Elucidation of the physiological functions of the EGF receptor downstream adaptor proteins GAREM and CLPABP

• Project/Area Number: 17K07341
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Shinshu University (2020); Prefectural University of Hiroshima (2017-2019)
• Principal Investigator: Konishi Hiroaki 信州大学, 学術研究院農学系, 教授 (40252811)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 細胞情報伝達 / タンパク質リン酸化 / アダプタータンパク質 / ノックアウトマウス / タンパク質凝集 / シグナル伝達 / 遺伝疾患 / 脳機能 / 脂質修飾 / 行動解析 / 蛋白質

Outline of Final Research Achievements

We generated knockout (KO) mice of GAREM1 (expressed in a wide range of organs) and GAREM2 (expressed specifically in the brain), and found that GAREM1 KO mice were light in weight (in preparation for publication), and GAREM2 KO mice showed low anxiety and high activity by behavioral analysis. Our collaborators also found that GAREM1 is involved in heart disease in humans.
They found that CLPABP can bind tightly to the outer mitochondrial membrane surface by myristoylation of its amino terminus. In addition, RNA-seq revealed that the expression levels of a number of mRNAs were altered depending on whether CLPABP was expressed or not.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は4報の国際学術誌にすでに発表済みである。また、今後のさらに研究を発展させるための科研費にも採択された。
近年、生命科学研究における技術や情報がさらに充実し、ヒト疾患等の係わる遺伝子の変異やタンパク質の異常に関して多数の報告がなされている。申請者の所属先でそのような規模の研究を単独で遂行することは困難であるが、申請者らが機能解析を続けてきたタンパク質とヒト疾患の関係についての報告が国内外から徐々に出始めている。

Research Products

• [Journal Article] Effect of the glycine-rich domain in GAREM2 on its unique subcellular localization upon EGF stimulation. (2021)
  • Author(s): Nishino T, Oshika T, Kyan M, Konishi H.
  • Journal Title: Cell Mol Biol Lett. Volume: 26 Issue: 1 Pages: 16-16
  • DOI: 10.1186/s11658-021-00260-1
  • Peer Reviewed / Open Access
• [Journal Article] Behavioral alterations in mice deficient for GAREM2 (Grb2-associated regulator of Erk/MAPK subtype2) that is a subtype of highly expressing in the brain (2019)
  • Author(s): Nishino, T., Tamada, K., Maeda, A., Abe, T., Kiyonari, H., Funahashi, Y., Kaibuchi, K., Takumi, T., and Konishi, H.
  • Journal Title: Mol. Brain Volume: 12 Issue: 1 Pages: 94-94
  • DOI: 10.1186/s13041-019-0512-x
  • Peer Reviewed / Open Access
• [Journal Article] Transglutaminase-mediated cross-linking of WDR54 regulates EGF receptor-signaling. (2019)
  • Author(s): Maeda A, Nishino T, Matsuzaki R, Yokoyama A, Suga H, Yagi T, Konishi H.
  • Journal Title: Biochim Biophys Acta Mol Cell Res. Volume: 1866 Issue: 2 Pages: 285-295
  • DOI: 10.1016/j.bbamcr.2018.11.009
  • Peer Reviewed / Open Access
• [Journal Article] Role of N-myristoylation in stability and subcellular localization of the CLPABP protein. (2018)
  • Author(s): Maeda A, Uchida M, Nishikawa S, Nishino T, Konishi H.
  • Journal Title: Biochem Biophys Res Commun. Volume: 495 Issue: 1 Pages: 1249-1256
  • DOI: 10.1016/j.bbrc.2017.11.112
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] GAREM1 regulates the PR interval on electrocardiograms. (2018)
  • Author(s): Kim HO, Lim JE, Kim MJ, Kang JO, Kim SM, Nam JM, Tak J, Konishi H, Nishino T, Koh IS, Jin YH, Baik HH, Kim JB, Kim MK, Choi BY, Lee SH, Jang Y, Shin J, Oh B.
  • Journal Title: J Hum Genet. Volume: 63 Issue: 3 Pages: 297-307
  • DOI: 10.1038/s10038-017-0367-x
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 基底膜の起源―単細胞ホロゾアのラミニン様遺伝子の機能解析 (2020)
  • Author(s): 傳保聖太郎、福原光海、小西博昭、八木俊樹、菅裕
  • Organizer: 日本進化学会第22回オンライン大会 PA-81
• [Presentation] 単細胞ホロゾア解析を通じた動物の細胞間連絡の起源解明 (2020)
  • Author(s): 日野礼仁、小野真実、小西博昭、八木俊樹、菅裕
  • Organizer: 日本進化学会第22回オンライン大会 PA-96
• [Presentation] 基底膜の起源－単細胞ホロゾアにおけるラミニン様遺伝子の機能解析 (2019)
  • Author(s): 傳保聖太郎、福原光海、國村尚人、佐藤香帆、畑村朱里、小西博昭、八木俊樹、菅裕
  • Organizer: 日本進化学会第21回大会 OA05-02
• [Presentation] 単細胞ホロゾアCapsaspora owczarazaki におけるNotch 様遺伝子の機能解析 (2019)
  • Author(s): 青野克俊、小出尚史、國村尚人、山原直樹、畑村朱里、八木俊樹、小西博昭、菅裕
  • Organizer: 日本進化学会第21回大会 PA-011
• [Presentation] 細胞内で架橋形成する機能未知タンパク質WDR（WD-like repeat）54の機能解析 (2018)
  • Author(s): 前田 朱音, 西野 扶, 菅 裕, 八木 俊樹, 小西 博昭
  • Organizer: 第91回日本生化学会大会