Clarification of the function and regulation of the rheostat molecule NLK, which fine-tunes the activity strength of signal transduction.

• Project/Area Number: 22689008
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: General medical chemistry
• Research Institution: Kyushu University
• Principal Investigator: ISHITANI Tohru 九州大学, 生体防御医学研究所, 准教授 (40448428)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥24,700,000 (Direct Cost: ¥19,000,000、Indirect Cost: ¥5,700,000); Fiscal Year 2012: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000); Fiscal Year 2011: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000); Fiscal Year 2010: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000)
• Keywords: リン酸化 / 器官形成 / がん / イメージング / NLK / Wntシグナル / Notchシグナル / シグナルレオスタット / Nemo-like kinase / ホモダイマー形成 / Lef1

Research Abstract

NLK is an evolutionarily conserved protein kinase, which fine-tunes the activity strength of various signal transduction systems. In this study, we discovered that NLK strengthen Wnt signaling activity by phosphorylating a transcription factor Lef1 in neural progenitor cells and this regulation contributes to the size expansion of vertebrate brain tissues. We also found that NLK autoactivates via its autophosphorylation and that DP1 protein inhibits NLK activity. Thus, we revealed new functions and regulations of NLK.

Research Products

• [Journal Article] NLK positively regulates Wnt/β-catenin signaling by phosphorylating LEF1 in neural progenitor cells (2012)
  • Author(s): Ota, S., Ishitani, S., Shimizu, N., Matsumoto, K., Itoh, M., and Ishitani. T
  • Journal Title: EMBO J Volume: 31 Issue: 8 Pages: 1904-1915
  • DOI: 10.1038/emboj.2012.46
  • Peer Reviewed
• [Journal Article] Context-dependent dual and opposite roles of nemo-like kinase in the Wnt/β-catenin signaling (2012)
  • Author(s): Ishitani T
  • Journal Title: Cell Cycle Volume: 11 Issue: 9 Pages: 1743-1745
  • DOI: 10.4161/cc.20183
• [Journal Article] Visualization and exploration of Tcf/Lef function using a highly responsive Wnt/β-catenin signaling-reporter transgenic zebrafish (2012)
  • Author(s): Shimizu N, Kawakami K, *Ishitani T
  • Journal Title: Developmental Biology Volume: 370. Issue: 1 Pages: 71-85
  • DOI: 10.1016/j.cellsig.2012.09.017
  • Peer Reviewed
• [Journal Article] Dual functions of DP1 promote and stabilize biphasic Wnt-on and Wnt-off states during anteroposterior neural patterning. (2012)
  • Author(s): Kim WT, Kim H, Katanaev VL, Joon Lee S, Ishitani T, Cha B, Han JK, *Jho EH.
  • Journal Title: EMBO Journal Volume: 31. Issue: 7 Pages: 3384-3397
  • DOI: 10.1038/emboj.2012.18
• [Journal Article] Dual functions of DP1 promote biphasic Wnt-on and Wnt-off states during anteroposterior neural patterning. (2012)
  • Author(s): Kim WT, Kim H, Katanaev VL, Joon Lee S, Ishitani T, Cha B, Han JK, Jho EH.
  • Journal Title: EMBO Journal Volume: 31 Issue: 16 Pages: 3384-3397
  • DOI: 10.1038/emboj.2012.181
  • Peer Reviewed
• [Journal Article] Visualization and exploration of Tcf/Lef function using a highly responsive Wnt/β-catenin signaling-reporter transgenic zebrafish. (2012)
  • Author(s): Shimizu N, Kawakami K, Ishitani T.
  • Journal Title: Developmental Biology Volume: 370 Issue: 1 Pages: 71-85
  • DOI: 10.1016/j.ydbio.2012.07.016
  • Peer Reviewed
• [Journal Article] Homo-dimerization of Nemo-like kinase is essential for activation and nuclear localization (2011)
  • Author(s): Ishitani S, Inaba K, Matsumoto K, *Ishitani T.
  • Journal Title: Molecular Biology of the Cel Volume: 22 Pages: 266-277
  • NAID: 120004979399
• [Journal Article] Homo-dimerization of Nemo-like kinase is essential for activation and nuclear localization (2011)
  • Author(s): Ishitani S, Inaba K, Matsumoto K, Ishitani T.
  • Journal Title: Molecular Biology of the Cell Volume: 22 Pages: 266-277
  • NAID: 120004979399
  • Peer Reviewed
• [Presentation] Roles of two Ser/The kinases, NLK and Hipk2, in the regulation of Wnt/β-catenin signaling (2013)
  • Author(s): Tohru Ishitani
  • Organizer: 1st International Symposium on Protein Modifications in Pathogenic Dysregulation of Signaling
  • Place of Presentation: The Auditorium The Institute of Medical Science, The University of Tokyo
  • Invited
• [Presentation] Nemo-like kinase Blocks Hedgehog signaling by phosphorylating Gli1 transcription factor. (2012)
  • Author(s): 石谷 太, 清水 誠之, 石谷 閑
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2012-12-16
• [Presentation] Exploration of Tcf/Lef function using a highly responsive Wnt/β-catenin signaling-reporter transgenic zebrafish (2012)
  • Author(s): Nobuyuki Shimizu, Koichi Kawakami, Tohru Ishitani
  • Organizer: 第18回小型魚類研究会
  • Place of Presentation: 京都大学
  • Year and Date: 2012-09-22
• [Presentation] NLK positively regulates Wnt/β-catenin signalling by phosphorylating LEF1 in neural progenitor cells (2012)
  • Author(s): Satoshi Ota, Shizuka Ishitani, Nobuyuki Shimizu, Kunihiro Matsumoto, Motoyuki Itoh, To hru Ishitani
  • Organizer: 第35回日本神経科学大会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2012-09-19
• [Presentation] A dual and opposite role of NLK-mediated Lef1 phosphorylation on the Wnt/beta-catenin signaling (2012)
  • Author(s): Tohru Ishitani, Shizuka Ishitani
  • Organizer: 第45回日本発生生物学会・第64回日本細胞生物学会合同年会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2012-05-31
• [Presentation] NLK positively regulates Wnt/β-catenin signalling by phosphorylating LEF1 in neural progenitor cells. (2012)
  • Author(s): Satoshi Ota, Shizuka Ishitani, Nobuyuki Shimizu, Kunihiro Matsumoto, Motoyuki Itoh, Tohru Ishitani
  • Organizer: 第35回日本神経科学大会
  • Place of Presentation: 名古屋国際会議場
• [Presentation] A dual and opposite role of NLK-mediated Lef1 phosphorylation on the Wnt/β-catenin signaling (2012)
  • Author(s): Tohru Ishitani, Shizuka Ishitani
  • Organizer: 第45回日本発生生物学会・第64回日本細胞生物学会 合同年会
  • Place of Presentation: 神戸国際会議場
• [Presentation] Nemo-like kinase regulates its own activity by sequential autophosphorylation (2012)
  • Author(s): Shizuka Ishitani, Tohru Ishitani
  • Organizer: 第45回日本発生生物学会・第64回日本細胞生物学会 合同年会
  • Place of Presentation: 神戸国際会議場
• [Presentation] NLK positively regulates Wnt⁄β-catenin signalling by phosphorylating LEF1 in neural progenitor cells. (2012)
  • Author(s): Satoshi Ota, Shizuka Ishitani, Nobuyuki Shimizu, Kunihiro Matsumoto, Motoyuki Itoh, Tohru Ishitani
  • Organizer: the 10th International Conference on Zebrafish Development and Genetics
  • Place of Presentation: Madison, USA
• [Presentation] Live imaging of Tcf/Lef activity in developing, growing, and regenerating tissues of the highly responsive Wnt/β-catenin signaling reporter-transgenic zebrafish (2012)
  • Author(s): Nobuyuki Shimizu and Tohru Ishitani
  • Organizer: the 10th International Conference on Zebrafish Development and Genetics
  • Place of Presentation: Madison, USA
• [Presentation] NLK positively regulates Wnt/β-catenin signalling by phosphorylating LEF1 in neural progenitor cells. (2012)
  • Author(s): Satoshi Ota, Shizuka Ishitani, Nobuyuki Shimizu, Kunihiro Matsumoto, Motoyuki Itoh, Tohru Ishitani
  • Organizer: EMBO conference 30 years of Wnt signaling
  • Place of Presentation: Egmond Aan Zee, Netherlands
• [Presentation] Exploration of Tcf/Lef function using a highly responsive Wnt/β-catenin signaling-reporter transgenic zebrafish (2012)
  • Author(s): Nobuyuki Shimizu, Koichi Kawakami, and Tohru Ishitani
  • Organizer: 第18回小型魚類研究会
  • Place of Presentation: 京都大学芝蘭会館
• [Presentation] Lef1 phosphorylation by NLK is essential for the Lef1-mediated Wnt/β-catenin signaling in neural progenitor cells (2011)
  • Author(s): Satoshi Ota, Shizuka Ishitani, Nobuyuki Shimizu, Kunihiro Matsumoto, Motoyuki Itoh, Tohru Ishitani
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2011-12-16
• [Presentation] Analysis of the molecular mechanisms that regulate the activity of Nemo-like kinase (2011)
  • Author(s): Shizuka Ishitani, Tohru Ishitani
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2011-12-15
• [Presentation] Analysis of the spatiotemporal dynamics and its regulatory mechanisms of Wnt/β-catenin and Hedgehog signaling pathways using the transgenic zebrafish lines carrying the signaling reporters. (2011)
  • Author(s): Nobuyuki Shimizu, Tohru Ishitani
  • Organizer: 第17回小型魚類研究会
  • Place of Presentation: 東レ総合研修センター
  • Year and Date: 2011-09-08
• [Presentation] Analysis of the spatiotemporal dynamics and its regulatory mechanisms of Wnt/β-catenin and Hedgehog signaling pathways using the transgenic zebrafish lines carrying the signaling reporters (2011)
  • Author(s): Nobuyuki Shimizu, Tohru Ishitani
  • Organizer: 第17回小型魚類研究会
  • Place of Presentation: 三島市東レ研修センター
  • Year and Date: 2011-09-08
• [Presentation] Homo-dimerization of Nemo-like kinase is essential for activation and nuclear localization. (2011)
  • Author(s): Shizuka Ishitani, Kenji Inaba, Kunihiro Matsumoto, Tohru Ishitani
  • Organizer: 第63回日本細胞生物学会大会
  • Place of Presentation: 北海道大学
  • Year and Date: 2011-06-28
• [Presentation] Homo-dimerization of Nemo-like kinase is essential for activation and nuclear localization (2011)
  • Author(s): Shizuka Ishitani, Kenji Inaba, Kunihiro Matsumoto, Tohru Ishitani
  • Organizer: 第63回日本細胞生物学会大会
  • Place of Presentation: 北海道大学
  • Year and Date: 2011-06-28
• [Presentation] Lef1 phosphorylation by NLK is essential for the Lef1-mediated Wnt/β-catenin signaling in neural progenitor cells (2011)
  • Author(s): Satoshi Ota, Shizuka Ishitani, Nobuyuki Shimizu, Kunihiro Matsumoto, Motoyuki Itoh, Tohru Ishitani
  • Organizer: 沖縄コンベンションセンター, 第44回日本発生生物学会
  • Year and Date: 2011-05-20
• [Presentation] Lef1 phosphorylation by NLK is essential for the Lef1-mediated Wnt/β-catenin signaling in neural progenitor cells (2011)
  • Author(s): Satoshi Ota, Shizuka Ishitani, Nobuyuki Shimizu, Kunihiro Matsumoto, Motoyuki Itoh, Tohru Ishitani
  • Organizer: 第44回日本発生生物学会
  • Place of Presentation: 沖縄コンベンションセンター
  • Year and Date: 2011-05-20
• [Presentation] Lef1 phosphorylation by NLK is essential for the Lef1-mediated Wnt/β-catenin signaling in Neural progenitor cells (2011)
  • Author(s): Satoshi Ota, Shizuka Ishitani, Nobuyuki Shimizu, Kunihiro Matsumoto, Motoyuki Itoh, To hru Ishitani
  • Organizer: 4th Strategic Conference of Zebrafish Investigators
  • Place of Presentation: Asilomar Conference Center, USA
  • Year and Date: 2011-01-31
• [Presentation] NLKによるLef1のリン酸化は神経前駆細胞におけるWnt/β-cateninシグナルの伝達に必須である (2010)
  • Author(s): 太田聡、石谷閑、清水誠之、松本邦弘、伊藤素行、石谷太
  • Organizer: BMB2010
  • Place of Presentation: 神戸ポートピアホテル
  • Year and Date: 2010-12-10
• [Presentation] ゼブラフィッシュ生個体におけるWnt シグナルの活動の時空間的動態の可視化 (2010)
  • Author(s): 清水 誠之、太田 聡、石谷 太
  • Organizer: BMB2010
  • Place of Presentation: 神戸ポートピアホテル
  • Year and Date: 2010-12-07
• [Presentation] NLKによるLef1のリン酸化は、神経前駆細胞におけるWnt/β-cateninシグナルの伝達に必須である (2010)
  • Author(s): 太田 聡、石谷 閑、清水 誠之、松本邦弘、伊藤素行、石谷 太
  • Organizer: BMB2010
  • Place of Presentation: 神戸ポートピアホテル
  • Year and Date: 2010-12-07
• [Presentation] ゼブラフィッシュ生個体におけるWntシグナルの活動の時空間的動態の可視化 (2010)
  • Author(s): 清水誠之、太田聡、五谷太
  • Organizer: BMB2010
  • Place of Presentation: 神戸ポートピアホテル
  • Year and Date: 2010-12-07
• [Presentation] 神経細胞におけるWnt-β カテニン経路の活性化には、NLK による転写因子Lef1 のリン酸化が必須である (2010)
  • Author(s): 太田 聡、石谷 閑、清水 誠之、松本邦弘、伊藤素行、石谷 太
  • Organizer: 第16回小型魚類研究会
  • Place of Presentation: 埼玉
  • Year and Date: 2010-09-18
• [Presentation] ゼブラフィッシュにおけるWnt シグナルの活動の時空間的動態の可視化 (2010)
  • Author(s): 清水 誠之、太田 聡、石谷 太
  • Organizer: 第16回小型魚類研究会
  • Place of Presentation: 埼玉
  • Year and Date: 2010-09-18
• [Presentation] Nemo-like kinase promotes neurogenesis by interfering with formation of Notch Vanscnption complex. (2010)
  • Author(s): Tohru Ishitani, Tomoko Hirao, Maho Suzuki, Miho Isoda, Shizuka Ishitani, Motoo Kitagawa, Kunihiro Matsumoto, Motoyuki Itoh
  • Organizer: Neuro-2010
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2010-09-03
• [Presentation] Nemo-like kinase promotes neurogenesis by interfering with formation of Notch transcription complex. (2010)
  • Author(s): Tohru Ishitani, Tomoko Hirao, Maho Suzuki, Miho Isoda, Shizuka Ishitani, Motoo Kitagawa, Kunihiro Matsumoto, & Motoyuki Itoh
  • Organizer: 第43回日本発生生物学会大会
  • Place of Presentation: 京都国際会議場
  • Year and Date: 2010-06-22
• [Presentation] Nemo-like kinase positively regulates Wnt signaling via phosphorylating Lef1 in developing midbrain tectum (2010)
  • Author(s): Satoshi Ota, Shizuka Ishitani, Nobuyuki Shimizu, Kunihiro Matsumoto, Motoyuki Itoh, Tohru Ishitani
  • Organizer: 第43回日本発生生物学会大会
  • Place of Presentation: 京都国際会議場
  • Year and Date: 2010-06-20
• [Presentation] Nemo-like kinase positively regulates Wnt signaling via phosphorylating Lefl in developing midbrain tectum. (2010)
  • Author(s): Satoshi Ota, Shizuka Ishitani, Nobuyuki Shimizu, Kunihiro Matsumoto, Motoyuki Itoh, Tohru Ishitani
  • Organizer: 第43回日本発生生物学会大会
  • Place of Presentation: 京都国際会議場
  • Year and Date: 2010-06-20
• [Presentation] Nemo-like kinase promotes neurogenesis by interfering with formation of Notch transcription complex (2010)
  • Author(s): Tohru Ishitani, Tomoko Hirao, Maho Suzuki, Miho Isoda, Shizuka Ishitani, Motoo Kitagawa, Kunihiro Matsumoto, & Motoyuki Itoh
  • Organizer: 9th International Zebrafish Development and Genetics Conference
  • Place of Presentation: Wisconsin, USA
  • Year and Date: 2010-06-17
• [Presentation] Nemo-like kinase promotes neurogenesis by interfering with formation of Notch transcription complex. (2010)
  • Author(s): Tohru Ishitani, Tomoko Hirao, Maho Suzuki, Miho Isoda, Shizuka Ishitani Motoo Kitagawa, Kunihiro Matsumoto, Motoyuki Itoh
  • Organizer: 9th International Zebrafish Development and Genetics Conference
  • Place of Presentation: Wisconsin, USA
  • Year and Date: 2010-06-17
• [Presentation] Nemo-like kinaseはNotch転写複合体の形成を阻害することによりNotchシグナルを抑制する (2010)
  • Author(s): 石谷 太、石谷 閑、 平尾 智子、鈴木 真帆、磯田 美帆、北川 元生、松本 邦弘、伊藤 素行
  • Organizer: 第62回日本細胞生物学会年会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2010-05-19
• [Book] 神経組織構築を担うタンパク質リン酸化酵素NLKの機能と制御ブレインサイエンス・レビュ (2012)
  • Author(s): 石谷太
• [Book] 実験医学 Nemo-like kinaseはNotch転写複合体の形成を阻害し、神経細胞形成を促進する (2010)
  • Author(s): 石谷太,松本邦弘, 伊藤素行
• [Book] 医学のあゆみ 転写因子TCF/LEFの修飾によるWntシグナル制御 (2010)
  • Author(s): 石谷太,石谷閑.
• [Book] 実験医学カレントトピックス「Nemo-like kinaseはNotch転写複合体の形成を阻害し神経細胞形成を促進する」 (2010)
  • Author(s): 石谷太, 松本邦弘, 伊藤素行
  • Total Pages: 4
  • Publisher: 羊土社
• [Book] 医学のあゆみ「転写因子TCF/LEFの修飾によるWntシグナル制御」 (2010)
  • Author(s): 五谷太, 石谷閑
  • Total Pages: 8
  • Publisher: 医歯薬出版
• [Remarks]
  • URL: http://www.bioreg.kyushu-u.ac.jp/labo/crs/top.html
• [Remarks] 石谷研究室プログレス
  • URL: http://www.bioreg.kyushu-u.ac.jp/labo/crs/sub11.html
• [Remarks]
  • URL: http://www.bioreg.kyushu-u.ac.jp/labo/crs/sub11.html
• [Remarks]
  • URL: http://www.bioreg.kyushu-u.ac.jp/labo/crs/sub11.html