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1999 Fiscal Year Final Research Report Summary

Functional analysis of Syk substrates in B cell receptor signaling

Research Project

Project/Area Number 09470099
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Immunology
Research InstitutionKansai Medical University

Principal Investigator

KUROSAKI Tomohiro  Kansai Medical University, Department of Medicine, Professor, 医学部, 教授 (50178125)

Co-Investigator(Kenkyū-buntansha) ADACHI Takahiro  Tokyo Medical and Dental University, Medical Research Institute, Department of Immunology, Asistant Professor, 難治疾患研究所, 講師 (50222625)
Project Period (FY) 1997 – 1999
KeywordsBCR signaling / Syk / adaptor molecule / BLNK / PLC-γ2
Research Abstract

The ability of B cells to respond to antigen relies on signals transmitted through the B cell antigen receptor (BCR) complex. Activation of cytoplasmic protein tyrosine kinases (PTKs) is the earliest measurable biochemical response to BCR cross-linking. The initial event leads to the generation of secondary signals including Ras activation, phosphatidylinositol 3-kinase (PI-3K) activation, phospholipase C (PLC)-γ2 activation.
While much has been learned as to the relationship between the BCR-associated PTKs and downstream effectors, the molecular mechanism by which these PTKs regulate downstream events remains unclear. Analogous to receptor tyrosine kinases, it has been thought that many signaling molecules directly bind phosphorylated tyrosine residues on the cytoplamic domains of the BCR complex. However, this does not appear to be a feature of the coupling mechanism to downstream signaling pathways. Attention instead has focused on adaptor proteins.
Based upon our previous evidence that Syk, among the BCR-associated PTKs, is essential for PLC-γ2 activation, we purified tyrosine-phosphorylated proteins mediated by Syk. Among several purified proteins, four internal peptide sequences obtained from microsequencing of pp80 were very homologous to those of human and mouse BLNK. To address the function of BLNK, we established DT40 B cells deficient in BLNK by genetargeting method. In contrast to wild-type DT40 cells, no PLC-γ2 activation was detected in BLNK-deficient cells. Taken together, we conclude that BLNK functions as an adaptor molecule in BCR signaling, which is required for coupling Syk to PLC-γ2 activation.

  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] Ishiai, M. et al.: "BLNK required for coupling Syk to PLCγ2 and Racl-JNK in B cells"Immunity. 10. 117-125 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ishiai, M. et al.: "Associattion of Phospholipase C-γ2 Src homology 2 domains with BLNK is critical for B cell antigen receptor signaling"J. Immunol.. 163. 1746-1749 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] DeBell, K. E. et al.: "Functional independence and interdependence of the Src-homology domains of phospholipase C-γ1 in B-cell receptor signal transduction"Mol. Cell. Biol.. 19. 7388-7398 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kurosaki, T.: "Genetic analysis of B cell antigen receptor signaling"Annu. Rev. Immunol.. 17. 555-592 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kurosaki, T. et al.: "BLNK : Connecting Syk and Btk to calcium signals"Immunity. 12. 1-5 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kurosaki, T.: "Functional dissection of BCR signaling molecules"Curr. Opin. Immunol.. (in press). (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ishiai, M. et al.: "BLNK required for coupling Syk to PLCγ2 and Racl-JNK in B cells."Immunity. 10. 117-125 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ishiai, M. et al.: "Association of Phospholipase C-γ2 Src homology 2 domains with BLNK is critical for B cell antigen receptor signaling."J. Immunol.. 163. 1746-1749 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] DeBell, K.E. et al.: "Functional independence and interdependence of the Src-homology domains of phospholipase C-γ1 in B-cell receptor signal transduction."Mol. Cell. Biol.. 19. 7388-7398 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kurosaki, T.: "Genetic analysis of B cell antigen receptor signaling."Annu. Rev. Immunol.. 17. 555-592 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kurosaki, T. et al.: "BLNK : Connecting Syk and Btk to calcium signals."Immunity. 12. 1-5 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kurosaki, T.: "Functional dissection of BCR signaling molecules."Curr. Opin. Immunol.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2001-10-23  

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