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Use of Wortmannin and its Derivatives for the Study on Phosphoinositide 3-Kinase

Research Project

Project/Area Number 09557192
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Biological pharmacy
Research InstitutionHIROSHIMA UNIVERSITY (1998)
The University of Tokyo (1997)

Principal Investigator

HIZEKI Osamu  Hiroshima University Faculty of Medicine Professor, 医学部, 教授 (80142751)

Co-Investigator(Kenkyū-buntansha) OKAMURA Naoki  Hiroshima University Faculty of Medicine Research Associate, 医学部, 助手 (30144827)
KUROKAWA Tomonori  Hiroshima University Faculty of Medicine Associate Professor, 医学部, 助教授 (00124793)
仁科 博史  東京大学, 大学院・薬学系研究科, 助手 (60212122)
星野 真一  東京大学, 大学院・薬学系研究科, 助手 (40219168)
柴崎 正勝  東京大学, 大学院・薬学系研究科, 教授 (30112767)
堅田 利明  東京大学, 大学院・薬学系研究科, 教授 (10088859)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥5,600,000 (Direct Cost: ¥5,600,000)
Fiscal Year 1998: ¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 1997: ¥3,000,000 (Direct Cost: ¥3,000,000)
KeywordsPI 3-KINASE / WORTMANNIN / G-PROTEINS / TYROSINE KINASE / SYNERGISM / PROTEIN KINASE B / METASTASIS / 阻害薬 / イノシトールリン脂質3-キナーゼ / ワ-トマニン
Research Abstract

Wortmannin, a potent inhibitor of phosphoinositide 3-kinase, and its derivatives were utilized to investigate the functions of the enzyme.
1. A novel catalytic subunit of phosphoinoside 3-kinase was isolated by use of a radiolabeled derivative of wortmannin. This subunit had a primary structure very similar to the beta-subtype of phosphoinositide 3-kinase. The novel subtype and the beta-subtype were found to be synergistically activated by a tyrosine-phosphorlated peptide and beta/gamma subunits of GYP-binding proteins. The alpha and gamma subtypes did not show the similar property.
2. The above synergism in vitro was operating in intact cell systems including rat adipocytes. The synergism was also observed as the cellular activity of protein kinase B, a downstream target of phosphoinositide 3-kinase. Thus a functional difference between the subtypes of the lipid kinase was newly suggested.
3. Wortmannin was found to inhibit the in vitro adhesion and motility of highly metastatic hepatoma cells. The effect was reproduced by introducing a dominant-negative mutant of phosphoinositide 3-kinase to the cells. Thus the enzyme was suggested to regulate the metastatic activity of hepatoma cells.
4. Derivatives of wortmannin lacking an ability to bind covalently to phosphoinositide 3-kinase were found. The compounds are expected to be utilized as ligands for affinity chromatography.

Report

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

    (20 results)

All Other

All Publications (20 results)

  • [Publications] Y.Saeki,et al.: "Involvement of phosphoinositide 3-kinase in regulation of adhesive activity of highly metastatic hepatoma cells." J.Biochem.124. 1020-1025 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] T.Imanaka,et al.: "Reconstitution of insulin signaling pathways in rat 3Y1 cells lacking insulin receptor and insulin receptor substrate-1." J.Biol.Chem.273. 25347-25355 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] O.Hazeki,et al.: "Activation of PI 3-kinase by G protein βγsubunits." Life Sci.62. 1555-1559 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] S.Inoue,et al.: "Protein tyrosine phosphorylation by IgG1-subclass CD38 monoclonal antibodies is mediated through stimulation of the FcγII receptors in human myeloid cell lines." J.Immunol.159. 5226-5232 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] N.Tsujimoto,et al.: "Potentiation of chemotactic peptide-induced superoxide generation by CD38 ligation in human myeloid cell lines." J.Biochem.121. 949-956 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] H.Kurose,et al.: "Heterodimeric phosphoinositide 3-kinase consisting of p85 and p110β is synergistically activated by the βγ-subunits of G proteins and phosphotyrosy1 peptide." J.Biol.Chem.272. 24252-24256 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Saeki, Y., et al.: "Involvement of phosphoinositide 3-kinase in regulation of adhesive activity of highly metastatic hepatoma cells." J.Biochem.124. 1020-1025 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Imanaka, T., et al.: "Reconstitution of insulin signaling pathways in rat 3Y1 cells lacking insulin receptor and insulin receptor substrate-1." J.Biol.Chem.273. 25347-25355 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hazeki, O., et al.: "Activation of PI 3-kinase by G protein betagamma subunits. Life Sci.62,1555-1559 (1998)" Life Sci.62. 1555-1559 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Inoue, S., et al.: "Protein tyrosine phosphorylation by IgG1-subclass CD38 monoclonal antibodies is mediated through stimulation of the FcgammaII receptors in human myeloid cell lines." J.Immunol.159. 5226-5232 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tsujimoto, N., et al.: "Potentiation of chemotactic peptide-induced superoxide generation by CD38 ligation in human myeloid cell lines." J.Biochem.121. 949-956 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kurosu, H., et al.: "Heterodimeric phosphoinositide 3-kinase consisting of p85 and p110beta is synergistically activated by the betagamma-subunits of G proteins and phosphotyrosyl peptide." J.Biol.Chem.272. 24252-24256 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Y.Saeki,et al.: "Involvement of phosphoinositide 3-kinase in regulation of adhesive activity of highly metastatic hepatoma cells." J.Biochem.124. 1020-1025 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] T.Imanaka,et al.: "Reconstitution of insulin signaling pathways in rat 3Y1 cells lacking insulin receptor and insulin receptor substrate-1." J.Biol.Chem.273. 25347-25355 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] O.Hazeki,et al.: "Activation of PI 3-kinase by G protein βγ subunits." Life Sci.62. 1555-1559 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] T.Sasaki,et al.: "Activation of c-Jun N-terminal kinase(JNK)by lysophosphatidic acid in Swiss 3T3 fibroblasts." J.Biochem.124. 934-939 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] N.Tsujimoto, et al.: "Potentiation of chemotactic peptide-induced superoxide generation by CD38 ligation in human myeloid cell lines." J.Biochem.121. 949-956 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] H.Kurosu, et al.: "Heterodimeric phosphoinositide 3-Kinase consisting of p85 and p110β is synergistically activated by the βγ subunits of G proteins and phosphotyrosyl peptide." J.Biol.Chem.272. 24252-24256 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] S.Inoue, et al.: "Protein-tyrosine phosphorylation by IgG1-subclass CD38 monoclonal antibodies is mediated through stimulation of the FcγII receptors in human myeloid cell lines." J.Immunol.159. 5226-5232 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 櫨木 修: "イノシトールリン脂質3キナーゼ" 蛋白質核酸酵素. 42. 394-402 (1997)

    • Related Report
      1997 Annual Research Report

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

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