Analysis of the signaling mechanisms that regulates brain stress responses through protein tyrosine phosphorylation

• Project/Area Number: 23500437
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Gunma University
• Principal Investigator: OHNISHI Hiroshi 群馬大学, 保健学研究科, 教授 (70334125)
• Project Period (FY): 2011-04-28 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: タンパク質チロシンリン酸化 / 脳 / ストレス / 神経細胞 / シグナル伝達 / 行動 / 神経科学 / 脳・神経

Outline of Final Research Achievements

Forced swim stress induced tyrosine phosphorylation of SIRPα, a membrane protein, in the brain of mice, and the lack of this molecule resulted in increased immobility of mice during forced swim in water. We have published our findings suggesting that the tyrosine phosphorylation of SIRPα in the brain primarily depended on the hypothermia induced by the immersion of mice in cold water. We have also found multiple src family tyrosine kinases participated in the hypothermia-dependent phosphorylation of SIRPα. We found that forced swim stress also induced changes in the phosphorylation level of other signaling molecules, CaMKII, MEK, and CREB. Hypothermia is important for the change of the phosphorylation of CaMKII, but not for MEK and CREB. We also found that a protein phosphatase Shp2, a down-stream signaling molecule of SIRPα, positively regulates tyrosine phosphorylation of SIRPα in the brain, by the use of neuron-specific conditional Shp2 knockout mice.

Research Products

• [Journal Article] Shp2 in forebrain neurons regulates synaptic plasticity, locomotion, and memory formation in mice (2015)
  • Author(s): Kusakari S, Saitow F, Ago Y, Shibasaki K, Sato-Hashimoto, M., Matsuzaki, Y., Kotani T, Murata Y, Hirai H, Matsuda T, Suzuki H, Matozaki T, Ohnishi H
  • Journal Title: Mol. Cell. Biol. Volume: 35 Issue: 9 Pages: 1557-1572
  • DOI: 10.1128/mcb.01339-14
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The CD47-SIRPα signalling system : its physiological roles and therapeutic application (2014)
  • Author(s): Murata Y, Kotani T, Ohnishi H, Matozaki T
  • Journal Title: J Biochem Volume: 155 Issue: 6 Pages: 335-344
  • DOI: 10.1093/jb/mvu017
  • NAID: 40020088978
  • Peer Reviewed
• [Journal Article] Comprehensive behavioral analysis of cluster of differentiation 47 knockout mice (2014)
  • Author(s): Koshimizu H, Takao K, Matozaki T, Ohnishi H, Miyakawa T
  • Journal Title: PLoSOne Volume: 9 Issue: 2 Pages: e89584-e89584
  • DOI: 10.1371/journal.pone.0089584
  • Peer Reviewed / Open Access
• [Journal Article] Autoimmune animal models in the analysis of the CD47-SIRPα signaling pathway (2014)
  • Author(s): Murata Y, Saito Y, Kaneko T, Kotani T, Kaneko Y, Ohnishi H, Matozaki T
  • Journal Title: Methods Volume: 65 Issue: 2 Pages: 254-9
  • DOI: 10.1016/j.ymeth.2013.09.016
  • Peer Reviewed
• [Journal Article] Inflammation-induced proteolytic processing of the SIRPα cytoplasmic ITIM in neutrophils propagates a proinflammatory state (2013)
  • Author(s): Zen K, Guo Y, Bian Z, Lv Z, Zhu D, Ohnishi H, Matozaki T, Liu Y
  • Journal Title: Nat Commun Volume: 4 Issue: 1 Pages: 2436-2436
  • DOI: 10.1038/ncomms3436
  • Peer Reviewed
• [Journal Article] SIRPα signaling regulates podocyte structure and function (2013)
  • Author(s): Takahashi S, Tomioka M, Hiromura K, Sakairi T, Hamatani H, Watanabe M, Ikeuchi H, Kaneko Y, Maeshima A, Aoki T, Ohnishi H, Matozaki T, Nojima Y
  • Journal Title: Am J Physiol Renal Physiol Volume: 305 Issue: 6 Pages: 861-70
  • DOI: 10.1152/ajprenal.00597.2012
  • Peer Reviewed
• [Journal Article] Hypothermia-dependent and -independent effects of forced swim on the phosphorylation states of signaling molecules in mouse hippocampus. (2012)
  • Author(s): Hayashi Y
  • Journal Title: Biochemical and biophysical research communications. Volume: 428 Issue: 4 Pages: 475-481
  • DOI: 10.1016/j.bbrc.2012.10.083
  • Peer Reviewed
• [Journal Article] Hypothermia-induced tyrosine phosphorylation of SIRPα in the brain (2012)
  • Author(s): Maruyama T., Kusakari S., Sato-Hashimoto M., Hayashi Y., Kotani T., Murata Y., Okazawa H., Oldenborg P.-A., Kishi S., Matozaki T., and Ohnishi H.
  • Journal Title: J. Neurochem Volume: 121 Issue: 6 Pages: 891-902
  • DOI: 10.1111/j.1471-4159.2012.07748.x
  • Peer Reviewed
• [Journal Article] Dendritic cell-specific ablation of the protein tyrosine phosphatase shp1 promotes Th1 cell differentiation and induces autoimmunity. (2012)
  • Author(s): Kaneko T., Saito Y., Kotani T., Okazawa H., Iwamura H., Sato-Hashimoto M., Kanazawa Y., Takahashi S., Hiromura K., Kusakari S.Kaneko Y., Murata Y., Ohnishi H., Nojima Y., Takagishi K., and Matozaki T.
  • Journal Title: J. Immunol Volume: 188 Issue: 11 Pages: 5397-5407
  • DOI: 10.4049/jimmunol.1103210
  • Peer Reviewed
• [Journal Article] Signal regulatory protein α regulates the homeostasis of T lymphocytes in the spleen. (2011)
  • Author(s): Sato-Hashimoto M., Saito Y., Ohnishi H., Iwamura H., Kanazawa Y., Kusakari S., Kotani T., Mori M., Murata Y., Okazawa H., Ware CF., Olodenbrg PA., Nojima Y., and Matozaki T.
  • Journal Title: J. Immunol Volume: 187 Issue: 1 Pages: 291-297
  • DOI: 10.4049/jimmunol.1100528
  • Peer Reviewed
• [Journal Article] Src family kinases: modulators of neurotransmitter receptor function and behavior. (2011)
  • Author(s): Ohnishi H., Murata Y., Okazawa H., and Matozaki T.
  • Journal Title: Trends Neurosci Volume: 34 Issue: 12 Pages: 629-637
  • DOI: 10.1016/j.tins.2011.09.005
  • Peer Reviewed
• [Presentation] Essential role of SIRPα on dendritic cells in organization and homeostasis of the spleen (2014)
  • Author(s): Washio K, Kotani T, Respatika D, Murata Y, Saito Y, Okazawa H, Ohnishi H, Fukunaga A, Nishigori C, Matozaki T
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Immunological analysis of autoimmune nephritis observed in DC-specific Shp1 conditional knockout mice (2014)
  • Author(s): Watanabe M, Kaneko Y, Hiromura K, Ohishi Y, Kinoshita M, Ohnishi H, Matozaki T, Nojima Y
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Functional analysis of protein tyrosine phosphatase Shp2 in post-mitotic neurons (2014)
  • Author(s): Kusakari S, Saitow F, Hashimoato M, Matsuzaki Y, Kotani T, Murata Y, Hirai H, Suzuki H, Matozaki T, Ohnishi H
  • Organizer: 11th International Conference on Protein Phosphatase Protein Phosphatases in Health and Diseases
  • Place of Presentation: 東北大学医学部 艮陵会館 （宮城県仙台市）
  • Year and Date: 2014-11-12 – 2014-11-14
• [Presentation] Regulation of microglial homeostasis through cell-cell interaction signal (2014)
  • Author(s): Sato-Hashimoto M, Hayashi Y, Kusakari S, Kotani T, Murata Y, Matozaki T, Ohnishi H
  • Organizer: Neuroscience 2014 第３７回日本神経科学大会 The 37th Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: パシフィコ横浜（神奈川県）
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Functional Analysis of protein tyrosine phosphatase Shp2 in the adult forebrain neurons (2014)
  • Author(s): Ohnishi H, Kusakari S, Saitow F, Hashimoto M, Matsuzaki Y, Kotani T, Murata Y, Hirai H, Suzuki H, Matozaki T
  • Organizer: Neuroscience 2014 第３７回日本神経科学大会 The 37th Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: パシフィコ横浜（神奈川県）
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] 腸上皮の恒常性維持におけるチロシンホスファターゼShp2の役割 Role of the protein tyrosine phosphatase Shp2 in maintaining homeostasis of the intestinal epithelium (2014)
  • Author(s): 小谷武徳、山下博成、村田陽二、岡澤秀樹、大西浩史、具英成、的崎尚
  • Organizer: 第66回日本細胞生物学会大会
  • Place of Presentation: 奈良県新公会堂・東大寺総合文化センター・奈良国立博物館（奈良県）
  • Year and Date: 2014-06-11 – 2014-06-13
• [Presentation] 樹状細胞とSLE：樹状細胞特異的SHP-1欠損マウスの解析 (2014)
  • Author(s): 廣村桂樹、渡辺光治、大石裕子、金子和光、斎藤泰之、金子哲也、高岸憲二、 大西浩史、的崎 尚、野島美久
  • Organizer: 第58回 日本リウマチ学会総会・学術集会
  • Place of Presentation: グランドプリンスホテル新高輪 国際間パミール（東京）
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 細胞質型チロシンホスファターゼShp2による脳機能制御 (2014)
  • Author(s): 草苅伸也、齋藤文仁、橋本美穂、柴崎貢志、吾郷由紀夫、小谷武徳、村田陽二、松田敏夫、Benjamin G. Neel、的崎尚、大西浩史
  • Organizer: 第6回日本プロテインホスファターゼ研究会学術集会
  • Place of Presentation: 三重大学/津
• [Presentation] 腸上皮の恒常性維持におけるチロシンホスファターゼShp2の役割 (2014)
  • Author(s): 小谷武徳、山下博成、朴貞河、村田陽二、岡澤秀樹、大西浩史、具英成、的崎尚
  • Organizer: 第6回日本プロテインホスファターゼ研究会学術集会
  • Place of Presentation: 三重大学/津
• [Presentation] 樹状細胞及び二次リンパ組織の恒常性維持におけるＳＩＲＰαの役割 (2014)
  • Author(s): 鷲尾健、小谷武徳、レスパティカ ダトゥ、村田陽二、岡澤秀樹、大西浩史、福永淳、錦織千佳子、的崎尚
  • Organizer: 第6回日本プロテインホスファターゼ研究会学術集会
  • Place of Presentation: 三重大学/津
• [Presentation] Functional Analysis of A non-receptor type protein tyrosine phosphatase Shp2 in the adult brain (2013)
  • Author(s): Kusakari, S., Saitow, F., Sato-Hashimoto, M., Shibasaki, K., Ago, Y., Matsuda, T., Neel B. G., Takenori, K., Yoji, M., Matozaki, T., Ohnishi, H.
  • Organizer: Neuro 2013 第36回日本神経科学大会・第56回日本神経化学大会・第２３回日本神経回路学会大会
  • Place of Presentation: 国立京都国際会館/京都
• [Presentation] Hypothermia-dependent and -independent effects of forced swim on the phosphorylation satates of signaling molecules in mouse hippocampus (2013)
  • Author(s): Sato-Hashimoto, M., Hayashi, Y., Kusakari, S., Urano, E., Shigeno, M., Sekijima, T., Kotani, T., Murata, Y., Murakami, H., Matozaki, T., Ohnishi, H.
  • Organizer: Neuro 2013 第36回日本神経科学大会・第56回日本神経化学大会・第２３回日本神経回路学会大会
  • Place of Presentation: 国立京都国際会館/京都
• [Presentation] 腸上皮の恒常性維持におけるチロシンホスファターゼShp2の役割 (2013)
  • Author(s): 小谷武徳、山下博成、村田陽二、岡澤秀樹、大西浩史、具英成、的崎尚
  • Organizer: 第12回生体機能研究会
  • Place of Presentation: ホテル木暮/群馬県渋川市
• [Presentation] Roles of the protein tyrosine phosphatase Shp2 in homeostasis of the intestinal epithelium (2013)
  • Author(s): Kotani, T., Yamashita, H., Murata, Y., Okazawa, H., Ohnishi, H., Matozaki, T.
  • Organizer: FASEB meeting
  • Place of Presentation: U.S.A
• [Presentation] 腸上皮の恒常性維持におけるチロシンホスファターゼShp2の役割 Roles of the protein tyrosine phosphatase Shp2 in maintaining homeostasis of the intestinal epithelium (2013)
  • Author(s): 小谷武徳、山下博成、村田陽二、岡澤秀樹、大西浩史、具英成、的崎尚
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: パシフィコ横浜/横浜
• [Presentation] 細胞質型チロシンホスファターゼShp2の成熟脳における機能解析 (2013)
  • Author(s): 草苅伸也、橋本美穂、柴崎貢志、吾郷由希夫、松田敏夫、Benjamin G. Neel、小谷武徳、村田陽二、的崎尚、大西浩史
  • Organizer: 第60回北関東医学会総会
  • Place of Presentation: 群馬大学刀城会館/前橋
• [Presentation] SIRPαによる脾臓T細胞の恒常性の調節 (2013)
  • Author(s): 橋本美穂、齊藤泰之、金子哲也、大西浩史、草苅伸也、小谷武徳、村田陽二、岡澤秀樹、的崎尚、
  • Organizer: 第60回北関東医学会総会
  • Place of Presentation: 群馬大学刀城会館/前橋
• [Presentation] 腸上皮の恒常性維持におけるチロシンホスファターゼShp2 の役割 Roles of the protein tyrosine phosphatase Shp2 in maintaining 213 homeostasis of the intestinal epithelium (2013)
  • Author(s): 山下博成、小谷武徳、村田陽二、岡澤秀樹、大西浩史、具英成、的崎尚
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜/横浜
• [Presentation] SIRPα-CD47 system regulates the homeostasis of dendritic cells in lymphoid tissues (2013)
  • Author(s): Washio, K., Kotani, T., Respatika, D., Murata, Y., Okazawa, H., Ohnishi, H., Fukunaga, A., Nishigori, C., Matozaki, T.
  • Organizer: 第42回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ/千葉
• [Presentation] Regulation of intestinal immunity by the protein tyrosine phosphatase SAP-1 (2013)
  • Author(s): Murata Y. et al.
  • Organizer: 第10回プロテインホスファターゼ国際カンファレンス
  • Place of Presentation: 国立がん研究センター
• [Presentation] Hypothermia-induced tyrosine phosphorylation of SIRPα in the brain (2013)
  • Author(s): Kusakari S. et al.
  • Organizer: 第10回プロテインホスファターゼ国際カンファレンス
  • Place of Presentation: 国立がん研究センター
• [Presentation] Dendritic cell-specific ablation of the protein tyrosine phosphatase Shp1 promotes Th1 cell differentiation and induces autoimmunity (2013)
  • Author(s): Kotani T. et al.
  • Organizer: 第10回プロテインホスファターゼ国際カンファレンス
  • Place of Presentation: 国立がん研究センター
• [Presentation] Tyrosine phosphorylation of CEACAM20 and its functional roles (2013)
  • Author(s): Daniwijaya, E.W. et al.
  • Organizer: 第10回プロテインホスファターゼ国際カンファレンス
  • Place of Presentation: 国立がん研究センター
• [Presentation] 細胞質型チロシンホスファターゼShp2の成熟脳における機能解析 (2012)
  • Author(s): 草苅伸也 他
  • Organizer: 第11回生体機能研究会
  • Place of Presentation: 箱根プリンスホテル
• [Presentation] 低温ストレスによる受容体型分子SIRPαのチロシンリン酸化誘導 (2012)
  • Author(s): 草苅伸也 他
  • Organizer: 第30回内分泌代謝学サマーセミナー
  • Place of Presentation: 伊香保 福一
• [Presentation] Hypothermia-induced tyrosine phoshporylation of SIRPα in the brain (2012)
  • Author(s): Kusakari S. et al.
  • Organizer: 11th Biennial Meeting of APSN/55th Annual Meeting of JSN
  • Place of Presentation: 神戸国際会議場
• [Presentation] Regulation of brain functions by a protein tyrosine phosphatase Shp2 (2012)
  • Author(s): Kusakari S. et al.
  • Organizer: 平成24年度国際シナプス研究会
  • Place of Presentation: 岡崎コンファレンスセンター
• [Presentation] 細胞質型チロシンホスファターゼShp2の成熟脳における機能解析 (2012)
  • Author(s): 草苅伸也 他
  • Organizer: 第85回生化学会大会
  • Place of Presentation: 福岡国際会議場
• [Presentation] 脾臓T細胞の恒常性調節へのSIRPαの関与 (2012)
  • Author(s): 橋本（佐藤）美穂 他
  • Organizer: 第85回生化学会大会
  • Place of Presentation: 福岡国際会議場
• [Presentation] 成熟脳におけるShp２の生理機能解析 (2012)
  • Author(s): 草苅伸也 他
  • Organizer: 第5回プロテインホスファターゼ研究会学術集会
  • Place of Presentation: 大阪大学 銀杏会館（大阪）
• [Presentation] Regulation by protein tyrosine phosphorylation of depression-like behavior (2011)
  • Author(s): 大西浩史 他
  • Organizer: 第34回日本神経科学大会 Neuroscience 2011(招待講演)
  • Place of Presentation: パシフィコ横浜（横浜）
• [Presentation] Stress-evoked tyrosine phosphorylation of SIRPα regulates depression-like behavior (2011)
  • Author(s): Hiroshi Ohnishi, Takashi Matozaki
  • Organizer: ISN-ESN-2011 23rd Biennial Meeting of the International Society for Neurochemistry jointly with the European Society for Neurochemistry(招待講演)
  • Place of Presentation: Megaron Athens International Conference Center (Athens, GREECE)
• [Presentation] 蛋白質チロシンホスファターゼShp2の成熟脳における機能解析 (2011)
  • Author(s): 草苅伸也 他
  • Organizer: 第2回国際放射線神経生物学会大会
  • Place of Presentation: 群馬大学 刀城会館（前橋）
• [Book] 脳内環境 ー 維持機構と破綻がもたらす疾患研究 (2014)
  • Author(s): （編集）高橋良輔、漆谷真、山中宏二、樋口真人 （著者）大西浩史 他
  • Total Pages: 228
  • Publisher: 株式会社 メディカルドゥ
• [Remarks] 群馬大学 大西研究室ホームページ
  • URL: http://biosignal.dept.med.gunma-u.ac.jp/
• [Remarks] 群馬大学大学院保健学研究科生体情報検査科学講座大西研究室
  • URL: http://biosignal.dept.med.gunma-u.ac.jp/
• [Remarks]
  • URL: http://biosignal.dept.med.gunma-u.ac.jp/