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多様な細胞間シグナルを変換するセクレターゼの生理活性脂質変換酵素による制御機構

Research Project

Project/Area Number 18060033
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionSapporo Medical University

Principal Investigator

坂根 郁夫  Sapporo Medical University, 医学部, 准教授 (10183815)

Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥4,600,000 (Direct Cost: ¥4,600,000)
Fiscal Year 2007: ¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2006: ¥2,300,000 (Direct Cost: ¥2,300,000)
Keywordsジアシルグリセロールキナーゼ / 上皮増殖因子受容体 / インスリン受容体 / ボスファチジン酸 / TACE / RACK / プロテインキナーゼC / リン酸化 / ホスファチジン酸 / lipid phosphate phosphatase
Research Abstract

我々は既に,ジアシルグリセロールキナーゼ(DGK)δのノックアウト(KO)マウスを作成し表現型を解析したところ,上皮増殖因子受容体(EGFR)や腫瘍壊死因子-α転換酵素(TACE)のKOマウスの表現型と酷似していることを見出している.更なる解析により,CDGKδがプロテインキナーゼC(PKC)の活性抑制を介しEGFRのシグナル伝達(セクレターゼ(TACE)を活性化する)を正に制御することにより,細胞外環境を変化させ,個体発生のキーエンザイムの一つとして機能することを明らかにしている.
次に,CDGKδによるEGFR活性の制御機構を明らかにする目的で,CDGKδとの相互作用因子を酵母two-hybrid法と免疫沈降法を用いて検索・同定した.その結果,DGKδのC末領域とreceptor for activated Ckinase 1 (RACKI)のC末約半分(WD repeat 5-7)が相互作用すること,更に,DGKδはRACKIをエンドソームヘリクルートすることが明らかになった.また,DGKδはsterile α motifドメインを介してポリマーを形成し,そのポリマー形成が細胞内局在性を制御することも見出した.
他の増殖因子受容体とDGKδの関連を検討した.高濃度の細胞外グルコースにより,CDGKδの活性と細胞内局在性が制御されること,また,DGKδによってPKC活性が抑制され,その結果,インスリン受容体活性が正に制御されていることが判明した.そして更に,2型糖尿病患者の骨格筋中ではDGKδのmRNA及び蛋白量が減少していることを見出した.また,CDGKδのKOマウスは,骨格筋組織中のDG量の増加に伴い,脂肪褥の増加,グルコースの取り込み能の低下,インスリン抵抗性の増大など,2型糖尿病様の表現型を示し,DGKδが本症発症、増悪化の新たな鍵酵素である可能性が高いことが明らかになった.

Report

(2 results)
  • 2007 Annual Research Report
  • 2006 Annual Research Report
  • Research Products

    (25 results)

All 2008 2007 2006 Other

All Journal Article (16 results) (of which Peer Reviewed: 9 results) Presentation (6 results) Remarks (1 results) Patent(Industrial Property Rights) (2 results) (of which Overseas: 1 results)

  • [Journal Article] Rab7 regulates maturation of the melanosomal matrix protein gp100/Pme117/Silv2008

    • Author(s)
      Kawakami, A., et. al.
    • Journal Title

      J.Invest.Dermatol 128

      Pages: 143-150

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Phorbol ester and hydrogen peroxide synergistically induce the interaction of diacylglycerol kinase γ with the Src honology 2 and C1domains of β2-chimaerin2008

    • Author(s)
      Yasuda, S., et. al.
    • Journal Title

      Biochem.J. 409

      Pages: 95-106

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Down-regulation of diacylglycerol kinase delta contributes to hyperglycemia-induced insulin resistance2008

    • Author(s)
      Chibalin, A. V., et. al.
    • Journal Title

      Cell 132

      Pages: 375-386

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Regulation of enzyme localization by polymerization:Polymer formation by the SAM domain of diacylglycerol kinase δ12008

    • Author(s)
      Harada, B. T., et. al.
    • Journal Title

      structur 16

      Pages: 380-387

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Diacylglycerol kinase α suppresses tumor necrosis factor-α-induced apoptosis of human melanoma cells through NF-KB activation2007

    • Author(s)
      Yanagisawa, K., et. al.
    • Journal Title

      Biochim.Biophys.Acta-Mol.Cell Biol.Lipids 1771

      Pages: 462-474

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Tyrosine phosphorylation of β2-chimaerin by Src-family kinase negatively regulates its Rac-specific GAP activity2007

    • Author(s)
      Kai, M., et. al.
    • Journal Title

      Biochim.Biophys.Acta-Mol.Cell Res. 1773

      Pages: 1407-1415

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Diacylglycerol Kinases:Why so many of them2007

    • Author(s)
      Sakane, F., et. al.
    • Journal Title

      Biochim.Biophys.Acta-Mol.Cell Biol.Lipids 1771

      Pages: 793-806

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Glucose regulates diacylglycerol intracellular levels and protein kinase C activity by modulating diacylglycetol-kinase subcellular localization2007

    • Author(s)
      Miele, C., et. al.
    • Journal Title

      J.Biol.Chem. 282

      Pages: 31835-31843

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Diacylglycerol kinase γ interacts with and activates β2-chimaerin, a Rac-specific GAP, in response to epidermal growth factor2007

    • Author(s)
      Yasuda, S.et al.
    • Journal Title

      FEBS Lett. 581 (3)

      Pages: 551-557

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Nuclear transportation of diacylglycerol kinase γ and its possible function in the nucleus2006

    • Author(s)
      Mastubara, T.et al.
    • Journal Title

      J.Biol.Chem. 281(10)

      Pages: 6152-6164

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Diacylglycerol kinase δ regulates protein kinase C and epidermal growth factor receptor signaling2006

    • Author(s)
      Crotty, T.et al.
    • Journal Title

      Proc.Natl.Acad.Sci.USA 103(42)

      Pages: 15485-15490

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Lipid phosphate phosphatases 1 and 3 are localized in distinct lipid rafts2006

    • Author(s)
      Kai, M.et al.
    • Journal Title

      J.Biochem. 140(5)

      Pages: 677-686

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Diacylglycerol kinases as emerging potential drug targets for a variety of diseases

    • Author(s)
      Sakane, F., et. al.
    • Journal Title

      Curr.Drug Targets (In press)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Diacylglycerol kinase α suppresses tumor necrosis factor-α-induced apoptosis of human melanoma cells through NF-κB activation

    • Author(s)
      Yanagisawa, K.et al.
    • Journal Title

      Biochim.Biophys.Acta-Mol.Cell Biol.Lipids (In press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Tyrosine phosphorylation of β2-chimaerin by Src-family kinase negatively regulates its Rac-specific GAP activity

    • Author(s)
      Kai, M.et al.
    • Journal Title

      Biochim.Biophys.Acta-Mol.Cell Res. (In press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Diacylglycerol kinases : Why so many of them?

    • Author(s)
      Sakane, F.et al.
    • Journal Title

      Biochim.Biophys.Acta-Mol.Cell Biol.Lipids (In press)

    • Related Report
      2006 Annual Research Report
  • [Presentation] ジアシルグリセロールキナーゼが制御する多彩な生理機能(シンポジウム「グリセリドとそのリン酸化体の産生・相互変換とそれらが織りなす細胞内外のシグナルネットワーク」)2007

    • Author(s)
      坂根 郁夫
    • Organizer
      第49回日本脂質生化学会研究集会
    • Place of Presentation
      札幌
    • Related Report
      2007 Annual Research Report
  • [Presentation] ジアシルグリセロールキナーゼγは細胞刺激に応答しβ2-chimaerin(Rac特異的GAP)を活性化する2007

    • Author(s)
      安田 智, ら
    • Organizer
      第49回日本脂質生化学会研究集会
    • Place of Presentation
      札幌
    • Related Report
      2007 Annual Research Report
  • [Presentation] β2-chimaerinのチロシンリン酸化によるRac特異的GAP活性の抑制2007

    • Author(s)
      甲斐 正広, ら
    • Organizer
      第49回日本脂質生化学会研究集会
    • Place of Presentation
      札幌
    • Related Report
      2007 Annual Research Report
  • [Presentation] 細胞刺激に応答したジアシルグリセロールキナーゼγ によるβ2-chimaerin活性化機構2007

    • Author(s)
      安田 智, ら
    • Organizer
      第30回日本分子生物学会・第80回日本生化学会合同大会
    • Place of Presentation
      横浜
    • Related Report
      2007 Annual Research Report
  • [Presentation] EGF刺激に応答したβ2-chimaerinのチロシンリン酸化とそのGAP活性の抑制2007

    • Author(s)
      甲斐 正広, ら
    • Organizer
      第30回日本分子生物学会・第80回日本生化学会合同大会
    • Place of Presentation
      横浜
    • Related Report
      2007 Annual Research Report
  • [Presentation] ジァシルグリセロールキナーゼδとRACK1は互いの複数のドメインを介して結合している2007

    • Author(s)
      今井 伸一, ら
    • Organizer
      第30回日本分子生物学会・第80回日本生化学会合同大会
    • Place of Presentation
      横浜
    • Related Report
      2007 Annual Research Report
  • [Remarks]

    • URL

      http://web.sapmed.ac.jp/biochem2/

    • Related Report
      2007 Annual Research Report
  • [Patent(Industrial Property Rights)] DGKα阻害剤を含有する抗がん剤2007

    • Inventor(s)
      坂根 郁夫ら
    • Industrial Property Rights Holder
      北海道
    • Filing Date
      2007-03-29
    • Related Report
      2006 Annual Research Report
  • [Patent(Industrial Property Rights)] Method of screening for a gents that regulate the shedding of membrane bound proteins and methods of use

    • Inventor(s)
      Prescott, S.M., et. al.
    • Industrial Property Rights Holder
      University of Utah Research Foundation, Salt Lake City(USA)
    • Related Report
      2007 Annual Research Report
    • Overseas

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Published: 2006-04-01   Modified: 2018-03-28  

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