Mechanism of regulation of ER stress sensor by protein phosphatases

• Project/Area Number: 24590339
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Tohoku University
• Principal Investigator: KOBAYASHI Takayasu 東北大学, 加齢医学研究所, 准教授 (10221970)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: プロテインホスファターゼ / PP2C

Outline of Final Research Achievements

PPM1L (formerly PP2Cε) was originally identified as a negative regulator of stress-activated protein kinase signaling pathways, in which PPM1L represses the activity of TGFβ-activated kinase 1 (TAK1) and apoptosis regulating kinase 1 (ASK1), two mitogen-activated protein kinase kinase kinases. Recently, I demonstrated that PPM1L is an endoplasmic reticulum (ER)-resident transmembrane protein and obtained the evidence that it is involved in regulation of transfer of ceramide between ER and Golgi. In this project, I examined whether PPM1L was involved in regulation of ER stress response. Overexpression of PPM1L in cells reduced ER-stress dependent phosphorylation of ER stress sensor IRE1. However, knockdown of PPM1L did not affect level of phosphorylation of IRE1. These results suggested that other protein phosphatase(s) may be involved in regulation of ER stress response.

Research Products

• [Journal Article] Exonic Mutations in the SLC12A3 Gene Cause Exon Skipping and Premature Termination in Gitelman Syndrome (2015)
  • Author(s): 竹内陽一、三島英換、他12名
  • Journal Title: J Am Soc Nephrol Volume: 26 Issue: 2 Pages: 271-279
  • DOI: 10.1681/asn.2013091013
  • Peer Reviewed
• [Journal Article] The expression of Fn14 via mechanical stress-activated JNK contributes to apoptosis induction in osteoblasts. (2014)
  • Author(s): Matsui, H., Fukuno, N., Kanda, Y., Kantoh, Y., Chida, T., Nagaura, Y., Suzuki, O., Nishitoh, H., Takeda, K., Ichijo, H., Sawada, Y., Sasaki, K., Kobayashi, T. and Tamura, S.
  • Journal Title: J. Biol. Chem. Volume: 289 Issue: 10 Pages: 6438-6450
  • DOI: 10.1074/jbc.m113.536300
  • Peer Reviewed / Open Access
• [Journal Article] N-Myristoylation is essential for protein phosphatases PPM1A and PPM1B to dephosphorylate their physiological substrates in cells (2013)
  • Author(s): Chida, T.
  • Journal Title: Biochem J Volume: 449 Issue: 3 Pages: 741-749
  • DOI: 10.1042/bj20121201
  • Peer Reviewed
• [Journal Article] Acyl-CoA binding domain containing 3 (ACBD3) recruits the protein phosphatase PPM1L to ER-Golgi membrane contact sites (2012)
  • Author(s): Shinoda, Y.
  • Journal Title: FEBS Letter Volume: 586 Issue: 19 Pages: 3024-3029
  • DOI: 10.1016/j.febslet.2012.06.050
  • Peer Reviewed
• [Presentation] Targeted disruption of the mouse protein phosphatase PPM1L gene leads to structural abnormalities in the brain. (2014)
  • Author(s): Fujita,K., Shinoda, Y., Nagaura, Y., Kusano, R., Watanabe, T., Matsui, Y., Sakagami, H., Ohnishi, M., Tamura, S., Kobayashi, T.
  • Organizer: 11th International Conference on Protein Phosphatases.
  • Place of Presentation: Sendai
  • Year and Date: 2014-11-12 – 2014-11-14
• [Presentation] プ口テインホスファターゼPPM1Lの欠損は大脳皮質において軸索線維の異常を引き起こす (2014)
  • Author(s): 小林孝安, 藤田宏介, 篠田康晴, 永浦裕子, 草野理恵, 渡邊利雄, 松居靖久, 舟橋淳一, 佐藤達也, 阪上洋行, 大西素子, 田村眞理
  • Organizer: 第69回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] リン酸化クロマチン構成因子Bcnt/Cfdp1の多様性の分子基盤 (2014)
  • Author(s): 岩下新太郎, 鈴木健裕, 中島健太郎, 小林孝安, 安田武嗣, 大野-岩下淑子, 今城-大海忍, 宋時栄, 堂前直
  • Organizer: 第69回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] セリンスレオニンホスファターゼPP2C ε のゴルジ体局在タンパク質GCP60との機能連関 (2013)
  • Author(s): 篠田康晴, 福永浩司, 藤田宏介, 永浦裕子, 田村眞理,小林孝安
  • Organizer: 日本生化学会東北支部会第79回例会
  • Place of Presentation: 仙台
• [Presentation] PP2CαおよびPP2Cβの機能におけるN-ミリストイル化の役割 (2013)
  • Author(s): 小林孝安, 千田透子, 安藤正勝, 松木佑, 枡悠太郎, 永浦裕子,田村眞理
  • Organizer: 日本生化学会東北支部会第79回例会
  • Place of Presentation: 仙台
• [Presentation] N-ミリストイル化はPP2CαおよびPP2Cβの生理的基質の認識に必須である (2013)
  • Author(s): 小林孝安, 千田透子, 安藤正勝, 松木佑, 枡悠太郎, 永浦裕子,田村眞理
  • Organizer: 第86回日本生化学会年会
  • Place of Presentation: 横浜
• [Presentation] Targeted disruption of the mouse protein phosphatase 2Cε gene leads to structural abnormalities in the brain. (2013)
  • Author(s): Fujita, K., Shinoda, Y., Nagaura, Y., Sakagami, H., Ohnishi, M., Tamura, S., Kobayashi, T.
  • Organizer: 10th International Conference on Protein Phosphatase
  • Place of Presentation: Tokyo
• [Presentation] Golgi complex-associated protein of 60 kDa (GCP60) recruits the protein phosphatase PPM1L to ER-Golgi membrane contact sites (2013)
  • Author(s): Shinoda, Y., Fujita, K., Nagaura, Y., Fukunaga, K., Tamura, S., Kobayashi, T.
  • Organizer: 10th International Conference on Protein Phosphatase
  • Place of Presentation: Tokyo
• [Presentation] ノックアウトマウスを用いたPP2Cεの新規機能解明 (2012)
  • Author(s): 藤田 宏介、篠田 康晴、千田 透子、永浦 裕子、草野 理恵、渡邊 利雄、松居 靖久、相澤 慎一、清成 寛、阿部 高也、阪上 洋行、大西 素子、田村 眞理、小林 孝安
  • Organizer: 第35回日本分子生物学会総会
  • Place of Presentation: 福岡
• [Presentation] Golgi complex-associated protein of 60 kDa (GCP60) recruits the protein phosphatase PPM1L to ER-Golgi membrane contact sites (2012)
  • Author(s): 篠田 康晴 藤田 宏介 永浦裕子 福永浩司 田村眞理 小林孝安
  • Organizer: 第35回日本分子生物学会総会
  • Place of Presentation: 福岡