Roles of Girdin in neural and cancer cell migration along vessels

• Project/Area Number: 15K08399
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Nagoya University
• Principal Investigator: Asai Naoya 名古屋大学, 医学系研究科, 准教授 (80273233)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 脳神経発生 / チロシンリン酸化 / GEF活性 / 遺伝子改変動物 / 細胞移動 / タンパク質リン酸化 / 中枢神経の発生 / 線維化 / 細胞運動 / 蛋白リン酸化 / 疾患モデルマウス / 癌 / 神経

Outline of Final Research Achievements

Girdin play important roles for brain development at hippocampus, olfacrory blub/RMS, anterior commissure and GABAergic neurons of cortex. Girdin has two tyrosine phosphorylation sites and GEF domain, but these functions in vivo have not been clear.
To study the function of Girdin tyrosine phosphorylation at Y1764 and Y1798, we generated Girdin Y1764,1798F mutant mice. Mutant mice show no obvious phenotype at hippocampus and olfactory bulb/RMS, which may indicate the less important roles of Girdin tyrosine phosphorylation for cell motility at developing brain. In addition, we generate Girdin F1696A mutant mice, which would lack GEF activity of Girdin. Mutant mice show abnormal brain structure at hippocampus and olfactory blub/RMS resembling Girdin knockout mice. Mutant mice also show milder phenotypes at anterior commissure and distribution of GABAergic neurons in cortex. These data suggest importance of Girdin GEF activity for cell motility.

Research Products

• [Int'l Joint Research] University of Cambridge/Addenbrooke’s Hospital(英国)
• [Journal Article] Negative regulation of amino acid signaling by MAPK-regulated 4F2hc/Girdin complex. (2018)
  • Author(s): Liang Weng , Yi-Peng Han, Atsushi Enomoto, Yasuyuki Kitaura, Shushi Nagamori, Yoshikatsu Kanai, Naoya Asai, Jian An, Maki Takagishi, Masato Asai, Shinji Mii, Takashi Masuko, Yoshiharu Shimomura, Masahide Takahashi.
  • Journal Title: PLoS Biol. Volume: 16
  • DOI: 10.1371/journal.pbio.2005090
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Significance of perivascular tumour cells defined by CD109 expression in progression of glioma. (2017)
  • Author(s): Shiraki Yukihiro、Mii Shinji、Enomoto Atsushi、Momota Hiroyuki、Han Yi-Peng、Kato Takuya、Ushida Kaori、Kato Akira、Asai Naoya、Murakumo Yoshiki、Aoki Kosuke、Suzuki Hiromichi、Ohka Fumiharu、Wakabayashi Toshihiko、Todo Tomoki、Ogawa Seishi、Natsume Atsushi、Takahashi Masahide
  • Journal Title: J Pathol. Volume: 243 Pages: 468-480
  • DOI: 10.1002/path.4981
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Daple Coordinates Planar Polarized Microtubule Dynamics in Ependymal Cells and Contributes to Hydrocephalus. (2017)
  • Author(s): Maki Takagishi, Masato Sawada, Shinya Ohata, Naoya Asai, Atsushi Enomoto, Kunihiko Takahashi, Liang Weng, Kaori Ushida, Hosne Ara, Shigeyuki Matsui, Kozo Kaibuchi,3Kazunobu Sawamoto, and Masahide Takahashi.
  • Journal Title: Cell Rep. Volume: 20 Pages: 960-972
  • DOI: 10.1016/j.celrep.2017.06.089
  • Peer Reviewed / Open Access
• [Journal Article] Significance of low mTORC1 activity in defining the characteristics of brain tumor stem cells. (2017)
  • Author(s): Han YP, Enomoto A, Shiraki Y, Wang SQ, Wang X, Toyokuni S, Asai N, Ushida K, Ara H, Ohka F, Wakabayashi T, Ma J, Natsume A, Takahashi M.
  • Journal Title: Neuro Oncol. Volume: 19 Pages: 636-647
  • DOI: 10.1093/neuonc/now237
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Tyrosine Phosphorylation of an Actin-Binding Protein Girdin Specifically Marks Tuft Cells in Human and Mouse Gut (2017)
  • Author(s): Kuga D, Ushida K, Mii S, Enomoto A, Asai N, Nagino M, Takahashi M, Asai M.
  • Journal Title: J Histochem Cytochem. Volume: 65(6) Pages: 347-366
  • DOI: 10.1369/0022155417702586
  • Peer Reviewed
• [Journal Article] Suppression of skin tumorigenesis in CD109-deficient mice (2016)
  • Author(s): Sunagawa M, Mii S, Enomoto A, Kato T, Murakumo Y, Shiraki Y, Asai N, Asai M, Nagino M, Takahashi M.
  • Journal Title: Oncotarget. Volume: 7 Pages: 82836-82850
  • DOI: 10.18632/oncotarget.12653
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Significance of low mTORC1 activity in defining the characteristics of brain tumor stem cells. (2016)
  • Author(s): Han YP, Enomoto A, Shiraki Y, Wang SQ, Wang X, Toyokuni S, Asai N, Ushida K, Ara H, Ohka F, Wakabayashi T, Ma J, Natsume A, Takahashi M.
  • Journal Title: Neuro Oncol. Volume: -
  • Peer Reviewed
• [Journal Article] CCDC88A mutations cause PEHO-like syndrome in humans and mouse. (2016)
  • Author(s): Nahorski MS, Asai M, Wakeling E, Parker A, Asai N, Canham N, Holder SE, Chen YC, Dyer J, Brady AF, Takahashi M, Woods CG.
  • Journal Title: Brain Volume: 139 Pages: 1036-1044
  • DOI: 10.1093/brain/aww014
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Collective invasion of cancer: Perspectives from pathology and development. (2016)
  • Author(s): Wang X, Enomoto A, Asai N, Kato T, Takahashi M
  • Journal Title: Pathology International Volume: 66 Pages: 183-192
  • DOI: 10.1111/pin.12391
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Akt-dependent Girdin phosphorylation regulates repair processes after acute myocardial infarction (2015)
  • Author(s): Hayano S, Takefuji M, Maeda K, Noda T, Ichimiya H, Kobayashi K, Enomoto A, Asai N, Takahashi M, Murohara T.
  • Journal Title: J. Mol. Cell. Cardiol. Volume: 88 Pages: 55-63
  • DOI: 10.1016/j.yjmcc.2015.09.012
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Potential involvement of kinesin-1 in the regulation of subcellular localization of Girdin. (2015)
  • Author(s): Aya Muramatsu, Atsushi Enomoto, Takuya Kato, Liang Weng, Keisuke Kuroda, Naoya Asai, Masato Asai, Shinji Mii, Masahide Takahashia
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 463 Pages: 999-1005
  • DOI: 10.1016/j.bbrc.2015.06.049
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Akt-Girdin as oncotarget. (2015)
  • Author(s): Takahashi M, Asai N, Enomoto A.
  • Journal Title: Oncoscience. Volume: 2(10) Pages: 811-812
• [Remarks] 腫瘍病理学／神経機能病理学(病理学第二) 独自ホームページ
  • URL: https://www.med.nagoya-u.ac.jp/patho2/
• [Remarks] 名古屋大学医学部・大学院医学系研究科 腫瘍病理学・分子病理学分野
  • URL: http://www.med.nagoya-u.ac.jp/patho2/