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Distinct roles of Chk and Csk in regulation of Src family kinases in hematopoietic cells

Research Project

Project/Area Number 09671124
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionKumamoto University

Principal Investigator

YAMAGUCHI Naoto  School of Medicine, Associate professor, 医学部, 助教授 (00166620)

Co-Investigator(Kenkyū-buntansha) SUDA Toshio  School of Medicine, Professor, 医学部, 教授 (60118453)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1998: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1997: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsCD36 / cell spreading / Csk homologous kinase (Chk) / fibronectin / integrin VLA5 / platelet / Src family kinase Lyn / thrombin / Csk / Src型チロシンキナーゼ / Lyn / インテグリン VLA5 / 細胞接着 / Csk homologous kinase (Chk) / translocation / チロシンリン酸化
Research Abstract

Src family protein-tyrosine kinases play crucial roles in regulating proliferation and differentiation of multiple cell types including hematopoietic cells. The activity of Src family kinases is tightly regulated by tyrosine phosphorylation and dephosphorylation events. The C-terminal Src kinase (Csk), which is expressed ubiquitously, has been shown to phosphorylate the C-terminal negative regulatory tyrosine residue of Src family kinases and suppress their kinase activity. A second member of the Csk family expressed in hematopoietic cells was recently identified as the Csk homologous kinase (Chk).
To understand the significance of co-expression of Chk and Csk in hematopoietic cells, we examined the subcellular localization of each protein. Chk but not Csk was localized close to CD36 (membrane glycoprotein IV)-anchored Lyn, and the kinase activity of Lyn was selectively suppressed. Upon stimulation with thrombin, the rapid and complete translocation of Chk away from CD36-anchored Lyn ca … More used concomitant activation of Lyn. The activation was accompanied by dephosphorylation of Lyn at its C-terminal negative regulatory tyrosine in cooperation with a protein tyrosine phosphatase. We propose that Chk but not Csk functions as a translocation-controlled negative regulator of CD36-anchored Lyn in thrombin-induced platelet activation.
To further examine die role of Chk in hematopoietic cells, we overexpressed Chk in the megakaryocytic cell line Dami. Overexpression of Chk suppressed VLA5 integrin-mediated cell spreading, but not cell attachment, throughout fibronectin stimulation. This suppression was dependent upon both the SH3 domain, which is responsible for membrane anchoring, and kinase activity. Sustained activation of Lyn, which is regulated by membrane-anchored Chk, was required for VLA5-mediated cell spreading on a fibronectin substrate.
Thus, these results suggest that Chk, unlike Csk, negatively regulates Src family kinases in vivo with selectivity toward Lyn and acts as a fine regulator in hematopoietic cells. Less

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (18 results)

All Other

All Publications (18 results)

  • [Publications] Hirao A: "Translocation of the Csk homologous kinase(Chk/Hyl)controls activity of CD36-anchored Lyn tyrosine kinase in thrombin-stimulated platelets." EMBO J. 16. 2342-2351 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hirao A: "Overexpression of C-terminal Src kinase homologous kinase suppresses activation of Lyn tyrosine kinase required for VLA5-mediated Dami cell spreading." J Biol Chem. 273. 10004-10010 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Sakamoto O: "Role of macrophage-stimulating protein and its receptor, RON tyrosine kinase, in ciliary motility." J Clin Invest. 99. 701-709 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Mera A: "Induction of cell shape changes through activation of the interleukin 3 common beta chain receptor by the RON receptor-type tyrosine kinase." J Biol Chem. (in press). (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tada J: "A common signaling pathway via Syk and Lyn tyrosine kinases generated from capping of the sialomucins CD34 and CD43 in immature hematopojetic cells." Blood. (in press). (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tada J: "Leukocyte Typing VI - White cell differentiation antigens." Garland Publishing, Inc., 1342 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hirao A et al.: "Translocation of the Csk homologous kinase (Chk/Hyl) controls activity of CD36-anchored Lyn tyrosine kinase in thrombin-stimulated platelets." EMBO J.16. 2342-2351 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hirao A et al.: "Overexpression of C-terminal Src kinase homologous kinase suppresses activation of Lyn tyrosine kinase required for VLA5-mediated Dami cell spreading." J.Biol.Chem.273. 10004-10010 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Sakamoto O et al.: "Role of macrophage-stimulating protein and its receptor, RON tyrosine kinase, in ciliary motility." J.Clin.Invest.99. 701-709 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Mera A et al.: "Induction of cell shape changes through activation of the interleukin-3 common beta-chain receptor by the RON receptor-type tyrpsine kinase." J.Biol.Chem.(in press). (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tada J et al.: "A common signaling pathway via Syk and Lyn tyrosine kinases generated from capping of the sialo-mucins CD34 and CD43 in immature hematopoietic cells." Blood. (in press). (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tada J et al.: "Leukocyte Typing VI" White Cell Differentiation Antigens (Kishimoto T et al eds), (Cross-linking of CD34 on hematopoietic cells reduces homotypic cell adhesion via clustering of CD 34 and mobilization of adhesion molecules.Garland Publishing Inc., New York, 982-984 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hirao A: "Overexpression of C-terminal Src kinase homologous kinase suppresses activation of Lyn tyrosine kinase required for VILA5-mediated Dami Cell Spreading." J.Biol.Chem.273. 10004-10010 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tada J: "A common signaling pathway via Syk and Lyn tyrosine kinase generated from Capping of the sialomucins CD34 and CD43 in immature hematopoietic cells." Blood. in press. (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Mera A: "Induction of cell shape changes through activation of the interleukin-3 common beta-chain receptor by the RON receptor-type tyrosine kinase" J.BIol.Chem.in press. (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Hirano A: "Translocation of the Csk homologous kinase (chk/Hyl) controls activity of CD36-anchored Lyn tyrosine kinase in thrombin-stimulated platelets." EMBO J.16. 2342-2351 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Hirao A: "Overexpression of Csk homologous kinase (chk) supresses activation of Lyn tyrosine kinase required for VLA5-mediated Dami cell spreading." J. Biol. Chem.(in press).

    • Related Report
      1997 Annual Research Report
  • [Publications] Sakamotro O: "Role of macrophase-stimulating protein and its receptor, RON tyrosine kinase, in ciliary motility." J. Clin. Invest.99. 701-709 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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