Control of B cell differentiation by manipulation of signal dynamics

• Project/Area Number: 15K08534
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: SHINOHARA HISAAKI 国立研究開発法人理化学研究所, 統合生命医科学研究センター, 上級研究員 (10391971)
• Research Collaborator: Inoue Kentarou ; Hoffman Alexander
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000); Fiscal Year 2016: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: B細胞シグナル / 反応速度数理モデル / 分子活性動態 / シグナル活性動態 / B細胞 / 細胞分化 / シグナルネットワーク / シグナル動態 / 数理モデル解析 / 遺伝子発現解析 / シグナル動態制御 / 分化決定システム

Outline of Final Research Achievements

In the BCR signal, the elements necessary for activation of NF-κB were indeterminate. The applicant investigated physiologically and clarified that TAK1 is essential for B cell activation and cell differentiation (Immunol Cell Biol. 2016, Genes Cells. 2016). In addition, molecular based analysis showed that TAK1-associated molecule TAB 2/3 is essential for activation of NF-κB (FEBS Lett. 2016).
Applicant quantitatively measured cell input / output and using mathematical model analysis, revealed that IKK's steep activity kinetics are controlled by "positive Feedback mechanism" (NPJ Syst Biol. 2016). In parallel with these, I find a ubiquitinating enzyme IAP controls the activity dynamics of ERK and IKK using gene expression analysis and reaction rate mathematical model (Sci Rep. 2016). Furthermore, it is clarified that epigenetic control by BCR stimulation is also mediated by NF-κB (submitting).

Research Products

• [Int'l Joint Research] カリフォルニア大学ロサンゼル ス校/テキサス大学オースティン校/ミシガン大学(米国)
• [Int'l Joint Research] マックス・デルブリュック・セ ンター(ドイツ)
• [Journal Article] LRRK1 is critical in the regulation of B-cell responses and CARMA1-dependent NF-κB activation. (2016)
  • Author(s): Morimoto K, Baba Y, Shinohara H, Kang S, Nojima S, Kimura T, Ito D, Yoshida Y, Maeda Y, Sarashina-Kida H, Nishide M, Hosokawa T, Kato Y, Hayama Y, Kinehara Y, Okuno T, Takamatsu H, Hirano T, Shima Y, Narazaki M, Kurosaki T, Toyofuku T, Kumanogoh A.
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 25738-25738
  • DOI: 10.1038/srep25738
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Stimulus-Dependent Inhibitor of Apoptosis Protein Expression Prolongs the Duration of B Cell Signalling. (2016)
  • Author(s): Shinohara H, Inoue K, Yumoto N, Nagashima T, Okada-Hatakeyama M.
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 27706-27706
  • DOI: 10.1038/srep27706
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] TAK1 adaptor proteins, TAB2 and TAB3, link the signalosome to B-cell receptor-induced IKK activation. (2016)
  • Author(s): Shinohara H, Yasuda T, Kurosaki T.
  • Journal Title: FEBS Letters. Volume: 590 Issue: 18 Pages: 3264-3269
  • DOI: 10.1002/1873-3468.12342
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Negative role of TAK1 in marginal zone B-cell development incidental to NF-κB noncanonical pathway activation. (2016)
  • Author(s): Shinohara H, Kurosaki T.
  • Journal Title: Immunology and Cell Biology Volume: 94 Issue: 9 Pages: 821-829
  • DOI: 10.1038/icb.2016.44
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Oscillation Dynamics Underlies Functional Switching of NF-κB for B Cell Activation. (2016)
  • Author(s): Inoue K, Shinohara H, Behar M, Yumoto N, Tanaka G, Hoffmann A, Aihara K, Okada-Hatakeyama M.
  • Journal Title: npj Systems Biology and Applications Volume: 2 Issue: 1 Pages: 16024-16024
  • DOI: 10.1038/npjsba.2016.24
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] TAK1 maintains the survival of immunoglobulin λ-chain-positive B cells. (2016)
  • Author(s): Shinohara H, Nagashima T, Cascalho MI, Kurosaki T.
  • Journal Title: Genes to Cells Volume: 21 Issue: 11 Pages: 1233-1243
  • DOI: 10.1111/gtc.12442
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Negative role of TAK1 for marginal zone B-cell development incidental to activation of the NF-κB non-canonical pathway (2016)
  • Author(s): Shinohara H, Kurosaki T.
  • Journal Title: Immunology and Cell Biology Volume: 印刷中
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A.LRRK1 controls B-cell responses by regulating CARMA1-dependent NF-κB activation (2016)
  • Author(s): 3.Morimoto K, Baba Y, Shinohara H, Kang S, Nojima S, Kimura T, Ito D, Yoshida Y, Maeda Y, Sarashina-Kida H, Nishide M, Hosokawa T, Kato Y, Hayama Y, Yuhei K, Takamatsu H, Hirano T, Shima Y, Narazaki M, Kurosaki T, Toyofuku T, Kumanogoh A.
  • Journal Title: Scientific Reports Volume: 印刷中
  • Peer Reviewed / Open Access
• [Presentation] Integrated analysis of the dynamic gene expression regulated by NF-κB. (2016)
  • Author(s): Iwamoto K, Shinohara H, Hayashi T, Nikaido I, Suzuki Y and Okada M.
  • Organizer: International Conference on Systems Biology (ICSB 2016).
  • Place of Presentation: Barcelona, Spain.
  • Year and Date: 2016-09-16
  • Int'l Joint Research
• [Presentation] 免疫・生体応答を制御するシステムの探究 (2016)
  • Author(s): 篠原久明
  • Organizer: 九州工業大学：BMIRCセミナー
  • Place of Presentation: 九州工業大学 (福岡県飯塚市)
  • Invited