• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

CUL3 network system in angiogenesis

Research Project

Project/Area Number 16H04698
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Tumor biology
Research InstitutionEhime University

Principal Investigator

HIGASHIYAMA SHIGEKI  愛媛大学, プロテオサイエンスセンター, 教授 (60202272)

Research Collaborator Sakaue Tomohisa  
Maekawa Masashi  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000)
Fiscal Year 2018: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2017: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2016: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
Keywords血管新生 / ユビキチンリガーゼ / cullin3 / BTBドメインタンパク質 / SPOP / ANKFY1 / KCTD10 / VEGFR2 / 血管内皮細胞 / RhoB / Rnd2 / BTBドメイン含有タンパク質 / CUL3 / integrin beta1 / アクチンダイナミクス / BTBP / タンパク質翻訳後修飾 / シグナル伝達 / エピゲノム / CUL3型ユビキチンリガーゼ / 翻訳後修飾
Outline of Final Research Achievements

New blood vessel formation, termed angiogenesis, is an essential process in normal physiology, including tissue development and wound healing, as well as in many pathological conditions such as cancer and diabetes, among other. Endothelial cells play a central role in angiogenesis which is homeostatically regulated on the balance between angiogenic and angiostatic force. We found that CUL3-based ubiquitin E3 ligases play a crucial role of not only sensing this balance, but also regulating multiple steps of angiogenesis, such as endothelial cell growth, spreading and network formation. In this study, we revealed that CUL3-SPOP-DAXX axis positively regulated VEGFR2 mRNA expression, CUL3-ANKFY1-substrate (unidentified yet) axis positively did intracellular membrane trafficking of beta1-Integrin to cell surface, and CUL3-KCTD10-RhoB axis did cell spreading and network formation through the actin dynamics, suggesting that these would be potent targets of anti-angiogenic therapy.

Academic Significance and Societal Importance of the Research Achievements

血管内皮細胞の増殖促進と抑制のシグナルバランス分子機構をタンパク質代謝回転の側面から深く解明することは、これまでの血管内皮細胞増殖シグナル経路以外の血管新生の新たな分子制御機構を解明できる。このことは、これまでのVEGF-VEGFRシステムを中心とした血管内皮細胞増殖シグナル伝達経路とは全く異なる新たな標的分子創薬の側面を作る事が期待でき、今までに無い治療戦略を提案することで社会貢献が可能となり、その意義は極めて大きい。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (34 results)

All 2019 2018 2017 2016 Other

All Int'l Joint Research (3 results) Journal Article (9 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 9 results,  Open Access: 8 results,  Acknowledgement Compliant: 1 results) Presentation (19 results) (of which Int'l Joint Research: 4 results,  Invited: 1 results) Remarks (3 results)

  • [Int'l Joint Research] Sanquin Research, Amsterdam/Vrije Universiteit University(オランダ)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] Sanquin Research, Amsterdam/Vrije University Medical Center/Erasmus University Medical Center(Netherlands)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] University of Amsterdam(オランダ)

    • Related Report
      2016 Annual Research Report
  • [Journal Article] SNX9 determines the surface levels of integrin β1 in vascular endothelial cells: Implication in poor prognosis of human colorectal cancers overexpressing SNX9.2019

    • Author(s)
      Tanigawa K, Maekawa M, Kiyoi T, Nakayama J, Kitazawa R, Kitazawa S, Semba K, Taguchi T, Akita S, Yoshida M, Ishimaru K, Watanabe Y, Higashiyama S.
    • Journal Title

      J Cell Physiol.

      Volume: in press Issue: 10 Pages: 17280-17294

    • DOI

      10.1002/jcp.28346

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cullin‐3/KCTD10 E3 complex is essential for Rac1 activation through RhoB degradation in human epidermal growth factor receptor 2‐positive breast cancer cells2019

    • Author(s)
      Murakami Akari、Maekawa Masashi、Kawai Katsuhisa、Nakayama Jun、Araki Nobukazu、Semba Kentaro、Taguchi Tomohiko、Kamei Yoshiaki、Takada Yasutsugu、Higashiyama Shigeki
    • Journal Title

      Cancer Science

      Volume: 110 Issue: 2 Pages: 650-661

    • DOI

      10.1111/cas.13899

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Biochemical and histological evidence of deteriorated bioprosthetic valve leaflets: the accumulation of fibrinogen and plasminogen2018

    • Author(s)
      Sakaue Tomohisa、Nakaoka Hirotomo、Shikata Fumiaki、Aono Jun、Kurata Mie、Uetani Teruyoshi、Hamaguchi Mika、Kojima Ai、Uchita Shunji、Yasugi Takumi、Higashi Haruhiko、Suzuki Jun、Ikeda Shuntaro、Higaki Jitsuo、Higashiyama Shigeki、Izutani Hironori
    • Journal Title

      Biology Open

      Volume: 7 Issue: 8

    • DOI

      10.1242/bio.034009

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cullin 3 regulates ADAMs-mediated ectodomain shedding of amphiregulin2018

    • Author(s)
      Nakayama Hironao、Sakaue Tomohisa、Maekawa Masashi、Fujisaki Ayako、Higashiyama Shigeki
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 499 Issue: 1 Pages: 17-23

    • DOI

      10.1016/j.bbrc.2018.03.097

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Cullin-3-Rbx1-KCTD10 complex controls endothelial barrier function via K63 ubiquitination of RhoB2018

    • Author(s)
      Kovacevic Igor、Sakaue Tomohisa、Majolee Jisca、Pronk Manon C.、Maekawa Masashi、Geerts Dirk、Fernandez-Borja Mar、Higashiyama Shigeki、Hordijk Peter L.
    • Journal Title

      The Journal of Cell Biology

      Volume: 217 Issue: 3 Pages: 1015-1032

    • DOI

      10.1083/jcb.201606055

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Prospect of divergent roles for the CUL3 system in vascular endothelial cell function and angiogenesis2017

    • Author(s)
      Sakaue Tomohisa、Maekawa Masashi、Nakayama Hironao、Higashiyama Shigeki
    • Journal Title

      The Journal of Biochemistry

      Volume: 162 Pages: 237-245

    • DOI

      10.1093/jb/mvx051

    • NAID

      40021380486

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cullin-3 and its adaptor protein ANKFY1 determine the surface level of integrin beta1 in endothelial cells.2017

    • Author(s)
      Maekawa M, Tanigawa K, Sakaue T, Hiyoshi H, Kubota E, Joh T, Watanabe Y, Taguchi T, Higashiyama S
    • Journal Title

      Biolology Open

      Volume: 6 Pages: 1707-1719

    • DOI

      10.1242/bio.029579

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The CUL3-SPOP-DAXX axis is a novel regulator of VEGFR2 expression in vascular endothelial cells2017

    • Author(s)
      Sakaue T, Sakakibara I, Fujisaki A, Uesugi T, Nakashiro K, Hamakawa H, Kubota E, Joh T, Imai Y, Izutani H, Higashiyama S.
    • Journal Title

      Sci Rep.

      Volume: 7 Issue: 1 Pages: 42845-42845

    • DOI

      10.1038/srep42845

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Neddylated Cullin 3 is required for vascular endothelial-cadherin-mediated endothelial barrier function.2017

    • Author(s)
      Sakaue T, Fujisaki A, Nakayama H, Maekawa M, Hiyoshi H, Kubota E, Joh T, Izutani H, Higashiyama S.
    • Journal Title

      Cancer Sci.

      Volume: 108 Issue: 2 Pages: 208-215

    • DOI

      10.1111/cas.13133

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] 血管内皮細胞運動を制御する新規CUL3複合体の解析2018

    • Author(s)
      坂上倫久、藤崎亜耶子、前川大志、高橋宏隆、澤崎達也、泉谷裕則、東山繁樹
    • Organizer
      第59回 日本生化学会 中国・四国支部例会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 血管新生を制御するCUL3ユビキチンE3複合体依存的な細胞内膜輸送2018

    • Author(s)
      前川大志,谷川和史,坂上倫久,渡部祐司、田口友彦,東山繁樹
    • Organizer
      第59回 日本生化学会 中国・四国支部例会
    • Related Report
      2018 Annual Research Report
  • [Presentation] CUL3複合体を標的とした新規血管新生阻害化合物の探索2018

    • Author(s)
      坂上倫久、藤崎亜耶子、竹田浩之、前川大志、高橋宏隆 、澤崎達也 、 泉谷裕則 、東山繁樹
    • Organizer
      第23回日本病態プロテアーゼ学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] CUL3型ユビキチンリガーゼ複合体による血管新生制御機構2018

    • Author(s)
      坂上倫久、前川大志、藤崎亜耶子、高橋宏隆、竹田浩之、中山寛尚、澤崎達也、泉谷裕則、東山繁樹
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Cullin-3-based E3 ubiquitin ligases as novel modulators of VEGF signal transduction2018

    • Author(s)
      Tomohisa Sakaue, Ayako Fujisaki, Masashi Maekawa, Hironori Izutani Shigeki Higashiyama
    • Organizer
      The 16th Korea-Japan Joint Symposium on Vascular Biology(K-J meeting)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] CUL3-based E3 ubiquitin ligase complex is essential for vascular endothelial cell motility2018

    • Author(s)
      14.Tomohisa Sakaue、Ayako Fujisaki、Masashi Maekawa、Hirotaka Takahashi、Tatsuya Sawasaki、Hironori Izutani、Shigeki Higashiyama
    • Organizer
      20th International Vascular Biology Meeting
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 血管新生を制御する細胞内膜輸送関連分子の探索2017

    • Author(s)
      谷川和史、前川大志、藤崎亜耶子, 渡部祐司、東山繁樹
    • Organizer
      第58回日本生化学会中国・四国支部例会
    • Related Report
      2017 Annual Research Report
  • [Presentation] ユビキチンリガーゼCUL3-BTB複合体解析システムの構築2017

    • Author(s)
      藤崎亜耶子、坂上倫久、前川大志、高橋宏隆、澤崎達也、泉谷裕則、東山繁樹
    • Organizer
      第22回日本病態プロテアーゼ学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 血管新生制御を担うCul3-based ubiquitin ligaseの機能解析2017

    • Author(s)
      坂上倫久、藤崎亜耶子、前川大志、高橋宏隆、澤崎達也、泉谷裕則、東山繁樹
    • Organizer
      第22回日本病態プロテアーゼ学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 血管内皮細胞におけるユビキチンE3リガーゼ複合体依存的な細胞内膜輸送2017

    • Author(s)
      前川大志、谷川和史、坂上倫久、渡部祐司、田口友彦、東山繁樹
    • Organizer
      ConBio2017
    • Related Report
      2017 Annual Research Report
  • [Presentation] NEDD8化シグナル伝達経路は血管内皮細胞運動を制御する2017

    • Author(s)
      坂上倫久、前川大志、藤崎亜耶子、高橋宏隆、澤崎達也、泉谷裕則、東山繁樹
    • Organizer
      ConBio2017
    • Related Report
      2017 Annual Research Report
  • [Presentation] 新規CUL3複合体による血管新生制御機構2017

    • Author(s)
      坂上倫久、前川大志、藤崎亜耶子、高橋宏隆、澤崎達也、泉谷裕則、東山繁樹
    • Organizer
      第25回日本血管生物医学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] CUL3-SPOP-DAXX axis is a novel regulator of VEGFR2 expression in endothelial cells.2016

    • Author(s)
      Sakaue Tomohisa, Fujisaki Ayako, Izutani Hironori, Higashiyama Shigeki
    • Organizer
      The 19th International Vascular Biology Meeting
    • Place of Presentation
      Boston
    • Year and Date
      2016-10-30
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 血管内皮細胞におけるCUL3によるVEGF-A応答制御機構2016

    • Author(s)
      坂上 倫久, 藤崎 亜耶子, 泉谷 裕則, 東山 繁樹
    • Organizer
      第89回日本生化学会大会
    • Place of Presentation
      仙台
    • Year and Date
      2016-09-25
    • Related Report
      2016 Annual Research Report
  • [Presentation] CUL3によるVE-cadherinモジュレーションを介した血管内皮細胞接着制御機2016

    • Author(s)
      藤崎亜耶子, 坂上倫久, 中山寛尚, 前川大志, 東山繁樹
    • Organizer
      第89回日本生化学会大会
    • Place of Presentation
      仙台
    • Year and Date
      2016-09-25
    • Related Report
      2016 Annual Research Report
  • [Presentation] CUL3-KLHL20軸による細胞内タンパク質輸送制御機構の解析2016

    • Author(s)
      宇都宮果歩, 深江舜也, 上杉恭広, 坂上倫久, 中山寛尚, 前川大志, 泉谷裕則, 東山繁樹
    • Organizer
      第89回日本生化学会大会
    • Place of Presentation
      仙台
    • Year and Date
      2016-09-25
    • Related Report
      2016 Annual Research Report
  • [Presentation] CUL3による血管内皮細胞活性化制御機構2016

    • Author(s)
      坂上倫久, 藤崎亜耶子, 泉谷裕則, 東山繁樹
    • Organizer
      日本病態プロテアーゼ学会
    • Place of Presentation
      大阪
    • Year and Date
      2016-08-05
    • Related Report
      2016 Annual Research Report
  • [Presentation] CUL3によるVE-cadherinを介した血管内皮細胞接着制御2016

    • Author(s)
      藤崎亜耶子, 坂上倫久, 中山寛尚, 前川大志, 東山繁樹
    • Organizer
      第57回日本生化学会中国・四国支部例会
    • Place of Presentation
      高知
    • Year and Date
      2016-05-27
    • Related Report
      2016 Annual Research Report
  • [Presentation] CUL3-SPOP-DAXX axis is a novel regulator of VEGFR2 expression in vascular endothelial cells.2016

    • Author(s)
      Tomohisa Sakaue, Ayako Fujisaki, Hironori Izutani, Shigeki Higashiyama
    • Organizer
      Protein Island Matsuyama 2016 & The 14th Matsuyama International Symposium
    • Place of Presentation
      Matsuyama
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Remarks] Ehime University Proteo-Science Center

    • URL

      https://www.m.ehime-u.ac.jp/school/biochem2/

    • Related Report
      2018 Annual Research Report
  • [Remarks] 愛媛大学プロテオサイエンスセンター 細胞増殖・腫瘍制御部門

    • URL

      https://www.m.ehime-u.ac.jp/school/biochem2/

    • Related Report
      2017 Annual Research Report
  • [Remarks] Proteo-Science Center (PROS), Ehime University

    • URL

      http://www.m.ehime-u.ac.jp/school/biochem2/

    • Related Report
      2016 Annual Research Report

URL: 

Published: 2016-04-21   Modified: 2022-02-01  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi