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Elucidation of pathogenesis of Noonan syndrome by novel causative gene LZTR1

Research Project

Project/Area Number 18K15657
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 52050:Embryonic medicine and pediatrics-related
Research InstitutionTohoku University

Principal Investigator

Abe Taiki  東北大学, 医学系研究科, 助教 (40810594)

Project Period (FY) 2018-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
KeywordsRASopathies / Noonan症候群 / ユビキチン・プロテアソーム経路 / LZTR1 / RAS/MAPK / RAS / ポリユビキチン修飾 / 遺伝学 / 先天奇形症候群 / RAS/MAPKシグナル伝達経路
Outline of Final Research Achievements

Leucine zipper-like transcriptional regulator 1 (LZTR1) encodes a member of the BTB-Kelch superfamily, which interacts with the Cullin3 (CUL3)-based E3 ubiquitin ligase complex. LZTR1 is a causative gene of RASopathies, which are caused by germline mutations in genes encoding various components of the RAS/MAPK signaling pathway. However, no evidence regarding the functional interaction between LZTR1 and the RAS/MAPK signaling pathway had been reported.
In this study, we revealed that (1) LZTR1 regulates RAS/MAPK signal activity through the interaction of RAS and PPP1CB/SHOC2 /cRAF-complex, and (2) LZTR1 is involved in RAS degradation via the ubiquitin-proteasome pathway.

Academic Significance and Societal Importance of the Research Achievements

LZTR1はRASopahitesの原因分子であるとされていたもののRAS/MAPKシグナル伝達経路との関係は不明であった。そのため、治療法や治療薬の開発に際して治療標的分子を絞り込むことができず、各症状に対する対症療法以外に手立てがなかった。加えて、RASopathiesに分類される疾患は希少疾患であるためがんなどの大衆疾患に比べて研究開発が遅れている領域である。今回、LZTR1とRAS/MAPKシグナル伝達経路との関係が解明されたことで、治療薬開発における標的分子が明確となり、将来的な治療薬の開発が大いに期待される。

Report

(3 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • Research Products

    (7 results)

All 2019 2018

All Journal Article (3 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 3 results,  Open Access: 2 results) Presentation (4 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] LZTR1 facilitates polyubiquitination and degradation of RAS-GTPases2019

    • Author(s)
      Abe Taiki、Umeki Ikumi、Kanno Shin-ichiro、Inoue Shin-ichi、Niihori Tetsuya、Aoki Yoko
    • Journal Title

      Cell Death & Differentiation

      Volume: 27 Issue: 3 Pages: 1023-1035

    • DOI

      10.1038/s41418-019-0395-5

    • NAID

      130007898368

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Germline-Activating RRAS2 Mutations Cause Noonan Syndrome2019

    • Author(s)
      Niihori Tetsuya、Nagai Koki、Fujita Atsushi、Ohashi Hirofumi、Okamoto Nobuhiko、Okada Satoshi、Harada Atsuko、Kihara Hirotaka、Arbogast Thomas、Funayama Ryo、Shirota Matsuyuki、Nakayama Keiko、Abe Taiki、Inoue Shin-ichi、Tsai I-Chun、Matsumoto Naomichi、Davis Erica E.、Katsanis Nicholas、Aoki Yoko
    • Journal Title

      The American Journal of Human Genetics

      Volume: 104 Issue: 6 Pages: 1233-1240

    • DOI

      10.1016/j.ajhg.2019.04.014

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes2018

    • Author(s)
      Umeki Ikumi、Niihori Tetsuya、Abe Taiki、Kanno Shin-ichiro、Okamoto Nobuhiko、Mizuno Seiji、Kurosawa Kenji、Nagasaki Keisuke、Yoshida Makoto、Ohashi Hirofumi、Inoue Shin-ichi、Matsubara Yoichi、Fujiwara Ikuma、Kure Shigeo、Aoki Yoko
    • Journal Title

      Human Genetics

      Volume: 138 Issue: 1 Pages: 21-35

    • DOI

      10.1007/s00439-018-1951-7

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Presentation] Noonan症候群原因遺伝子産物LZTR1によるRAS分解促進機構の解明2019

    • Author(s)
      阿部 太紀、梅木 郁美、菅野 新一郎、井上 晋一、新堀 哲也、青木 洋子
    • Organizer
      第42回日本分子生物学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Noonan症候群の原因遺伝子LZTR1―臨床的特徴と結合タンパクRAF1/PPP1CBの同定2019

    • Author(s)
      梅木郁美,新堀哲也,阿部太紀,長崎啓祐,井上晋一,藤原幾磨,呉繁夫,青木洋子
    • Organizer
      日本内分泌学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Noonan症候群類縁疾患の網羅的解析とLZTR1の機能解明2019

    • Author(s)
      青木 洋子,梅木 郁美,阿部 太紀,岡本 伸彦,水野 誠司,黒澤 健司,長崎 啓祐,吉田 真,大橋 博文,井上 晋一,松原 洋一,藤原 幾磨,呉 繁夫,新堀 哲也
    • Organizer
      日本遺伝カウンセリング学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] LZTR1 facilitates polyubiquitination and degradation of RAS-GTPases2019

    • Author(s)
      Taiki Abe,Ikumi Umeki,Shin-ichiro Kanno,Shin-ichi Inoue,Tetsuya Niihori,Yoko Aoki
    • Organizer
      Tohoku University Thematic Forum for Creativity Cancer from Biology to Acceptance
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research

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Published: 2018-04-23   Modified: 2021-02-19  

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