Physiological functions of the Akt substrate Girdin and its family proteins and their roles in pathogenesis

• Project/Area Number: 19209013
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Nagoya University
• Principal Investigator: TAKAHASHI Masahide (TAKAHASHI Mashide) Nagoya University, 大学院・医学系研究科, 教授 (40183446)
• Co-Investigator(Kenkyū-buntansha): ASAI Naoya 名古屋大学, 大学院・医学系研究科, 准教授 (80273233) ; ENOMOTO Atsushi 名古屋大学, 大学院・医学系研究科, 特任准教授 (20432255)
• Project Period (FY): 2007 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥49,530,000 (Direct Cost: ¥38,100,000、Indirect Cost: ¥11,430,000); Fiscal Year 2010: ¥12,090,000 (Direct Cost: ¥9,300,000、Indirect Cost: ¥2,790,000); Fiscal Year 2009: ¥12,090,000 (Direct Cost: ¥9,300,000、Indirect Cost: ¥2,790,000); Fiscal Year 2008: ¥12,090,000 (Direct Cost: ¥9,300,000、Indirect Cost: ¥2,790,000); Fiscal Year 2007: ¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000)
• Keywords: Girdin / Akt / アクチン結合蛋白 / 細胞運動 / がん細胞の浸潤 / 血管新生 / 神経新生 / Gipie / GRP78 / ERストレス / 血管内皮 / 内膜損傷モデル / 海馬 / 嗅球 / ノックアウトマウス / 神経発生 / AKT / VEGF

Research Abstract

We investigated the physiological roles of Akt substrate Girdin using a variety of cell lines and gene-targeting mice. Girdin knockdown by siRNA in various cell lines including fibroblasts, cancer cells, endothelial cells and vascular smooth muscle cells, significantly impaired their migration. Impaired cell migration by Girdin knockdown was due to the impairment of lamellipodia formation at the leading edge of migrating cells, suggesting that Girdin plays a role in actin reorganization at the leading edge. In addition, analysis of Girdin knockout mice demonstrated that Girdin plays a crucial role in postnatal angiogenesis and neurogenesis. Vascular development in the retina and brain cortex in Girdin knockout mice decreased to 60-70% compared with that of wild-type mice. Girdin deficiency also leads to overextended migration and mispositioning of the dentate granule cells, resulting in profound cytoarchitectural disorganization of the dentate gyrus which is known to develop during the early postnatal period. A novel Girdin family protein, Gipie, is expressed in endothelial cells, where it interacts with GRP78, a master regulator of ER stress. Our study indicated that Gipie/GRP78 interaction protects endothelial cells against ER stree-induced apoptosis.

Research Products

• [Journal Article] Loss of Sprouty2 partially rescues renal hypoplasia and stomach hypoganglionosis but not intestinal aganglionosis in Ret Y1062F mutant mice. (2011)
  • Author(s): Miyamoto, R., Jijiwa, M., Asai, M., Kawai, K., Ishida-Takagishi, M., Mii, S., Asai, N., Enomoto, A., Murakumo, Y., Yoshimura, A., Takahashi M.
  • Journal Title: Dev.Biol. 349 Pages: 160-168
  • Peer Reviewed
• [Journal Article] Protective role of Gipie, a Girdin family protein, in endoplasmic reticulum stress responses in endothelial cell (2011)
  • Author(s): Etsushi Matsushita
  • Journal Title: Molecular Biology of the Cell Volume: (印刷中,未定)
  • Peer Reviewed
• [Journal Article] dGirdin a new player of Akt /PKB signaling in Drosophila Melanogaster. (2010)
  • Author(s): Yamaguchi, M., Suyari, O., Nagai, R., Takahashi M.
  • Journal Title: Front Biosci. 15 Pages: 1164-1171
  • Peer Reviewed
• [Journal Article] Girding for migratory cues: Role of the Akt substrate Girdin in cancer progression and angiogenesis. (2010)
  • Author(s): Weng, L., Enomoto, A., Ishida-Takagishi, M.,Asai, N., Takahashi M.
  • Journal Title: Cancer Sci. 101 Pages: 836-842
  • NAID: 10026590367
  • Peer Reviewed
• [Journal Article] Girding for migratory cues : Role of the Akt substrate Girdin incancer progression and angiogenesis (2010)
  • Author(s): Liang Weng
  • Journal Title: Cancer Science Volume: 101 Pages: 836-842
  • Peer Reviewed
• [Journal Article] dGirdin a new player of Akt /PKB signaling in Drosophila Melanogaster (2010)
  • Author(s): Masamitsu Yamaguchi
  • Journal Title: Frontier Bioscience Volume: 15 Pages: 1164-1171
  • Peer Reviewed
• [Journal Article] Loss of Sprouty2 partially rescues renal hypoplasia and stomach hypoganglionosis but not intestinal aganglionosis in Ret Y1062F mutant mice (2010)
  • Author(s): Eriko Miyamoto
  • Journal Title: Developmental Biology Volume: 349 Pages: 160-168
  • Peer Reviewed
• [Journal Article] Girding for migratory cues : Role of the Akt substrate Girdin in cancer progression and angiogenesis (2010)
  • Author(s): Liang Weng
  • Journal Title: Cancer Science (印刷中)
  • Peer Reviewed
• [Journal Article] Cell biology of the movement of breast cancer cells: intracellular signaling and the actin cytoskeleton. (2009)
  • Author(s): Jiang, P., Enomoto, A., Takahashi M.
  • Journal Title: Cancer Lett. 284 Pages: 122-130
  • Peer Reviewed
• [Journal Article] Roles of Disrupted-in-Schizophrenia 1-interacting protein Girdin in postnatal development of the dentate gyrus. (2009)
  • Author(s): Enomoto, A., Asai, N., Namba, T., Wang, Y., Kato, T., Tanaka, M., Tatsumi, H., Taya, S., Tsuboi, D., Kuroda, K., Kaneko, N., Sawamoto, K., Miyamoto, R., Jijiwa, M., Murakumo, Y., Sokabe, M., Seki, T., Kaibuchi, K., Takahashi M.
  • Journal Title: Neuron 63 Pages: 774-787
  • Peer Reviewed
• [Journal Article] A novel Drosophila Girdin-like protein is involved in Akt pathway control of cell size. (2009)
  • Author(s): Puseenam, A., Yoshioka, Y., Nagai R, Hashimoto R, Suyari O, Itoh M, Enomoto A, Takahashi M., Yamaguchi M.
  • Journal Title: Exp.Cell Res. 315 Pages: 3370-3380
  • Peer Reviewed
• [Journal Article] Cell biology of the movement of breast cancer cells : intracellular signaling and the actin cytoskeleton (2009)
  • Author(s): Jiang, P., Enomoto, A., Takahashi, M.
  • Journal Title: Cancer Lett. 284 Pages: 122-130
• [Journal Article] Roles of Disrupted-in-Schizophrenia 1-interacting protein Girdin in postnatal development of the dentate gyrus (2009)
  • Author(s): Enomoto, A., Asai, N., Namba, T., Wang, Y., Kato, T., Tanaka, M., Tatsumi, H., Taya, S., Tsuboi, D., Kuroda, K., Kaneko, N., Sawamoto, K., Miyamoto, R., Jijiwa, M., Murakumo, Y., Sokabe, M., Seki, T., Kaibuchi, K., Takahashi, M.
  • Journal Title: Neuron 63 Pages: 774-787
• [Journal Article] A novel Drosophila Girdin-like protein is involved in Akt pathway control of cell size (2009)
  • Author(s): Puseenam, A., Yoshioka, Y., Nagai, R., Hashimoto, R., Suyari, O., Itoh, M., Enomoto, A., Takahashi, M., Yamaguchi, M
  • Journal Title: Exp.Cell Res. 315 Pages: 3370-3380
• [Journal Article] Roles of Disrupted-in-Schizophrenia 1-interacting protein Girdin in postnatal development of the dentate gyrus (2009)
  • Author(s): Atsushi Enomoto
  • Journal Title: Neuron 63 Pages: 774-787
  • Peer Reviewed
• [Journal Article] A novel Drosophila Girdin-like protein is involved in Akt pathway control of cell size (2009)
  • Author(s): Aekkachai Puseenam
  • Journal Title: Experimental Cell Research 315 Pages: 3370-3380
  • Peer Reviewed
• [Journal Article] Cell biology of the movement of breast cancer cells : intracellular signaling and the actin cytoskeleton (2009)
  • Author(s): Ping Jiang
  • Journal Title: Cancer Letters 284 Pages: 122-130
  • Peer Reviewed
• [Journal Article] Regulation of VEGF-mediated angiogenesis by the Akt/PKB substrate Girdin. (2008)
  • Author(s): Kitamura, T., Asai, N., Enomoto, A., Maeda, K., Kato, T., Ishida, M., Jiang, P., Watanabe, T., Usukura, J., Kondo, T., Costantini, F., Murohara, T., Takahashi M.
  • Journal Title: Nature Cell Biol. 10 Pages: 329-337
  • Peer Reviewed
• [Journal Article] An actin-binding protein Girdin regulates the motility of breast cancer cells. (2008)
  • Author(s): Jiang, P., Enomoto, A., Jijiwa, M., Kato, T., Hasegawa, T., Ishida, M., Sato, T., Asai, N., Murakumo, Y., Takahashi M.
  • Journal Title: Cancer Res. 68 Pages: 1310-1318
  • Peer Reviewed
• [Journal Article] Regulation of VEGF-mediated angiogenesis by the Akt/PKB substrate Girdin (2008)
  • Author(s): Kitamura, T., Asai, N., Enomoto, A., Maeda, K., Kato, T., Ishida, M., Jiang, P., Watanabe, T., Usukura, J., Kondo, T., Costantini, F., Murohara, T., Takahashi, M.
  • Journal Title: Nature Cell Biol. 10 Pages: 329-337
• [Journal Article] An actin-binding protein Girdin regulates the motility of breast cancer cells (2008)
  • Author(s): Jiang, P., Enomoto, A., Jijiwa, M., Kato, T., Hasegawa, T., Ishida, M., Sato, T., Asai, N., Murakumo, Y., Takahashi, M.
  • Journal Title: Cancer Res. 68 Pages: 1310-1318
• [Journal Article] An actin-binding protein Girdin regulates the motility of breast cancer cells (2008)
  • Author(s): Ping Jiang
  • Journal Title: Cancer Research 68 Pages: 1310-1318
  • Peer Reviewed
• [Journal Article] Regulation of VEGF-mediated angiogenesis by the Akt/PKB substrate Girdin (2008)
  • Author(s): Tomoya Kitamura
  • Journal Title: Nature Cell Biology 10 Pages: 329-337
  • Peer Reviewed
• [Journal Article] Roles of induced expression of MAPK phosphatase-2 in tumor development in RET-MEN2A transgenic mice (2008)
  • Author(s): Taisaku Hasegawa
  • Journal Title: Oncogene 27 Pages: 5684-5695
  • Peer Reviewed
• [Journal Article] An actin-binding protein Girdin regulates the motility of breast cancer cells (2008)
  • Author(s): Ping Jung
  • Journal Title: Cancer Research 68 Pages: 1310-1318
  • Peer Reviewed
• [Journal Article] Protective role of Gipie, a Girdin family protein, in endoplasmic reticulum stress responses in endothelial cell.
  • Author(s): .Matsushita, E., Asai, N., Enomoto, A., Kawamoto, Y., Kato, T., Mii, S., Maeda, K., Shibata, R., Hattori, S., Hagikura, M., Takahashi, k., Sokabe, M., Murakumo, Y., Murohara, T., Takahashi M.
  • Journal Title: Mol.Biol.Cell. in press.
  • Peer Reviewed
• [Journal Article] Girding for migratory cues : Role of the Akt substrate Girdin in cancer progression and angiogenesis
  • Author(s): Weng, L., Enomoto, A., Ishida-Takagishi, M., Asai, N., Takahashi, M.
  • Journal Title: Cancer Sci. (in press)
  • NAID: 10026590367
• [Presentation] Akt-Girdinシグナル伝達系による細胞運動制御の個体レベルでの解析 (2011)
  • Author(s): 高橋雅英
  • Organizer: 平成22年度「個体レベルでのがん研究支援活動」ワークショップ
  • Place of Presentation: 琵琶湖ホテル(滋賀県)
  • Year and Date: 2011-02-04
• [Presentation] がん遺伝子の発見から個体レベルの研究へAkt-Girdinシグナル伝達系による細胞運動制御の個体レベルでの解析 (2011)
  • Author(s): 高橋雅英
  • Organizer: 平成22年度「個体レベルでのがん研究支援活動」ワークショップ
  • Place of Presentation: (琵琶湖ホテル)(大津)
• [Presentation] Regulation of angiogenesis and neointima formation by the Akt substrate Girdin (2010)
  • Author(s): 高橋雅英、北村倫也、三宅裕史、前田健吾、榎本篤、浅井直也、室原豊明
  • Organizer: 第33回日本分子生物学会年会、第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-08
• [Presentation] Regulation of angiogenesis and neointima formation by the Akt substrate Girdin (2010)
  • Author(s): 高橋雅英
  • Organizer: 第33回日本分子生物学会年会、第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸ポートアイランド(兵庫県)
  • Year and Date: 2010-12-08
• [Presentation] Akt/Girdinシグナル伝達系による血管新生、新生内膜形成の制御 (2010)
  • Author(s): 高橋雅英
  • Organizer: Recent advance in tumor angiogenesis 2010
  • Place of Presentation: 浜松
  • Year and Date: 2010-11-20
• [Presentation] Akt/Girdinシグナル伝達系による血管新生、新生内膜形成の制御 (2010)
  • Author(s): 高橋雅英
  • Organizer: Recent advance in tumor angiogenesis 2010
  • Place of Presentation: アクトシティ浜松(静岡県)
  • Year and Date: 2010-11-20
• [Presentation] 細胞運動を制御する新規蛋白Girdinの発見と機能解析 (2010)
  • Author(s): 高橋雅英
  • Organizer: 第4回日本病理学会中部支部夏の学校2010富山
  • Place of Presentation: 富山
  • Year and Date: 2010-08-22
• [Presentation] 細胞運動を制御する新規蛋白Girdinの発見と機能解析 (2010)
  • Author(s): 高橋雅英
  • Organizer: 第4回日本病理学会中部支部夏の学校2010富山
  • Place of Presentation: 立山(富山県)
  • Year and Date: 2010-08-22
• [Presentation] Aktの基質蛋白Girdinの細胞運動における役割 (2009)
  • Author(s): 高橋雅英
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2009-10-23
• [Presentation] Aktの基質蛋白 Girdin の細胞運動における役割 (2009)
  • Author(s): 高橋雅英
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2009-10-23
• [Presentation] Girdin は成体脳における新生ニューロンの移動をコントロールする (2009)
  • Author(s): 王芸
  • Organizer: 第98回日本病理学会総会
  • Place of Presentation: 京都
  • Year and Date: 2009-05-01
• [Presentation] Role of an actin-binding protein Girdin in cancer cell motility and angiogenesis. (2009)
  • Author(s): 高橋雅英
  • Organizer: Global Center of Excellence (COE) Program, 1st International Symposium Signaling of Cancer Cells
  • Place of Presentation: Nagoya
  • Year and Date: 2009-01-23
• [Presentation] Role of an actin-binding protein Girdin in cancer cell motility and angiogenesis (2009)
  • Author(s): Takahashi, M.
  • Organizer: Global Center of Excellence (COE) Program, 1st International Symposium Signaling of Cancer Cells
  • Place of Presentation: Nagoya
  • Year and Date: 2009-01-23
• [Presentation] アクチン結合蛋白 Girdin のがん転移、血管新生、神経系における機能 (2008)
  • Author(s): 高橋雅英
  • Organizer: 第1回グローバルCOE国内シンポジウム
  • Place of Presentation: 名古屋
  • Year and Date: 2008-11-14
• [Presentation] Regulation of VEGF-mediated angiogenesis by the Akt/PKB substrate Girdin (2008)
  • Author(s): Tomoya Kitamura
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-29
• [Presentation] An actin-binding protein Girdin regulates the motility of breast cancer cells (2008)
  • Author(s): Ping Jiang
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-28
• [Presentation] Aktの新規基質Girdinの細胞運動と血管新生における役割 (2008)
  • Author(s): 高橋雅英
  • Organizer: 第5回日本病理学会カンファレンス「がん」と「幹細胞」
  • Place of Presentation: 湘南国際村
  • Year and Date: 2008-08-01
• [Presentation] Aktの新規基質 Girdin の細胞運動と血管新生における役割 (2008)
  • Author(s): 高橋雅英
  • Organizer: 第5回日本病理学会カンファレンス「がん」と「幹細胞」
  • Place of Presentation: 湘南国際村
  • Year and Date: 2008-08-01
• [Presentation] Aktの新規基質Girdinの細胞運動と血管新生における役割第3次対がん10か年総合戦略 (2008)
  • Author(s): 高橋雅英
  • Organizer: 第2回合同シンポジウム「がんの罹患率と死亡率の激減を目指して」
  • Place of Presentation: 東京
  • Year and Date: 2008-02-29
• [Presentation] Aktの新規基質 Girdin の細胞運動と血管新生における役割第3次対がん10か年総合戦略 (2008)
  • Author(s): 高橋雅英
  • Organizer: 第2回合同シンポジウム「がんの罹患率と死亡率の激減を目指して」
  • Place of Presentation: 東京
  • Year and Date: 2008-02-29
• [Presentation] アクチン結合蛋白Girdinのがん転移、血管新生、神経系における機能 (2008)
  • Author(s): 高橋雅英
  • Organizer: 第1回グローバルCOE国内シンポジウム,第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] Regulation of VEGF-mediated angiogenesis by the Akt/PKB substrate Girdin (2007)
  • Author(s): 北村 倫也
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-05
• [Presentation] Regulation of cancer progression by the Akt/PKB substrate Girdin, a novel actin-binding protein (2007)
  • Author(s): Ping Jiang
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-05
• [Presentation] Role of a new Akt substrate, Girdin in cancer and angiogenesis. (2007)
  • Author(s): 高橋雅英
  • Organizer: The 21st Century COE program, 4th international symposium on functional molecules linked to neurogeneration and oncogenesis -Towards molecular targeted therapy-
  • Place of Presentation: Nagoya
• [Presentation] Role of a new Akt substrate, Girdin in cancer and angiogenesis. (2007)
  • Author(s): 高橋雅英
  • Organizer: Kyoto 21st Century COE international symposium 2007 Genomic analysis of disease model animals with multiple genetic alterations
  • Place of Presentation: Kyoto
• [Remarks] ホームページ等
  • URL: http://www.med.nagoya-u.ac.jp/patho2/
• [Remarks]
  • URL: http://www.med.nagoya-u.ac.jp/patho2/
• [Remarks] ホームページ等
  • URL: http://www.med.nagoya-u.ac.jp/patho2/