究では、シグナル下流で生じる生命現象（タンパク質分子間相互作用）に着目し、その制御を目指した。本研究の成果に基づき、シグナル伝達系下流における制御が可能となれば、より副作用の少ない形でTGF-βシグナルが制御できるようになると期待され、がんや線維症の新たな治療法の開発へとつながる可能性がある。

Research Products

• [Journal Article] Structural basis for receptor-regulated SMAD recognition by MAN1 (2018)
  • Author(s): Miyazono Ken-ichi、Ohno Yosuke、Wada Hikaru、Ito Tomoko、Fukatsu Yui、Kurisaki Akira、Asashima Makoto、Tanokura Masaru
  • Journal Title: Nucleic Acids Research Volume: 46 Issue: 22 Pages: 12139-12153
  • DOI: 10.1093/nar/gky925
  • Peer Reviewed / Open Access
• [Journal Article] Hydrophobic patches on SMAD2 and SMAD3 determine selective binding to cofactors. (2018)
  • Author(s): K. Miyazono, S. Moriwaki, T. Ito, A. Kurisaki, M. Asashima, M. Tanokura.
  • Journal Title: Sci. Signal. Volume: 11 Issue: 523
  • DOI: 10.1126/scisignal.aao7227
  • Peer Reviewed / Open Access
• [Presentation] TGF-βシグナル伝達系における主要転写因子SMAD2/3の補因子選択機構 (2018)
  • Author(s): 宮園健一、森脇沙帆、大野陽介、和田ひかる、伊藤友子、栗崎晃、浅島誠、田之倉優
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] TGF-βシグナル伝達系における主要転写因子SMAD2/3の補因子選択機構 (2018)
  • Author(s): 宮園健一、森脇沙帆、大野陽介、和田ひかる、伊藤友子、栗崎晃、浅島誠、田之倉優
  • Organizer: 日本結晶学会 2018年度年会
• [Remarks] TGF-βシグナルが多様な生命現象を制御できる仕組みの一端を解明
  • URL: http://www.a.u-tokyo.ac.jp/topics/2018/20180328-1.html