The mechanism of regulation for cell polarity in heart targeting ischemic heart disease treatment

• Project/Area Number: 25461119
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: Nakano Atsushi 国立研究開発法人国立循環器病研究センター, 研究開発基盤センター, 室長 (90648106)
• Co-Investigator(Kenkyū-buntansha): KITAKAZE Masafumi 国立循環器病研究センター, 研究開発基盤センター, 部長 (20294069)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 循環器・高血圧 / 細胞極性 / 分子生物学

Outline of Final Research Achievements

In cell biology, AMP activated protein kinase (AMPK) is known to be a key protein kinase to regulate and maintain cell migration and polarity by phosphorylating cytoplasmic linker protein 170 (CLIP-170), a downstream target of AMPK. However, the function in vivo is not understood. In this study, we examined whether AMPK-CLIP-170 axis play a crucial role for cell migration and polarity at early development stage of heart. By using a line of zebrafish (hspGEF3A) that express target genes specifically at 1 atrial 1 ventricle zebrafish heart, we expressed mutant CLIP-170 gene resistant to phosphorylation by AMPK in heart, and found that the fish showed opposite direction of heart looping. These results suggest that AMPK-CLIP-170 axis play a crucial role for establishment of cell migration and polarity in heart.

Research Products

• [Journal Article] Augmented AMPK activity inhibits cell migration by phosphorylating the novel substrate Pdlim5. (2015)
  • Author(s): Yan Y, Tsukamoto O, Nakano A, Kato H, Kioka H, Ito N, Higo S, Yamazaki S, Shintani Y, Matsuoka K, Liao Y, Asanuma H, Asakura M, Takafuji K, Minamino T, Asano Y, Kitakaze M, Takashima S.
  • Journal Title: Nat Commun. Volume: 6 Issue: 1 Pages: 6137-6137
  • DOI: 10.1038/ncomms7137
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Higdla is a oositive regulaator of cytochrome c oxidase (2015)
  • Author(s): T. Hayashi, Y. Asano, Y. Shintani, H. Aoyama, H. Kioka, O. Tsukamoto, M. Hikita, K. Shinzawa-Itoh, K. Takajuji, S. Higo, H. Kato, S. Yamazaki, K. Matsuoka, A. Nakano, H. Asanuma, M. Asakura, T. Minamino, Y. Goto, T. Ogura, M. Kitakaze, I. Komuro, Y. Sakata, T. Tsukihara, S. Yoshikawa, S. Takashima
  • Journal Title: Proc. Nat. Acad. Sci. U.S.A. Volume: 112 Issue: 5 Pages: 1553-1558
  • DOI: 10.1073/pnas.1419767112
  • Peer Reviewed / Open Access
• [Journal Article] Plk1 phosphorylates CLIP-170 and regulates its binding to microtubules for chromosome alignment (2014)
  • Author(s): Kakeno M, Matsuzawa K, Matsui T, Akita H, Sugiyama I, Ishidate F, Nakano A, Takashima S, Goto H, Inagaki M, Kaibuchi K, Watanabe T
  • Journal Title: Cell Struct Funct Volume: 39 Pages: 45-59
  • NAID: 130004053900
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Evaluation of intra-mitochondrial ATP levels identifies G0/G1 switch gene 2 as a positive regulator of oxidative phosphorylation (2013)
  • Author(s): Kioka H, Kato H, Fujikawa M, Tsukamoto O, Suzuki T, Imamura H, Nakano A, Higo S, Yamazaki S, Matsuzaki T, Tkafuji K, Asanuma H, Asakura M, Minamino T, Shintani Y, Yoshida M, Noji H, Kitakaze M, Komuro I, Asano Y and Takashima S
  • Journal Title: PNAS Volume: 111 Issue: 1 Pages: 273-278
  • DOI: 10.1073/pnas.1318547111
  • Peer Reviewed / Open Access
• [Presentation] Phosphorylation of CLIP-170 by AMPK plays a crucial role for the speed of microtubule polymerization and directional cell migration (2014)
  • Author(s): Atsushi Nakano, Seiji Takashima, Naoki Mochizuki, Masafumi Kitakaze
  • Organizer: Federation of American Societies for Experimental Biology Science Research Conference, AMPK: Biological Action and Therapeutic Perspectives
  • Place of Presentation: Barga, Lucca, Italy
  • Year and Date: 2014-09-28 – 2014-10-03