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1998 Fiscal Year Final Research Report Summary

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)
Project Period (FY) 1997 – 1998
KeywordsPI 3-KINASE / WORTMANNIN / G-PROTEINS / TYROSINE KINASE / SYNERGISM / PROTEIN KINASE B / METASTASIS
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.

  • Research Products

    (12 results)

All Other

All Publications (12 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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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

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Published: 1999-12-08  

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