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Intracellular signal transduction by SH3 domain-containing proteins

Research Project

Project/Area Number 09670134
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General medical chemistry
Research InstitutionKYUSHU UNIVERSITY

Principal Investigator

SUMIMOTO Hideki  KYUSHU UNIV., SCH.MEDICINE,PROFFESOR, 医学部, 教授 (30179303)

Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1998: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1997: ¥1,700,000 (Direct Cost: ¥1,700,000)
KeywordsSH3 Domain / p47^<phox> / p67^<phox> / NADPH Oxidase / p40^<phox> / Rac / Cytochrome b_<558> / Rac. / シトクローム=_<558> / p22^<phox> / 殺菌 / スーパーオキシド
Research Abstract

In this project we have studied molecular mechanism by which p47^<phox> and p67^<phox>, each containing two SH3 domains, activate the phagocyte NADPH oxidase, to obtain the following results. (1) The SH3 domains of p47^<phox> are masked via intramolecular interaction with its C-terminal region. The interaction is disrupted by arachidonic acid or by phosphorylation of three serine residues in the p47^<phox> C-terminus, which allows the domains to bind to cytochrome b_<558>, the enzymatic core of the oxidase. The intermolecular interaction functions as a switch for the oxidase activation. (2) The two SH3 domains are tandemly arranged with a linker of 10 amino acid residues. The length of the linker plays an important role in both intramolecular and intermolecular interactions. (3) Another switch for the activation is conversion of the small GTPase Rac to the GTP-bound active state, which leads to interaction with p67^<phox>. This binding is mediated via the TPR domain of the latter protein. (4) We have developed a novel method to detect the GTP-bound Rac at a cell level. Using this procedure, we find that Rac activation of human neutrophils stimulated with G1-coupled receptor agonists requires phosphoinositide 3-kinase. (5) Discovered is a novel module in the N-terminus of p47P^<phox>, designated PB2 domain, that positively regulates the oxidase activation. (6) The oxidase regulator p4O^<phox> constitutively associates with p67^<phox>, which is mediated via a novel type of interaction between two modules that are discoverd in this project : the PB 1 domain of p67PhOx and the PC motif of p40^<phox>.

Report

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

    (25 results)

All Other

All Publications (25 results)

  • [Publications] Kenichiro Hata: "Anionic Amephiphile-independent Activation of the Phagocyte NADPH Oxidase in a Cell-free System by p47^<phox> and p67^<phox>, Both in C Terminally truncated Forms" THE JOURNAL OF BIOLOGICAL CHEMISTRY. 273・7. 4232-4236 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kazuhito MIZUKI: "Functional modules and expression of mouse p40^<phox> and p67^<phox>,SH3-domain-containing proteins in voled in the phagocyte NADPH oxidase complex" European Journal of Biochemistry. 573-582 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Rila NAKAMURA: "The PC motif : a novel and evolutionarily conserved sequence in volved in interaction between p40^<phox> and p67^<phox>, SH3 domain-containing cytosolic factors of the phagocyte NADDH oxidase" European Journal of Biochemistry. 583-589 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yasushi Kikuta: "Purification and characterization of Recombinant Human Neutrophil Leukotriene B_4 ω-Hydroxylase(Cytochrome p450 4F3)" ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS. 355・2. 201-205 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Higasa, K.: "Molecular basis of hereditary methemoglobinemia, types I and II : two novel mutations in the NADPH-cytochrome b_5 reductasegene" British Journal of Haematology. 922-930 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Izuhara, K.: "Association of the interleukin-4 receptor α chain with p47^<phox>,an activator of the phagocyte NADPH oxidase in B cells" Molecular Immunology. (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] Hata, K., et al.: "Anionic Amphiphile-independent Activation of the Phagocyte NADPH Oxidase in a Cell-free System by p47^<phox> and p67^<phox>, Both in C Terminally Truncated Forms : Implication for regulatory SH3 domain-mediated interactions." Journal of Biological Chemistry. 273. 4232-4236 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Mizuki, K., et al.: "Functional modules and expression of mouse p40^<phox> and p67^<phox>, SH3 domain-containing proteins involved in the phagocyte NADPH oxidase complex." European Journal of Biochemistry. 251. 573-582 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Nakamura, R., et al.: "PC Motif : A novel and evolutionarily conserved sequence involved in interaction between p40^<phox> and p67^<phox>, SH3 domain-containing cytosolic factors of the phagocyte NADPH oxidase." European Journal of Biochemistry. 251. 483-589 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kikuta, Y., et al.: "Purification and Characterization of Recombinant Human Neutrophil Leukotriene B_4omega-Hydroxylase (Cytochrome P450 4F3)." Archives of Biochemistry and Biophysics. 355. 201-205 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Higasa, K., et al.: "Molecular basis of hereditary methemoglobinemia, types I and II : two novel mutations in the NADH-cytochrome b_5 reductase gene." British Journal of Haematology. 103. 922-930 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Izuhara, K., et al.: "Association of the interleukin-4 receptor alpha chain with p47^<phox>, an activator of the phagocyte NADPH oxidase in B cells." Molecular Immunology. (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] Hata, K., et al.: "Roles for proline-rich regions of p47^<phox> and p67^<phox> in the phagocyte NADPH oxidase activation in vitro." Biochemical and Biophysical Research Communications. 241. 226-231 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Sumimoto, H., et al.: Membrane Proteins : Structure, Function and Expression Control. Kyushu University Press/Basel, S.Karger AG, 413 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kenichiro Hata: "Anionic Amphiphile-independent Activeation of the Phagoeyte NADOH Oxidase in a Cell-free system by p47^<phox> and p67^<phox>, Both in C Terminally truncated Forms" THE JOURNAL OF BIOLOGICAL CHEMISTRY. 273・7. 4232-4236 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kazuhito MIZUKI: "Functional modules and expression of mousep40^<phox> and p67^<phox>, SH3-domain-containing proteins in voled in the phagocyte NADPH oxidase complex" European Journal of Biochemistry. 573-582 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Rila NAKAMURA: "The PC motif: a novel and evolutionarily conserved Sequence in volved in interaction between p40^<phox> and p67^<phox>, SH3 domain-containing cytosolic factors of the phagocyte NADPH oxidase" European Journal of Biochemistry. 583-589 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yasushi Kikuta: "Purification and characteriztion of Rercombinant Human Neutrophil Leukotriene B4 W-Hydroxylase (Cytochrome p450 4F3)" ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS. 355・2. 201-205 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Higosa,K.: "Molecular basis of hereditary methemoglobinemia, types I and II: two novel mutations in the NADPH-cytochrome b5 euctasegene" British Journal of Haematology. 922-930 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 922-930: "Association of the interleukin-4 receptor and chain with p47^<phox>, an activator of the phagotyte NADPH oxidose in B cells" Molecular Immunology. (in press). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Hata,K.,et al.: "Anionic Amphiphile-independent Activation of the Phagocyte NADPH Oxidase in a Cell-free System by p47^<phox> and p67^<phox>,Both in C Terminally Trancated Forms" Journal of Biological Chemistry. 273・7. 4232-4236 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Mizuki,K.,et al.: "Functional Modules and Expression of Mouse p40^<phox> and p67^<phox>,SH3-domain-containing Proteins Involved in the Phagocyte NADPH Oxidase Complex" European Journal of Biochemistry. 251・3. 573-582 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Nakamura,R.,et al.: "The PC motif:a novel and evolutionarily conserved sequence involved in interaction between p40^<phox> and p67^<phox>,SH3-domain-containing cytosolic factcrs of the phagocyte NADPH oxidase" European Journal of Biochemistry. 251・3. 583-589 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Hata,K.,et al.: "Roles for Proline-Rich Regions of p47^<phox> and p67^<phox> in the Phagocyte NADPH Oxidase Activation in Vitro" Biochemical and Biophysical Research Communications. 241・2. 226-231 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Sumimoto,H.,et al.: "Membrane Proteins:Structure,Function and Expression Control" Kyushu University Press, 413 (1997)

    • Related Report
      1997 Annual Research Report

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

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