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Common mechanism in the regulation of s and hansaiption in muscle cell differentiation

Research Project

Project/Area Number 15590246
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General medical chemistry
Research InstitutionOsaka University

Principal Investigator

HAYASHI Ken'ichiro  Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (90238105)

Co-Investigator(Kenkyū-buntansha) SHIBATA Katsushi  Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (70296565)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2004: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2003: ¥2,300,000 (Direct Cost: ¥2,300,000)
Keywordssmooth muscle cell / skeletal muscle cell / phenotypic modulation / IGF-I / signal transduction / IRS-1 / SHP-2 / ERK / 骨格筋細胞分化 / SHPS-1 / PI3K / PKB(Akt) / MAPK / Ras / Grb2-Sos
Research Abstract

IGF-I is a potent mitogen and motogen for dedifferentiated vascular smooth muscle cells (VSMCs) in vivo and in vitro. However, in differentiated VSMCs, IGF-I plays a vital role for maintaining the differentiated phenotype, which depends on IGF-I-induced activation of PI3K/PKB(Akt) pathway. In this study, we investigated the molecular mechanism underlying VSMC phenotype-dependent biological effects of IGF-I. In differentiated VSMCs, IGF-I activated a protein tyrosine phosphatase, SHP-2, by recruiting to tyrosine-phosphorylated IRS-1. The activated SHP-2 then dephosphorylated IRS-1 pTyr-895, resulting in blockade of the pathways from IRS-1/Grb2-Sos/Ras to the ERK and p38MAPK. Conversely, such negative regulation was silent in dedifferentiated VSMCs, where IGF-I activated both MAPKs, leading to VSMC proliferation and migration. Thus, these results demonstrate that the IRS-1/SHP-2 interaction acts as a switch controlling VSMC phenotype-dependent IGF-I signalings and biological effects. Alt … More hough, in myogenic differentiation of skeletal muscle cells, IGF-I-induced activation of PI3K/PKB(Akt) pathway plays a critical role, the ERK pathway shows contrast effects depending on cell types of myoblast. Treatment of MEK (ERK kinase) inhibitor (PD98059) markedly enhanced IGF-I-induced myotube formation of L6 myoblasts. By contrast, in C2C12 myoblasts, treatment of PD98059 activated the expression of molecular markers for skeletal muscle differentiation, but significantly suppressed myotube formation. In IGF-I-stimulated L6 myoblasts, PI3Kp85, SHP-2, and Grb2 were recruited to tyrosine-phosphorylated IRS-1, resulting in activation of PI3K/PKB(Akt), SHP-2, and ERK ; the activation of PI3K/PKB(Akt) and SHP-2 was continuous, whereas the ERK activation was transient. In C2C12 myoblasts, PI3K/PKB(Akt) and SHP-2 were also activated during IGF-I-triggered myogenic differentiation, but the activation level of ERK was weak compared with that in L6 myoblasts. However, the PI3K/PKB(Akt) pathway was activated via tyrosine-phosphorylated IRS-1 as in L6 myoblasts, SHP-2 was recruited to tyrosine-phosphorylated SHPS-1 but not to IRS-1. From these results, we concluded that in smooth and skeletal muscle cells the PI3K/PKB(Akt) pathway is activated by the same signaling pathway mediated through IGF-I receptor but the activation of SHP-2 by IGF-I depends on cell-type specific pathways. Less

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (8 results)

All 2004 2003 Other

All Journal Article (6 results) Publications (2 results)

  • [Journal Article] Insulin receptor substrate-1/SHP-2 interaction, a phenotype-dependent switching machinery of IGF-I signaling in vascular smooth muscle cells.2004

    • Author(s)
      Hayashi K.
    • Journal Title

      J.Biol.Chem. 279

      Pages: 40807-40818

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Insulin receptor substrate-1/SHP-2 interaction, a phenotype-dependent switching machinery of IGF-I signaling in vascular smooth muscle cells.2004

    • Author(s)
      Hayashi K
    • Journal Title

      J.Biol.Chem. 279

      Pages: 40807-40818

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Vascular remodeling induced by naturally occurring unsaturated lysophosphatidic acid in vivo.2003

    • Author(s)
      Yoshida K.
    • Journal Title

      Circulation 108

      Pages: 1746-1752

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Epiregulin as a major autocrine/paracrine factor released from the ERK- and p38MAPK-activated vascular smooth muscle cells.2003

    • Author(s)
      Takahashi M.
    • Journal Title

      Circulation 108

      Pages: 2524-2529

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Vascular remodeling induced by naturally Occurring unsaturated lysophosphatidic acid in vivo.2003

    • Author(s)
      Yoshida K
    • Journal Title

      Circulation 108

      Pages: 1746-1752

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Epiregulin as a major autocrine/paracrine factor released from the ERK and p38MAPK-activated vascular smooth muscle cells.2003

    • Author(s)
      Takahashi M
    • Journal Title

      Circulation 108

      Pages: 2524-2529

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Yoshida K.: "Vascular remodeling induced by naturally occurring unsaturated lysophosphatidic acid in vivo"Circulation. 108. 1746-1752 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Takahashi M.: "Epiregulin as a major autocrine/paracrine factor released from the ERK- and p38MAPK-activated vascular smooth muscle cells"Circulation. 108. 2524-2529 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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