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Analysis of MAP kinase cascade in the immune response

Research Project

Project/Area Number 13670316
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Immunology
Research InstitutionMie University (2002)
Osaka University (2001)

Principal Investigator

OGATA Masato  Mie University, Faculty of Medicine, Professor, 医学部, 教授 (60224094)

Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2001: ¥2,000,000 (Direct Cost: ¥2,000,000)
KeywordsProtein Tyrosine Phosphatase / immune cells / MAP kinase / p38 / ERK
Research Abstract

Mitogen-activated protein kinases (MAPKs) such as p38 and ERK are key signaling molecules in the regulation of the immune system. Each MAPK has unique functions and redundant functions. Though the gene-knockout of each MAPK in mice is useful to elucidate the unique functions, it is difficult to find out its redundant functions. Therefore alternative approach using gain-of-function mutants of MAPK might be helpful.
1) Generation and analysis of constitutively active MAPK fusion molecules.
MKK6, a MAPKK (MAPK kinase) of p38, reveals a weak kinase activity without upstream activation signals. To create a constitutively active MAPK mutant, we fused MKK6 with p38α (MKK6-p38α). p38α in MKK6- p38α was constitutively phosphorylated and ATF2 reporter activity was augmented. Thus, it is possible to make a constitutively active p38 by fusing it to MKK6.
On the other hand, when MKK6-p38β was tested, p38β was constitutively phosphorylated but ATF2 reporter activity was not increased. Accession of MKK6-p38 with downstream substrates may be limited in some cases.
2) Establishment and analysis of MAPK^<sem>-knockin mice.
Sevenmaker (sem) is a single amino acid substitution of MAPK in the CD region. Others and we have demonstrated that p38^<sem> and ERK^<sem> fail to associate with protein-tyrosine-phosphatases and are resistant to inactivation by these phosphatases.
No hyperphosphorylation of p38 has been observed in the p38^<sem> knockin mice, so far. These mice are viable. It is possible that protein-tyrosine-phosphatases and a redundant phosphatase such as Wip1, a serine/threonine phosphatase, might be working in the negative regulation of p38.
In a sharp contrast, hyperphosphorylation of ERK was observed in the ERK^<sem> knockin mice. These mice revealed high perinatal morbidity. In the future project, it is possible to study the effect of ERK^<sem> in the immune system by conditional expression of ERK^<sem>.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (19 results)

All Other

All Publications (19 results)

  • [Publications] Kosugi, A., et al.: "Involvement of SHP-1 tyrosine phosphatase in TCR-mediated signaling pathways in lipid rafts : Targeting of activated SHP-1 to lipid rafts induces a defective function of LAT and impairs T cell activation after TCR engagement"Immunity. 14. 669-680 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Miyake, K., et al.: "Essential role of MD-2 in B-cell responses to lipopolysaccharide and Toll-like receptor 4 distribution"J Endotoxin Res.. 8. 449-452 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nagai, Y., et al.: "Essential role of MD-2 in LPS responsiveness and TLR4 distribution"Nat. Immunol.. 3. 667-672 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Uchida, Y., et al.: "Localization of PTP-FERM in nerve processes through its FERM domain"Biochem Biophys Res Commun.. 292. 13-19 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tanimura, N., et al.: "Dynamic changes in the mobility of LAT in aggregated lipid rafts upon T cell activation"J Cell Biol.. 160. 125-135 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Cottom, J., et al.: "Follicle-stimulating hormone activates extracellular signal-regulated kinase but not extracellular signal regulated kinase kinase through a 100 kDa phosphotyrosine phosphatase"J Biol Chem.. 278. 7167-7179 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kosugi,A.: "Involvement of SHP-1 tyrosine phosphatase in TCR-mediated signaling pathways in lipid rafts : Targeting of activated SHP-1 to lipid rafts induces a defective function of LAT and impairs T cell activation after TCR engagement"Immunity. 14. 669-680 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Miyake,K.: "Essential role of MD-2 in B-cell responses to lipopolysaccharide and Toll-like receptor 4 distribution"J Endotoxin Res.. 8. 449-452 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nagai,Y.: "Essential role of MD-2 in LPS responsiveness and TLR4 distribution"Nat.Immunol.. 3. 667-672 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Uchida,Y.: "Localization of PTP-FERM in nerve processes through its FERM domain"Biochem Biophys Res Commun. 292. 13-19 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tanimura,N.: "Dynamic changes in the mobility of LAT in aggregated lipid rafts upon T cell activation"J Cell Biol.. 160. 125-135 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Cottom,J.: "Follicle Stimulating Hormone Activates Extracellular Signal Regulated Kinases but not Extracellular Signal Regulated Kinase Kinase through a 100 kDa Phosphotyrosine Phosphatase"J Biol Chem.. 278. 7167-7179 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Miyake, K., et al.: "Essential role of MD-2 in B-cell responese to lipopolysaccharide and Toll-like receptor 4 distribution"J Endotoxin Res.. 8. 449-452 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nagai, Y., et al.: "Essential role of MD-2 in LPS responsiveness and TLR4 distribution"Nat. Immunol.. 3. 667-672 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Uchida, Y., et al.: "Localization of PTP-FERM in nerve processes through its FERM domain"Biochem Biophys Res Commun.. 292. 13-19 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tanimura, N., et al.: "Dynamic changes in the mobility of LAT in aggregated lipid rafts upon T cell activation"J Cell Biol.. 160. 125-135 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Cottom, J., et al.: "Follicle Stimulating Hormone Activates Extracellular Signal Regulated Kinases but Extracellular Signal Regulated Kinases Kinase through a 100 kDa Phosphotyrosine Phosphatase"J Biol Chem.. 278. 7167-7179 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Uchida Y., et al.: "Localization of PTP-FERM in nerve processes through its FERM domain"Biochm. Biophys. Res. Commun.. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kosugi, A., et al.: "Involvement of SHP-1 tyrosine phoshatase in TCR-mediated signaling pathways in lipid rafts : Targeting of activated SHP-1 to lipid rafts induces a defective function of LAT and impairs T cell activation after TCR engagement"Immunity. 14. 669-680 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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