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ErbBファミリーの二量体形成におけるN型糖鎖の機能

Research Project

Project/Area Number 16790167
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeSingle-year Grants
Research Field General medical chemistry
Research InstitutionSaga University

Principal Investigator

高橋 素子  佐賀大学, 医学部, 助教授 (00303941)

Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2005: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2004: ¥2,000,000 (Direct Cost: ¥2,000,000)
KeywordsN-glycan / ErbBファミリー / EGFR / ErbB2 / ErbB3 / dimerization / autophophorylation / glycosylation / ErbB family / autophosphorylation
Research Abstract

N型糖鎖は、タンパクの構造や可塑性、親水性を変化させ、その機能を修飾することが明らかとなっているが、シグナル分子における役割はいまだ明確ではない。本研究ではモデルの糖タンパクとしてErbBファミリーを選び、その二量体形成におけるN型糖鎖の役割を検討した。EGFRでは、そのドメインIIIの糖鎖のうち、Asn420に付加する糖鎖を失うとリガンド非依存性に二量体を形成することがわかっている。ドメインIIIの構造がEGFRと比較的似ているErbB3で、EGFRのAsn420に相当するAsn418をGlnに変えN型糖鎖の付加部位を欠失させると、やはりリガンド非依存性に二量体を形成することがわかった。このN418Q変異ErbB3をErbB2と共発現させた細胞では、Erkのリン酸化が著明に上昇し、ErbB3ホモ二量体のみならずErbB2-ErbB3のヘテロ二量体形成も増加することがわかった。さらに、この下流のシグナルの増強により足場非依存性の増殖能を獲得すること、ヌードマウスにおける腫瘍形成能が著しく上昇することが明らかとなった。一方、ErbB2においてはドメインIIIにN型糖鎖の付加部位は存在しないが、EGFRのAsn420、ErbB3のAsn418に相当する部位に糖鎖の付加部位を導入したG449N変異ErbB2では、リガンド非依存性の二量体形成が減少することがわかった。ErbB2の立体構造は、EGFRやErbB3にリガンドが結合したときの構造に近いことが報告されている。今後、EGFRやErbB3ではドメインIIIの糖鎖を除くとリガンドが結合したときと近い立体構造をとること、またErbB2ではドメインIIIの糖鎖がないことがリガンド非依存性の二量体形成や細胞の増殖能といった癌原性を示す原因になっていることを証明したい。

Report

(2 results)
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • Research Products

    (17 results)

All 2006 2005 2004

All Journal Article (14 results) Book (3 results)

  • [Journal Article] The internalization and metabolism of 3-deoxyglucosone in human umbilical vein endothelial cells2006

    • Author(s)
      Sakiyama H., Takahashi M., et al.
    • Journal Title

      J. Biochem., 139

      Pages: 245-253

    • NAID

      10018847726

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Loss of core fucosylation of low-density lipoprotein receptor-related protein-1 impairs its function, leading to the upregulation of serum levels of insulin-like growth factor-bindgin protein 3 in Fut8^<-/-> mice2006

    • Author(s)
      Lee SH., Takahashi M., et al.
    • Journal Title

      J. Biochem (in press)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Overexpression of mutated Cu, Zn-SOD in neuroblastoma cells results in cytoskeletal change2005

    • Author(s)
      Takamiya R., Takahashi M.et al.
    • Journal Title

      Am. J. Physiol. Cell Physiol 288

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Different immunoreactivity against monoclonal antibodies between wild-type and mutant copper/zinc superoxide dismutase linked to amyotrophic lateral sclerosis2005

    • Author(s)
      Fujiwara N. et al.
    • Journal Title

      J. Biol. Chem. 280

      Pages: 5061-5070

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Induction of thioredoxin reductase as an adaptive response to acrolein in human umbilical vein endothelial cells2005

    • Author(s)
      Park YS. et al.
    • Journal Title

      Biochem. Biophys. Res. Commun 327

      Pages: 1058-1065

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Acrolein induces Hsp72 via both PKCd/JNK and calcium signaling pathways in human umbilical vein endothelial cells2005

    • Author(s)
      Misonou Y., Takahashi M.et al.
    • Journal Title

      Free Radic Res. 39

      Pages: 507-512

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Dysregulation of TFG-beta 1 receptor activation leads to abnormal lung development and emphysema-like phenotype in core fucose-deficient mice2005

    • Author(s)
      Wang.X., et al.
    • Journal Title

      Proc. Natl. Acad. Sci. USA 102

      Pages: 15791-15796

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Overexpression of mutated Cu,Zn-SOD in neuroblastoma cells results in cytoskeltal change2005

    • Author(s)
      Takamiya R., Takahashi M.et al.
    • Journal Title

      Am.J.Physiol.Cell Physiol. 288

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Different immunoreactivity against monoclonal antibodies between wiol-type and mutant copper/zinc superoxide dismutase linked to amyotrophic lateral sclerosis2005

    • Author(s)
      Fujiwara N.et al.
    • Journal Title

      J.Biol.Chem. 280

      Pages: 5061-5070

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Induction of thioredoxin reductase as an adaptive response to acrolein in human umbilical vein endothelial cells2005

    • Author(s)
      Park YS.et al.
    • Journal Title

      Biochem.Biophys.Res.Commun. 327

      Pages: 1058-1065

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Acrolein induces Hsp72 via both PKCd/JNK and calcium signaling pathways in human umbilical vein endothelial cells2005

    • Author(s)
      Misonou Y., Takahashi M.et al.
    • Journal Title

      Free Radic.Res. (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Role of N-glycan in growth factor signaling2004

    • Author(s)
      Takahashi M.et al.
    • Journal Title

      Glycoconj.J. 20

      Pages: 207-212

    • Related Report
      2004 Annual Research Report
  • [Journal Article] β1,4-N-actylglucosaminyltransferase III down-regulates neurite outgrowth induced by co-stimulation of epidermal growth factor and integrins through the Ras/ERK signaling pathway in PC12 cells2004

    • Author(s)
      Gu J.et al.
    • Journal Title

      Glycobiology 14

      Pages: 177-186

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Introduction of bisecting GlcNAc into integrin alpha5beta1 reduces ligand binding and down-regulates cell adhesion and cell migration2004

    • Author(s)
      Isaii T.et al.
    • Journal Title

      J.Biol.Chem. 279

      Pages: 19747-19754

    • Related Report
      2004 Annual Research Report
  • [Book] 未来を拓く糖鎖科学2005

    • Author(s)
      永井 克孝
    • Total Pages
      467
    • Publisher
      金芳堂
    • Related Report
      2005 Annual Research Report
  • [Book] 糖鎖科学の新展開2005

    • Author(s)
      谷口 直之
    • Total Pages
      536
    • Publisher
      NTS
    • Related Report
      2005 Annual Research Report
  • [Book] 遺伝子医学MOOK 糖鎖と病気2005

    • Author(s)
      谷口 直之
    • Total Pages
      291
    • Publisher
      メディカルビュー
    • Related Report
      2005 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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