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New Insights into the GH-IGF1 axis of Signal Transduction: Elucidation of the Molecular Interactions

Research Project

Project/Area Number 25461394
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Endocrinology
Research InstitutionWakayama Medical University

Principal Investigator

Jing Xuefeng  和歌山県立医科大学, 先端医学研究所, 准教授 (70316123)

Co-Investigator(Kenkyū-buntansha) 澤田 貴宏  和歌山県立医科大学, 先端医学研究所, 非常勤講師 (00382325)
古島 謙亮  和歌山県立医科大学, 医学部, 助教 (50392105)
坂口 和成  和歌山県立医科大学, 先端医学研究所, 教授 (60178548)
宮嶋 正康  和歌山県立医科大学, 共同利用施設, 准教授 (80137257)
新井 大貴  和歌山県立医科大学, 先端医学研究所, 学内助教 (90725574)
Research Collaborator Frank Stuart J.  University of Alabama at Birmingham, Department of Medicine, Division of Endocrinology and Metabolism, MD. Professor and Director
Project Period (FY) 2013-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsEphA4 / GHR / JAK2 / STAT5B / GH-IGF1 / GH-IGF1 軸 / ATAT5B / Eph / ephrin / 分子間相互作用 / GH-IGF1軸シグナル伝達系
Outline of Final Research Achievements

We previously reported that EphA4, a member of the Eph family of RTK, is an important modulator of growth hormone (GH) signaling, leading to augmented synthesis of IGF1 for postnatal body growth. We report here the molecular interactions of EphA4, GH receptor (GHR), JAK2 and STAT5B. EphA4 binds to GHR at both its extracellular and intracellular domains and phosphorylates GHR when stimulated with a ligand. The cytoplasmic domain of EphA4 binds to the carboxy-terminus of JAK2. STAT5B binds to the amino-terminal kinase domain of EphA4. Ligand-activated EphA4 and JAK2 phosphorylate each other and STAT5B, but JAK2 does not appear to phosphorylate EphA4-bound STAT5B. Ligand-activated EphA4 induces the nuclear translocation of STAT5B in a JAK2-independent manner. GHR expression is required for the activation of STAT5B signaling, even via the JAK2-independent pathway. These findings suggest the molecular mechanisms by which ephrin/EphA4 signaling enhances the canonical GH-IGF1 axis.

Report

(5 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Research-status Report
  • 2014 Research-status Report
  • 2013 Research-status Report
  • Research Products

    (11 results)

All 2016 2015 2014 2013 Other

All Int'l Joint Research (1 results) Journal Article (3 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 3 results,  Open Access: 3 results,  Acknowledgement Compliant: 3 results) Presentation (7 results) (of which Invited: 2 results)

  • [Int'l Joint Research] Department of Medicine/Division of Endocrinology and Metabolism/University of Alabama at Birmingham(米国)

    • Related Report
      2016 Annual Research Report
  • [Journal Article] EphA4-deleted microenvironment regulates cancer development and leukemoid reaction of the isografted 4T1 murine breast cancer via reduction of an IGF1 signal2016

    • Author(s)
      Xuefeng Jing (京 雪楓 Corresponding Author), Takashi Sonoki, Masayasu Miyajima, Takahiro Sawada, Nanako Terada, Shigeki Takemura and Kazushige Sakaguchi
    • Journal Title

      Cancer Medicine

      Volume: 1 Issue: 8 Pages: 1-14

    • DOI

      10.1002/cam4.470

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Trans-Activation between EphA and FGFR Regulates Self-Renewal and Differentiation of Mouse Embryonic Neural Stem/Progenitor Cells via Differential Activation of FRS2α2015

    • Author(s)
      Sawada T, Arai D, Xuefeng Jing (京 雪楓 co-first author), Furushima K, Chen Q, Kawakami K, Yokote H, Miyajima M, Sakaguchi K
    • Journal Title

      PLoS One

      Volume: 1 Issue: 5 Pages: 1-15

    • DOI

      10.1371/journal.pone.0128826

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] EphA4 Regulates the Balance between Self-Renewal and Differentiation of Radial Glial Cells and Intermediate Neuronal Precursors in Cooperation with FGF Signaling2015

    • Author(s)
      Chen Q, Arai D, Kawakami K, Sawada T, Xuefeng Jing (京 雪楓), Miyajima M, Hirai S, Sakaguchi K
    • Journal Title

      PLoS One

      Volume: 1 Issue: 5 Pages: 1-24

    • DOI

      10.1371/journal.pone.0126942

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] Host EphA4 regulates Breast cancer progression via crosstalk of humoral and cell-cell contact-mediated signals.2015

    • Author(s)
      Xuefeng Jing (京 雪楓), Takashi Sonoki, Masayasu Miyajima, Takahiro Sawada, Nanako Terada, Shigeki Takemura, Kazushige Sakaguchi
    • Organizer
      The 38th Annual Meeting of the Molecular Biology Society of Japan with the 88th Annual Meeting of the Biochemistry
    • Place of Presentation
      神戸国際会議場
    • Year and Date
      2015-12-01
    • Related Report
      2015 Research-status Report
  • [Presentation] Eph-FGFR-FRS2alpha複合体シグナルがマウス胎生神経細胞の増殖と分化を調節する2015

    • Author(s)
      48.澤田貴宏、新井大貴、京雪楓、古島謙亮、陳清法、河上和紀、横手秀行、宮嶋正康、鎌田一、坂口和成
    • Organizer
      第38回日本分子生物学会年会・第88回日本生化学会大会合同大会
    • Place of Presentation
      神戸国際会議場
    • Year and Date
      2015-12-01
    • Related Report
      2015 Research-status Report
  • [Presentation] EphA4/GH受容体ヘテロ複合体を介するIGF1産生シグナル制御メカニズムの解析(続報)2014

    • Author(s)
      新井大貴、澤田貴宏、京雪楓、古島謙亮、坂口和成
    • Organizer
      日本分子生物学会
    • Place of Presentation
      パシフィコ横浜
    • Year and Date
      2014-11-25 – 2014-11-27
    • Related Report
      2014 Research-status Report
  • [Presentation] 新規体格形成シグナル伝達系における分子機構の解析2014

    • Author(s)
      新井大貴、澤田貴宏、京 雪楓、古島謙亮、河上和紀、陳清法、坂口和成
    • Organizer
      日本内分泌学会
    • Place of Presentation
      福岡国際会議場
    • Year and Date
      2014-04-24 – 2014-04-26
    • Related Report
      2014 Research-status Report
  • [Presentation] 体格決定の新規分子機構2013

    • Author(s)
      坂口和成、澤田貴宏、京雪楓、新井大貴、古島謙亮、飯田啓二、千原和夫、宮嶋正康
    • Organizer
      第86回日本内分泌学会学術総会(招待講演)
    • Place of Presentation
      仙台国際センター
    • Related Report
      2013 Research-status Report
    • Invited
  • [Presentation] Molecular mechanisms of EphA4-mediated signal modulation of the growth hormone (GH)-Insulin-like growth factor 1 (IGF1) axis2013

    • Author(s)
      Takahiro Sawada, Daiki Arai, Xuefeng Jing, Masayasu Miyajima, Qingfa Chen, Kazuki Kawakami, Kenryo Furushima, and Kazushige Sakaguchi
    • Organizer
      ENDO2013 (Endocrine Society's 95th Annual Meeting)
    • Place of Presentation
      San Francisco Convention Center, USA
    • Related Report
      2013 Research-status Report
  • [Presentation] 成長ホルモン(GH)-インスリン様成長因子(IGF1)軸(GH-IGF1 axis)シグナル伝達系の新展開2013

    • Author(s)
      坂口和成、澤田貴宏、新井大貴、京雪楓、古島謙亮、河上和紀、宮嶋正康
    • Organizer
      第56回日本甲状腺学会学術集会(招待講演)
    • Place of Presentation
      和歌山県民文化会館
    • Related Report
      2013 Research-status Report
    • Invited

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Published: 2014-07-25   Modified: 2022-02-16  

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