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"Research of crosstalk between nutrient sensing mTOR signaling pathway and energy metabolic sensing AMPK"

Research Project

Project/Area Number 15590273
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionKobe University

Principal Investigator

TOKUNAGA Chiharu  Kobe University, Biosignal Research Center, Assistant Professor, バイオシグナル研究センター, 助手 (70335462)

Co-Investigator(Kenkyū-buntansha) YONEZAWA Kazuyoshi  Kobe University, Biosignal Research Center, Professor, バイオシグナル研究センター, 教授 (70283900)
YOSHINO Ken-ichi  Kohe University, Biosignal Research Center, Assistant Professor, バイオシグナル研究センター, 助手 (90280792)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2004: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000)
KeywordsmTOR / AMPK / nutrient sensor / energy metabolic sensor / p70 S6 kinase / 4EBP1 / raptor / TOS motif / rapamycin / リン酸化 / Kog1
Research Abstract

1.The inhibition of mTOR signaling pathway by AMPK
We isolated a portion of the γ1 subunit of AMPK, which played a role as an energy metabolic sensor, by yeast two-hybrid screening using mTOR kinase domain as a bait. This result suggests the possibility of the linkage between the nutrient sensing mTOR signaling pathway and the cellular energy metabolic system. Actually the treatments of mammalian cells with AMPK activators inhibit phosphorylations of p70 S6 kinase (p70 S6k) and eukaryotic translational initiation factor 4E binding protein (4EBP1) which function as downstream effectors of mTOR, however a rapamycin-resistant p70 S6k variant is insensitive to AMPK activators. In addition, overexpression of the constitutively active form of AMPK in mammalian cells inhibits phosphorylations of both p70 S6k and 4EBP1. On the other hand, in the dominant negative form of AMPK-over-expressing cells, these inhibitions are restored. These results suggest a possible linkage between AMPK and mTOR signaling.
2.The analysis of a role of mTOR interacting protein raptor as a scaffold protein
Both p70 S6k and 4EBP1 have evolutionally conserved TOS (TOR signaling) motif. The mutants of this motif are no longer pbosphorylated by mitogens in cells. We showed that the TOS motif was a binding site of mTOR binding protein raptor. The mutants of the TOS motif cannot bind to raptor and these mutants can be no longer phosphorylated by mTOR in the presence of both mTOR and raptor.

Report

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

    (60 results)

All 2005 2004 2003 Other

All Journal Article (47 results) Book (3 results) Patent(Industrial Property Rights) (1 results) Publications (9 results)

  • [Journal Article] Signal transduction of egg fertilization : Focused proteomics on membrane/lipid rafts.2005

    • Author(s)
      Sato, K.
    • Journal Title

      Methods Mol.Biol. in press(未定)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mammalian target of rapamycin (mTOR).2005

    • Author(s)
      Kazuyoshi, Yonezawa
    • Journal Title

      NASH and Nutritional Therapy(Okita, K.(Ed.))

      Pages: 92-99

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Signal transduction of egg fertilization : Focused proteomics on membrane/lipid rafts.2005

    • Author(s)
      Ken-ichi, Sato
    • Journal Title

      Methods Mol.Biol. (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Raptor, a binding partner of target of rapamycin.2004

    • Author(s)
      Yonezawa, K.
    • Journal Title

      Biochem.Biophys.Res.Commun. 313

      Pages: 437-441

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] mTOR integrates amino acid- and energy-sensing pathways.2004

    • Author(s)
      Tokunaga, C.
    • Journal Title

      Biochem.Biophys.Res.Commun. 313

      Pages: 443-446

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function.2004

    • Author(s)
      Oshiro, N.
    • Journal Title

      Genes Cells 9

      Pages: 359-366

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ラパマイシン標的タンパク質mTORシグナル伝達系2004

    • Author(s)
      徳永 千春
    • Journal Title

      細胞工学 23

      Pages: 340-348

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells.2004

    • Author(s)
      Murakami, M.
    • Journal Title

      Mol.Cell Biol. 24

      Pages: 6710-6718

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites.2004

    • Author(s)
      Takei, N.
    • Journal Title

      J.Neurosci. 24

      Pages: 9760-9769

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] mTOR signaling pathway.2004

    • Author(s)
      Yonezawa, K.
    • Journal Title

      Hepatol.Res. 30S

    • NAID

      10015455361

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 細胞環境中のアミノ酸バランスを感知するmTORシグナル伝達機構2004

    • Author(s)
      中嶋 昭雄
    • Journal Title

      BIO Clinica 19

      Pages: 18-22

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 質量分析法と配列データベースを利用するタンパク質同定法2004

    • Author(s)
      吉野 健一
    • Journal Title

      J.Mass Spectrom.Soc.Jpn. 52

      Pages: 106-129

    • NAID

      10013283351

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] mTOR (mammalian Target of Rapamycin).2004

    • Author(s)
      米澤 一仁
    • Journal Title

      生体の科学 55

      Pages: 382-383

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 肝臓病の最近の話題「mTOR」について2004

    • Author(s)
      米澤 一仁
    • Journal Title

      Liv 日常診療に診る肝臓病治療 6

      Pages: 11-11

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Raptor, a binding partner of target of rapamycin.2004

    • Author(s)
      Kazuyoshi, Yonezawa
    • Journal Title

      Biochem.Biophys.Res.Commun. 313-2

      Pages: 437-441

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] mTOR integrates amino acid- and energy-sensing pathways.2004

    • Author(s)
      Chiharu, Tokunaga
    • Journal Title

      Biochem.Biophys.Res.Commun. 313-2

      Pages: 443-446

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function.2004

    • Author(s)
      Noriko, Oshiro
    • Journal Title

      Genes Cells 9-4

      Pages: 359-366

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mammalian Target of Rapamycin (mTOR) Signaling System.2004

    • Author(s)
      Chiharu, Tokunaga
    • Journal Title

      Cell Technol. 23-3

      Pages: 340-348

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells.2004

    • Author(s)
      Mirei, Murakami
    • Journal Title

      Mol.Cell Biol. 24-15

      Pages: 6710-6718

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites.2004

    • Author(s)
      Nobuyuki, Takei
    • Journal Title

      J.Neurosci. 24-44

      Pages: 9760-9769

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Kinase activities associated with mTOR.2004

    • Author(s)
      Kazuyoshi, Yonezawa
    • Journal Title

      TOR: Target of Rapamycin (Curr.Top.Microbiol.Immunol.)(Thomas, G., Sabatini, D.M., Hall, M.N.(Eds.)) 279

      Pages: 271-282

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] mTOR signaling pathway.2004

    • Author(s)
      Kazuyoshi, Yonezawa
    • Journal Title

      Hepatol.Res. 30S

      Pages: 9-13

    • NAID

      10015455361

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Sensing of extra-cellular amino acid balance by mTOR signaling system.2004

    • Author(s)
      Akio, Nakashima
    • Journal Title

      Bio Clinica 19-4

      Pages: 18-22

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mass spectrometry-based protein identification by correlation with sequence database.2004

    • Author(s)
      Ken-ichi, Yoshino
    • Journal Title

      J.Mass Spectrom.Soc.Jpn. 52-3

      Pages: 106-129

    • NAID

      10013283351

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] mTOR (mammalian Target of Rapamycin).2004

    • Author(s)
      Kazuyoshi, Yonezawa
    • Journal Title

      Seitai no Kagaku 55-5

      Pages: 382-383

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Kanzobyo no Saikin no Wadai 「mTOR」 ni tsuite.2004

    • Author(s)
      Kazuyoshi, Yonezawa
    • Journal Title

      Liv Nichijo Shinryo ni miru Kanzobyochiryo 6

      Pages: 11-11

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Raptor, a binding partner of target of rapamycin.2004

    • Author(s)
      Yonezawa, K.
    • Journal Title

      Biochem.Biophys.Res.Commun. 313・2

      Pages: 437-441

    • Related Report
      2004 Annual Research Report
  • [Journal Article] mTOR integrates amino acid- and energy-sensing pathways.2004

    • Author(s)
      Tokunaga, C.
    • Journal Title

      Biochem.Biophys.Res.Commun. 313・2

      Pages: 443-446

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function.2004

    • Author(s)
      Oshiro, N.
    • Journal Title

      Genes Cells 9・4

      Pages: 359-366

    • Related Report
      2004 Annual Research Report
  • [Journal Article] ラパマイシン標的タンパク質mTORシグナル伝達系2004

    • Author(s)
      徳永 千春
    • Journal Title

      細胞工学 23・3

      Pages: 340-348

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 質量分析法と配列データベースを利用するタンパク質同定法2004

    • Author(s)
      吉野 健一
    • Journal Title

      J.Mass Spectrom.Soc.Jpn. 52・3

      Pages: 106-129

    • NAID

      10013283351

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif.2003

    • Author(s)
      Nojima, H.
    • Journal Title

      J.Bid.Chem. 278

      Pages: 15461-15464

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Identification of TOR-interacting proteins.2003

    • Author(s)
      Yonezawa, K.
    • Journal Title

      Mol.Interv. 3

      Pages: 19183-19189

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] mTOR/raptor-p70S6キナーゼ2003

    • Author(s)
      米澤 一仁
    • Journal Title

      栄養評価と治療 20

      Pages: 81-85

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ラプター(raptor)2003

    • Author(s)
      米澤 一仁
    • Journal Title

      生化学 75

      Pages: 323-323

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 細胞成長を司る情報伝達システムの中央情報集積装置mTOR複合体2003

    • Author(s)
      吉野 健一
    • Journal Title

      蛋白質核酸酵素 48

      Pages: 1378-1385

    • NAID

      40005884433

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] アミノ酸と細胞内シグナル伝達-蛋白質合成を中心に2003

    • Author(s)
      大城 紀子
    • Journal Title

      栄養評価と治療 20

      Pages: 478-482

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif.2003

    • Author(s)
      Hiroki, Nojima
    • Journal Title

      J.Biol.Chem. 278-18

      Pages: 15461-15646

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Identification of TOR-interacting proteins.2003

    • Author(s)
      Kazuyoshi, Yonezawa
    • Journal Title

      Mol.Interv. 3-4

      Pages: 189-193

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] mTOR/raptor-p 70S6 kinase.2003

    • Author(s)
      Kazuyoshi, Yonezawa
    • Journal Title

      Jpn.J.Nutr.Assess. 20-2

      Pages: 81-85

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] raptor.2003

    • Author(s)
      Kazuyoshi, Yonezawa
    • Journal Title

      Seikagaku 75-4

      Pages: 323-323

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] mTOR complex as an integrating controller of cell growth.2003

    • Author(s)
      Ken-ichi, Yoshino
    • Journal Title

      Tanpakushitsu Kakusan Koso 48-10

      Pages: 1378-1385

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Regulation of protein synthesis by amino acid-dependent signaling system.2003

    • Author(s)
      Noriko, Oshiro
    • Journal Title

      Jpn.J.Nutr.Assess. 20-5

      Pages: 478-482

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Amino san-mTOR-raptor Sigunaru Dentatsukei no Kaimei to Insulin Sayo.2003

    • Author(s)
      Chiharu, Tokunaga
    • Journal Title

      Tonyobyogaku 2003

      Pages: 21-31

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif.2003

    • Author(s)
      Nojima, H.
    • Journal Title

      J.Biol.Chem. 278・18

      Pages: 15461-15464

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 細胞成長を司る情報伝達システムの中央情報集積装置mTOR複合体2003

    • Author(s)
      吉野 健一
    • Journal Title

      蛋白質核酸酵素 48・10

      Pages: 1378-1385

    • NAID

      40005884433

    • Related Report
      2004 Annual Research Report
  • [Journal Article] アミノ酸と細胞内シグナル伝達-蛋白質合成を中心に2003

    • Author(s)
      大城 紀子
    • Journal Title

      栄養評価と治療 20・5

      Pages: 478-482

    • Related Report
      2004 Annual Research Report
  • [Book] NASH and Nutritional Therapy2005

    • Author(s)
      Yonezawa, K.
    • Total Pages
      117
    • Publisher
      Springer-Verlag
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] TOR : Target of Rapamycin (Curr.Top.Microbiol.Immunol.)2004

    • Author(s)
      Yonezawa, K.
    • Total Pages
      366
    • Publisher
      Springer-Verlag
    • 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
  • [Book] 糖尿病学 20032003

    • Author(s)
      徳永 千春
    • Total Pages
      168
    • Publisher
      診断と治療社
    • 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
  • [Patent(Industrial Property Rights)] 哺乳動物のラパマイシン標的蛋白質(mTOP)に結合する性質を持つ新規蛋白質及びその遺伝子2004

    • Inventor(s)
      米澤 一仁, 原 賢太, 吉野 健一, 徳永 千暮
    • Industrial Property Rights Holder
      米澤 一仁, 原 賢太, 吉野 健一, 徳永 千暮
    • Filing Date
      2004-05-27
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Nojima, H.: "The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif"Journal of Biological Chemistry. 278・18. 15461-15464 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 吉野 健一: "細胞成長を司る情報伝達システムの中央情報集積装置mTOR複合体"蛋白質 核酸 酵素. 48・12. 1378-1385 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 大城 紀子: "アミノ酸と細胞内シグナル伝達-蛋白質合成を中心に"栄養評価と治療. 20・5. 478-482 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yonezawa, K.: "Raptor, binding partner of target of rapamycin"Biochemical and Biophysical Research Communications. 313・2. 437-441 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tokunaga, C.: "mTOR integrates amino acid- and energy-sensing pathways"Biochemical and Biophysical Research Communications. 313・2. 443-446 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 徳永 千春: "ラパマイシン標的タンパク質mTORシグナル伝達系"細胞工学. 23・3. 340-348 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Oshiro, N.: "Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function"Genes to Cells. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] 徳永 千春: "糖尿病学2003"(株)診断と治療社. 168 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yonezawa, K.: "TOR : Target of Rapamycin (Current Topics in Microbiology and Immunology)"Springer-Verlag. 366 (2004)

    • Related Report
      2003 Annual Research Report

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

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