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Molecular mechanisms of lymphocyte proliferation during the development

Research Project

Project/Area Number 09470093
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Immunology
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

MINATO Nagahiro  Kyoto University.Dept.of.Immunol.Prof., 医学研究科, 教授 (40137716)

Co-Investigator(Kenkyū-buntansha) IWAI Kazuhiro  Kyoto University.Dept.of.Immunol.Assist.Prof., 医学研究科, 助教授 (60252459)
HATTORI Masakazu  Kyoto University.Dept.of.Immunol.Assist.Prof., 医学研究科, 助教授 (40211479)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥13,100,000 (Direct Cost: ¥13,100,000)
Fiscal Year 1998: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1997: ¥9,900,000 (Direct Cost: ¥9,900,000)
KeywordsSmall GTPases / Rap 1 / Ras / Cytaskleton / Signal transduction / Antigen receptors / Immune response / GTPase activating protain(GAP) / アナ-ジ- / バキュロウイルス / 低分子量G蛋白 / クローン増巾 / GTPase活性化蛋白
Research Abstract

We have isolated a new gene termed Spa-I that is predominantly expressed in the Iymphohematopoietic tissues, and indicated that Spa-I encodes a protein SPA-I which exhibits specific GTPase-activating activity (GAP) for Ras-related small GTPase Rap1 in vitro. In the present study, we have proved that SPA-l indeed exhibits Rap1 GAP activity in the cells, counteracting the GDP/GTP exchanger activity of C3G for Rapt. Transfection experiments indicated that overexpression of SPA-I induced cell rounding and detachment, while C3G overexpression resulted in the enlargement and extensive spreading of cells, strongly suggesting that SPA-I controls cell morphology and adherence via regulation of Rapt. SPA-I was shown to be associated with cytoskeleton in the cells. In lymphocytes, SPA-I also regulates Rap1 activation downstream of antigen receptors. By using antigen specific T cell clones, it has been indicated that Rapl is activated by antigenic stimulation in a distinct kinetics with Ras. Furthermore, Rap1 was activated selectively by the suboptimal stimulation in the absence of co-receptor engagement, while Ras was activated only in the presence of co-receptor engagement. The activation of Rapl in the optimal antigenic stimulation was strongly suggested to be suppressed by the activation of SPA-1. These results have strongly suggested that Rapl mediates a distinct, possibly compensatory signals from Ras downstream of antigen receptors. To gain the distinct insights for the enigmatic Rapl and SPA-1 in the immunological responsiveness of lymphocytes, we have recently succeeded in establishing Spa-1 gene-targeted mice. Analysis of immune responsiveness in such mice should help to understand the roles Rapl and Spa-I play in vivo.

Report

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

    (23 results)

All Other

All Publications (23 results)

  • [Publications] Noriyuki Tsukamoto, et al: "Rap1 GTPase-activating protein SPA-1 negatively regulates cell adhesion" J.Biol.chem. (印刷中). (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Koichi Tomita, et al: "The bHLH gene Hes1 is essential for expansion of early T cell precursors" Genes and Development. (印刷中). (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Eijiro Nakamura, et al: "4F2/CD98 Heary Chain Covalently Associates with LAT1 Amino Acid Transprter and Dictates Membrane Targeting and Topology of 4F2/CD98 Heterodimer" J.Biol.chem.274. 3009-3016 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hiroyuki Nishimura, et al: "Inmunalogical & tudios on PD-1 deficient noice : Implication of PD-1 as a negative regulator for B cell responses" Int.Immunol. 10. 1563-1572 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Junichi Yamaoka, et al: "Superantigon activity is responsible for the induction of shin erythemo by streptocaccal phrogonic endotoxin C : A mutational anlysis" Infection and Immunity. 66. 5020-5026 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kazuhiro Iwai, et al: "Inon-dependent oxidation, Ubiquitination and degradation of IRP2 : complications for degradation of oxidiyed proteins" Proc.Natl.Acad.Sci.USA. 95. 4924-4928 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tsukamoto, N., Hattori, M., Yang, H., Bos, J.L., and Minato, N.: "Rap1 GTPase-activating protein SPA-1 negatively regulates cell adhesion" J.Biol.Chem.(In the press). (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tomita, K., Hattori, M., Nakamura, E., Nakanishi, S., Minato, N., and Kageyama, R.: "The bHLH gene Hes1 is essential for expansion of early T cell precursors." Genes and Development. (In the press). (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Nakamura, E., Sato, M., Yang, H., Harazaki, M., Matsuoka, H., Noma, A., Iwai, K., and Minato, N.: "4F2/CD98 Heavy Chain Covalently Associates With LAT1 Amino Acid Transporter And Dictates Membrane Targeting And Topology of 4F2/CD98 Heterodimer." J.Biol.Chem.274. 3009-3016 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Nishimura.H., Nakano.T., Minato.N., and Honjo.T: "Immunological studies on PD-1 deficient mice : Implication of PD-1 as a negative regulator for B cell responses." Int.Immunol.10. 1563-1572 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yamaoka, J., E.Nakamura, Y.Takeda, S.Imamura, and N.Minato: "Superantigen activity is responsible for the induction of skin erythema by streptococcal pyrogenic endotoxin C : A mutational anlysis." Infection and Immunoty. 66. 5020-5026 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Iwai, K., S,K.Drake, N.B.Wehter, A.M.Wessman, T.La Vaute, N.Minato, R.D.Klausner, R.L.Levine, and T.A.Rouault.: "Iron-dependent oxidation, ubiquitination and degradation of IRP2 ; implications for degradation of oxidized proteins." Proc.Natl.Acad.Sci.USA 95. 4924-4928 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Noriyuki Tsukamoto,et al.: "Rap1GTPase-activating protein SPA-1 negatively regulates cell adhesion." J.Biol.Chem.(印刷中). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Koichi Tomita,et al.: "The bHLH gene Hes1 is essential for expansion of early T cell precursors." Genes and Development. (印刷中). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Eijiro Nakamura,et al.: "4F2/CD98 Heavy Chain Covalently Associates with LAT1 Amino Acid Transporter And Dictates Membrane Targeting And Topology of 4F2/CD98 Heterodimer." J.Biol.Chem.274. 3009-3016 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Hiroyuki Nishimura,et al.: "Immunological Studies on PD-1 dificient mice:Implication of PD-1 as a negative regulator for B cell responses." Int.Immunol.10. 1563-1572 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Junichi Yamaoka,et al.: "Superantigen actirity is responsible for the induction of skin erythema by streptococcat pyrogenic endotoxin C:A mutational anlysis." Infection and Immunity. 66. 5020-5026 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kazuhiro Iwai,et al.: "Iron-dependent oxidation,Ubiquitination and degradation of IRP:implications for degradation of oxidized proteins." Proc.Natl.Acad.Sci.USA. 95. 4924-4928 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kazuhiro Iwai, et al.: "Iron-dependent oxidation,ubiquitiration and degradation of IRP2;implications for degradation of oxidized proteins." Proc.Natl.Acad.Sci.USA. (印刷中). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Hironori Kurachi, et al.: "Human SPA-1 Gene Product Selectively Expressed in Lymphoid Tissues is a Specific GTPase-activating Protein for Rap1 and Rap2.Segregate expression profiles from a rap1 GAP gene product" J.Biol.Chem.272. 28081-28088 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Eijiro Nakamura, et al.: "Involvement of NK1^+CD4^-CD8^- abT cells and endogenous interleukin 4 in non-MHC restricted rejection of embryonal carcinoma in genetically resistant mice." J.Immunol.158. 5338-5348 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yasuo Wada, et al.: "Mitogen-inducible SPA-1 is mapped at the conserved syntenic groups of the chromosome 19 in mouse and chromosome 11q13.3 centromeric to BCL1 in human." Genomics. 39. (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yasuo Wada, et al.: "Mitogen-inducible SPA-1 is mapped at the conserved syntenic groups of the chromosome 19 in mouse and chromosome 11q13.3 centromeric to BCL1 in human." Genomics. 39. (1997)66-73

    • Related Report
      1997 Annual Research Report

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

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