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1999 Fiscal Year Final Research Report Summary

Analysis of the functions of G protein βγ-Subunit and application to drug design

Research Project

Project/Area Number 10557220
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Biological pharmacy
Research InstitutionThe University of Tokyo

Principal Investigator

KATADA Toshiaki  The University of Tokyo, Graduate School of Pharmaceutical Sciences, Dept. of Physiol. Chem., Professor, 大学院・薬学系研究科, 教授 (10088859)

Co-Investigator(Kenkyū-buntansha) KONTANI Kenji  The University of Tokyo, Graduate School of Pharmaceutical Sciences, Dept. of Physiol. Chem., Research fellow, 大学院・薬学系研究科, 助手 (30302615)
HOSHINO Shin-ichi  The University of Tokyo, Graduate School of Pharmaceutical Sciences, Dept. of Physiol. Chem., Research fellow, 大学院・薬学系研究科, 助手 (40219168)
NISHINA Hiroshi  The University of Tokyo, Graduate School of Pharmaceutical Sciences, Dept. of Physiol. Chem., Associate Professor, 大学院・薬学系研究科, 助教授 (60212122)
Project Period (FY) 1998 – 1999
KeywordsG protein / βγ subunits / membrane receptor / tyrosine kinase / lipid kinase / Rab5
Research Abstract

Stimulation of G protein-coupled receptors (GPCRs) by agonists induces the dissociation of the signal coupling proteins into GTP-bound α and βγ subunits (Gβγ). In addition to the α subunit, Gβγ has recently been shown to regulate activities of effector enzymes or ion channels. In the present study, we investigated the molecular mechanisms by which βγ subunits regulate the effector activities. Moreover, we studied phosphatidylinositol 3-OH kinase (PI 3-kinase) consisting of p110β catalytic and p85 regulatory subunits, which is synergistically activated by the stimulation of GPCRs and tyrosine-kinase receptors. 1. The first WD motif of Gβγ appeared to be involved in the stimulation of GィイD2sィエD2-dependent activation of type-2 adenylyl cyclase. In contrast, the third and sixth motifs of Gβγ interacted with Raf-1 kinase in yeast two-hybrid system. 2. Lipid kinase activity of p110β/p85 PI 3-kinase was synergistically stimulated by Gβγ and a tyrosine-phosphorylated peptide. 3. The small GTPase, Rab5, was identified as one of p110β-binding proteins in yeast two-hybrid system. In in vitro-binding experiments, p110β was indeed capable of associating with GTP-bound Rab5. However, such interaction was not observed with GDP-bound Rab5 or the various forms of Ras. 4. In cultured cells, insulin-induced activation of protein kinase B (Akt), which is the target enzyme of PI 3-kinase product, appeared to be simulated by active Rab5 and inhibited by the dominant-negative form. 5. A novel effector for Rab5, which contained SH2 domain, was also identified in yeast two-hybrid system, and the effector appeared to present in early endosomes. 6. Gab 2 was identified as one of adaptor molecules involved in signal transduction pathway from Fcγ receptors to PI 3-kinase, and the adaptor was phosphorylated in Tyr and Ser/Thr residues upon stimulation of Fcγ and chemotactic peptide (GPCR) receptors.

  • Research Products

    (15 results)

All Other

All Publications (15 results)

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

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] J.A. Sanchez, et al.: "Modulation of reconstituted ATP-sensitive K^+ channels by GTP-binding proteins in a mammalian cell line"J. Physiol.. 507. 315-324 (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] S. Takasuga, et al.: "Enhancement by adenosine of insulin-induced activation of phosphoinositide 3-kinase and protein kinase B in rat adipocytes"J. Biol. Chem.. 274. 19545-19550 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] T. Nakano, et al.: "G-Protein betagamma subunit-dependent phosphorylation of 62-kDa protein in the early signaling pathway of starfish oocyte maturation induced by 1-methyladenine"Developmental Biology. 209. 200-209 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] T. Katada, et al.: "Synergistic activation of a family of phosphoinositide 3-kinase via G-protein coupled and tyrosine kinase-related receptors"Chemistry and Physics of Lipids. 98. 79-86 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 堅田 利明(分担): "シグナル伝達 総集編(竹縄 忠臣 編)"羊土社. 235 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 0. Hazeki, T. Okada, H. Kurosu, S. Takasuga, T. Suzuki, & T. Katada: "Activation of PI 3-kinase by G protein βγ subunits"Life Sci.. 62. 1555-1559 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] J. A. Sanchez, T. Gonoi, N. Inagaki, T. Katada, & S. Seino: "Modulation of reconstituted ATP-sensitive KィイD1+ィエD1 channels by GTP-binding proteins in a mammalian cell line."J. Physiol.. 507. 315-324 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] A. Smine, X. Xu, K. Nishiyama, T. Katada, P. Gambetti, S. P. Yadav, X. Wu, Y.-C. Shi, S. Yasuhara, V. Homburger, & T. Okamoto: "Regulation of brain G-protein Go by Alzheimer's disease gene presenilin-1."J. Biol. Chem.. 273. 16281-16288 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] T. Imanaka, H. Hayashi, K. Kishi, L. Wang, K. Ishii, O. Hazeki, T. Katada, & Y. Ebina: "Reconstitution of insulin signaling pathways in rat 3Y1 cells lacking insulin receptor and insulin receptor substrate-1. Evidence that activation of akt is insufficient for insulin-stimulated glycogen synthesis or glucose uptake in rat 3y1 cells."J. Biol. Chem.. 273. 25347-25355 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] T. Sasaki, T. Maehama, T. Yamamoto, S. Takasuga, S. Hoshino, H. Nishina, O. Hazeki, & T. Katada: "Activation of c-Jun N-terminal kinase (JNK) by lysophosphatidic acid in Swiss 3T3 fibroblasts."J. Biochem. 124. 934-939 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] T. Nakano, K. Kontani, H. Kurosu, T. Katada, M. Hoshi, & K. Chiba: "G-Protein betagamma subunit-dependent phosphorylation of 62-kDa protein in the early signaling pathway of starfish oocyte maturation induced by 1-methyladenine"Dev. Biol.. 209. 200-209 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] T. Katada, H. Kurosu, T. Okada, T. Suzuki, N. Tsujimoto, S. Takasuga, K. Kontani, O. Hazeki, & M. Ui: "Synergistic activation of a family of phosphoinositide 3-kinase via G-protein coupled and tyrosine kinase-related receptors"Chemistry and Physics of Lipids. 98. 79-86 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] S. Takasuga, T. Katada , M. Ui, & O. Hazeki: "Enhancement by adenosine of insulin-induced activation of phosphoinositide 3-kinase and protein kinase B in rat adipocytes."J. Biol. Chem.. 274. 19545-19550 (1999)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2001-10-23  

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