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B細胞の抗原認識と活性化制御

Research Project

Project/Area Number 12051239
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionKansai Medical University

Principal Investigator

黒崎 知博  関西医科大学, 医学部, 教授 (50178125)

Co-Investigator(Kenkyū-buntansha) 阪口 薫雄  熊本大学, 医学部, 教授 (70192086)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥78,300,000 (Direct Cost: ¥78,300,000)
Fiscal Year 2002: ¥26,400,000 (Direct Cost: ¥26,400,000)
Fiscal Year 2001: ¥27,000,000 (Direct Cost: ¥27,000,000)
Fiscal Year 2000: ¥24,900,000 (Direct Cost: ¥24,900,000)
KeywordsBCR / BLNK / BCAP / GANP / PLC-γ2 / c-Rel / PI-3K / α4 / MCM3
Research Abstract

ITAMに含まれるチロシン残基がリン酸化されることがBCRシグナルを展開する上で必須であり、なおかつ細胞内タンパク質のチロシンリン酸化がBCR刺激後一番最初に検出できる生化学的反応という事実に基づき、1990年代チロシンキナーゼ群(PTKs)のBCRシグナルにおける役割が活発に検討されてきた。特に、Lyn,Syk,BtkのBCRシグナルにおける重要性、およびLyn,Syk,Btkの活性化機構が明らかにされてきた。
このような今までの成果を踏まえて、B細胞の活性化を担っているアダプター分子、BLNK,BCAPを単離しその役割解明、又細胞表面レセプター、特にB細胞レセプター(BCR)とのカップリング機構の解明を行った。BLNKはPLC-γ2活性化に必須の分子であることをすでに明らかにしていたが、PLC-γ2のみならず、Vavの活性化にも必須であること、さらにVavの活性化にはBLNKがVavをGEM分画にholdすることにより生じていることを明らかにした。
BCAPノックアウトマウスにおいては、B2 B細胞の最終分化が障害を受けていることを既に明らかにしていたが、その原因が、転写因子c-Relのdown-regulationであることを見出した。B細胞の核内で起こる分子メカニズムについては核内因子GANPを単離し、GANPはDNAプライマーゼ活性をもち、DNAヘリカーゼ活性を有するMCMと結合することにより、胚中心B細胞における細胞増殖を制御している機能分子である可能性を示した。

Report

(3 results)
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (13 results)

All Other

All Publications (13 results)

  • [Publications] Yamazaki, T., Takeda, K., Gotoh, K., Takeshima, H., Akira, S., Kurosaki, T.: "Essential immunoregulatory role for BCAP in B cell development and function"J. Exp. Med.. 195. 535-545 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Mori, Y., Wakamori, M., Miyakawa, T., Hermosura, M., Hara, Y., Nishida, M., Hirose, K., Mizushima, A., Kurosaki, M., Mori, E., Gotoh, K., Okada, T., Fleig, A., Penner, R., Iino, M., Kurosaki.T.: "Transient receptor potential 1 regulates capacitative Ca^<2+> entry and Ca^<2+> release from endoplasmic reticulum in B lymphocytes"J. Exp. Med.. 195. 673-681 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yasuda, T., Tezuka, T., Maeda, A., Inazu, T., Yamanashi, Y., Gu, H., Kurosaki, T., Yamamoto, T.: "Cbl-b positively regulates Btk-mediated activation of phospholipase C-γ2 in B cells"J. Exp. Med.. 196. 51-63 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kuwahara, K. et al.: "Germinal center-associated nuclear protein(GANP) has a phosphorylation-dependent DNA-primase activity that is up-regulated in germinal center regions"Proc.Natl.Acad.Sci.U.S.A.. 98. 10279-10283 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Igarashi, H. et al.: "Localization of recombination activating gene 1/green fluorescent protein (RAG1/GFP)expression in secondary lymphoid organs after immunization with T-dependent antigens in rag1/gfp knockin mice"Blood. 97. 2680-2687 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Inabe, K. et al.: "Tyrosine phosphorylation of B-cell adaptor for phosphoinositide 3-kinase is required for Akt activation in response to CD19 engagement"Blood. 99. 584-589 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Inabe, K. et al.: "Vav3 modulates B cell receptor responses by regulating phosphoinositide 3-kinase activation"J.Exp.Med.. 195. 189-200 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Inui, S. et al.: "BCR signal through α4 is involved in S6 kinase activation and required for B cell maturation including isotype switching and V region somatic hypermutation"Int.Immunol.. 14. 177-187 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yamazaki, T. et al.: "Essential immunoregulatory role for BCAP in B cell development and function"J.Exp.Med.. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yasuda,T. et al.: "Cbl suppresses B cell receptor-mediated phospholopase C (PLC)-γ 2 activation by regulating B cell linker protein-PLC-γ2 binding."J.Exp.Med.. 191. 641-650 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ishiai,M. et al.: "Involvement of LAT, Gads, and Grb2 in compartmentation of SLP-76 to the plasma membrane."J.Exp.Med.. 192. 847-856 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Okada,T. et al.: "BCAP : The tyrosine kinase substrate that connects B cell receptor to phosphoinositide 3-kinase activation."Immunity. 13. 817-827 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kuwahara,K. et al.: "A novel nuclear phosphoprotein GANP is upregulated in centrocytes of the germinal center and is associated with MCM3, a protein essential for DNA replication."Blood. 95. 2321-2328 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2018-03-28  

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