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Establishment and Analysis of mice disrupted with DNAM-1 gene

Research Project

Project/Area Number 10833002
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 免疫の制御機構
Research InstitutionUniversity of Tsukuba

Principal Investigator

SHIBUYA Akira  Institute of Basic Medical Sciences, University of Tsukuba Associate Professor, 基礎医学系, 助教授 (80216027)

Co-Investigator(Kenkyū-buntansha) SHIBUYA Kazuko  Institute of Basic Medical Sciences, University of Tsukuba Assistant Professor, 基礎医学系, 講師 (00302406)
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 1999: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1998: ¥1,600,000 (Direct Cost: ¥1,600,000)
KeywordsDNAM-1 / Adhesion Molecules / Lymphocyte / 細胞障害性リンパ球
Research Abstract

DNAM-1 is a signal transducing adhesion molecule involved in the cytolytic function mediated by CTL and NK cells. Cross-linking DNAM-1 with anti-DNAM-1 mAb induces cytolysis mediated by CTL and NK cells and also results in tyrosine phosphorylation of the DNAM-1 molecule. We studied regulation of DNAM-1-mediated signaling and adhesion. We report here that specific inhibitors of PKC activity prevented DNAM-1-mediated cytolytic activation of NK cells. Adhesion of DNAM-1 to its ligand does not require divalent cations, such as magnesium or calcium, and is regulated by PKC, as demonstrated by augmentation of DNAM-1 adhesion by PMA and inhibition by specific PKC inhibitors. Mutation of the putative PKC binding site in the cytoplasmic domain of DNAM-1 (SerィイD1329ィエD1 to PheィイD1329ィエD1) prevents ligand binding and PMA-induced serine phosphorylation of the DNAM-1 receptor. These results indicate that PKC phosphorylates SerィイD1329ィエD1 of DNAM-1 and plays a critical role for both DNAM-1 adhesion and signaling.
Whereas ligation of DNAM-1 adhesion molecule triggers cytotoxicity mediated by normal NK and T cells, this function was defective in NK cell clones from leukocyte adhesion deficiency syndrome. However, genetic reconstitution of cell surface expression of LFA-1 restored the ability of DNAM-1 to initiate anti-DNAM-1 mAb induced cytotoxicity, indicating a functional relationship between DNAM-1 and LFA-1. Further studies demonstrated that LFA-1 physically associates with DNAM-1 in NK cells and anti-CD3 mAb stimulated T cells, for which serine phosphorylation of DNAM-1 plays a critical role. In addition, cross-linking of LFA-1 induces tyrosine phosphorylation of DNAM-1, for which the fyn protein tyrosine kinase is responsible. These results indicate that DNAM-1 is involved in the LFA-1-mediated intracellular signals.

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (7 results)

All Other

All Publications (7 results)

  • [Publications] Shibuya A.et al.: "Protein-kinase C in involved in the regulation of both signaling and adhesion mediated DNAM-1"J. Immunology. 161. 1671-1676 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Shibuya K.et al.: "Physical and functional association of LFA-1 with DNAM-1 adhesion molecule"Immunity. 11. 615-623 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Shibuya A., Lanier LL., Phillips JH.: "Protein kinase C is involved in the regulation of both signaling and adhesion mediated by DNAM-1 receptor."J. Immunol.. 161. 1671-1676 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Shibuya K., Lanier LL., Phillips JH., Ochs D., Shimizu K., Nakayama E., Nakauchi H., Shibuya A.: "Physical and functional association of LFA-1 with DNAM-1 adhesion molecule."Immunity. 11. 615-623 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Shibuya, A, et al: "Protein kinase C is involved in the regulation of both signaling and adresion mediated DNAM-1"J. Immunology. 161. 1671-1676 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Shibuya, K. et al: "Physical and functional association of LFA-1 with DNAM-1 adhesion molecule"Immunity. 11. 615-623 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Shibuya,A,et al: "Protein kinase C is involved in the regulation of both signaling and adhesion mediated by DNAM-1" J.Immunology. 161. 1671-1676 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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