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Impact of the regulation of PI3-kinase product on insulin action and its role in the disease state.

Research Project

Project/Area Number 11671110
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Metabolomics
Research InstitutionTOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY

Principal Investigator

SASAOKA Toshiyasu  Pharmaceutical Research, Associate Professor, 大学院・薬学研究科, 助教授 (00272906)

Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2000: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1999: ¥2,100,000 (Direct Cost: ¥2,100,000)
KeywordsInsulin / Insulin action / PI3-kinase / Lipid phosphatase / SHIP2 / Glucose uptake / Glycogen synthesis
Research Abstract

PI3-kinase plays an important role in various metabolic actions of insulin including glucose uptake and glycogen synthesis. Although PI3-kinase primarily functions as a lipid kinase which preferentially phosphorylates the D-3 position of phospholipids, the effect of hydrolysis of the key PI3-kinase product PI (3, 4, 5) P3 on these biological responses is unknown. We have cloned rat SHIP2 cDNA which possesses the 5'-phosphatase activity to hydrolyze PI (3, 4, 5) P3 to PI (3, 4) P2 and which is mainly expressed in the target tissues of insulin. To study the role of SHIP2 in insulin signaling, wild-type (WT)- and 5'-phosphatase defective SHIP2 (ΔIP-SHIP2) were overexpressed in 3T3-L1 adipocytes and L6 myocytes by means of adenovirus mediated gene transfer. Early events of insulin signaling including insulin-induced tyrosine phosphorylation of the insulin receptor p-subunit and IRS-1, IRS-1 association with p85 subunit, and PI3-kinase activity were not affected by expression of either WT- … More or ΔIP-SHIP2. As expected from possessing the 5'-phosphatase catalytic region, insulin-induced PI (3, 4, 5) P3 production was markedly decreased by overexpression of WT-SHIP2. In contrast, the amount of PI (3, 4, 5) P3 was oppositely increased by expression of ΔIP-SHIP2, indicating that ΔIP-SHIP2 functions in a dominant negative manner in 3T3-L1 adipocytes. Both PI (3, 4, 5) P3 and PtdIns (3, 4) P2 were known to possibly activate downstream targets Akt and PKCλ in vitro. Importantly, expression of WT-SHIP2 inhibited insulin-induced activation of Akt and PKCλ, whereas these activations were increased by expression of ΔIP-SHIP2 in vivo. Consistent with the regulation of downstream molecules of PI3-kinase, insulin-induced 2-deoxyglucose uptake and Glut4 translocation were decreased by expression of WT-SHIP2 and increased by expression of ΔIP-SHIP2. In addition, insulin-induced phosphorylation of GSK-3β and activation of PP1 followed by activation of glycogen synthase and glycogen synthesis were decreased by expression of WT-SHIP2, and these insulin actions were increased by the expression of ΔIP-SHIP2. These results indicate that SHIP2 negatively regulates metabolic signaling of insulin via the 5'-phosphatase activity. Less

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (14 results)

All Other

All Publications (14 results)

  • [Publications] Tsutomu Wada,Toshiyasu Sasaoka et al.: "Overexpression of SH2-containing Inositol Phosphatase 2 Results in Negative Regulation of Insulin-Induced Metaboli Actims in 3T3-L1 Adiposytes via Its 5'-phosphatase catalytic Activity."Molecular and Cellular Biology. 21. 1633-1646 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hajime Ishihara Toshiyaso Sasaoka et al.: "Molecular Cloning of Rat SH2-Containing Inositol Phasphatase 2 (SHIP2) and Its Rols in the Regulation of Insulin Signaling."Biochemical and Biophyoical Research Communications. 260. 265-272 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tsutomu Wada,Toshiyaso Sasaoka et al.: "Role of the Src Homology 2 (SH2) Domain and C-Terminus Tyrosine Phosphorylation sites of SH2-Containing Inositol Phosphatase (SHIP) in the Regulation of Insulin-Induced Mitogenesis."Endocrinology. 140. 4585-4594 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tsutomu Wada, Toshiyasu Sasaoka, Makoto Funaki, Hiroyuki Hori, Shihou Murakami, Manabu Ishiki, Tetsuro Haruta, Tomoichiro Asano, Wataru Ogawa, Hajime Ishihara, and Masashi Kobayashi.: "Overexpression of SH2-containing inositol phosphatase 2 results in negative regulation of insulin-induced metabolic actions in 3T3-L1 adipocytes via its 5'-phosphatase catalytic activity."Molecular and Cellular Biology. 21. 1633-1646 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hajime Ishihara, Toshiyasu Sasaoka, Hiroyuki Hori, Tsutomu Wada, Hiroki Hirai, Tetsuro Haruta, W.John Langlois, and Masashi Kobayashi.: "Molecular cloning of rat SH2-containing inositol phosphatase 2 (SHIP2) and its role in the regulation of insulin signaling."Biochem. Biophys. Res. Commun.. 260. 265-272 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tsutomu Wada, Toshiyasu Sasaoka, Manabu Ishiki, Hiroyuki Hori, Tetsuro Haruta, Hajime Ishihara, and Masashi Kobayashi.: "Role of the src homology 2 (SH2) domain and C-terminus tyrosine phosphorylation sites of SH2-containing inositol phosphatase (SHIP) in the regulation of insulin-induced mitogenesis."Endocrinology. 140. 4585-4594 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] A.Sato,T.Sasaoka et al.: "Glucosamine enhances platelet-derived growth factor-induce DNA synthesis via phosphatidylinositol 3-kinase in rat aortic smooth muscle cells,"Atherosclerosis. (In Press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] T.Wada,T.Sasaoka et al.: "Overexpression of SH2-containing nositol phosphatase 2 results in negative regulation of insulim-induced metabolic actions in 3T3-L1 adipocytes via its 5'-phosphatase catalytic activity."Mol.Cell.Biol.. 21. 1633-1646 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] T.Sasaoka,M.Kobayashi: "The functional significance of Shc in insulin signaling as a substrate of the insulin receptor"Endocrine J.. 47. 373-381 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] I.Usui,T.Sasaoka et al: "Retinoblastoma protein phosphorylation via PI3-kinase and mTOR pathway regulates adipocyte differentiation."Biochem.Biophys.Res.Commun.. 275. 115-120 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] H. Ishihara, T. Sasaoka, et al.: "Molecular cloning of rat SH2-containing inositol phosphatase 2 (SHIP2) and its role in the regulation of insulin signaling."Biochem. Biophys. Res. Commun.. Vol260No1. 265-272 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] T. Sasaoka, et al.: "Synergistic role of the phosphatidylinositol 3-kinase and MAP kinase cascade in the regulation of insulin receptor trafficking."Endocrinology. Vol140No8. 3826-3834 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] T. Wada, T. Sasaoka, et al.: "Role of the Src homology 2 (SH2) domain and c-terminus tyrosine phosphorylation sites of SH2-containing inositol phosphatase (SHIP) in the regulation of insulin-induced mitogenesis."Endocrinology. Vol140No10. 4585-4594 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] T. Sawa, T. Sasaoka, et al: "Intracellular signaling pathways of okadaic acid leading to mitogenesis in Rat 1 fibroblasts overexpressing insulin receptors: okadaic acid regulates Shc phosphorylation by mechanisms independent of insulin."Cellular Signalling. vol11No11. 797-803 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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