Studies on physiological function and neuropathology of novel brain protein kinase LMTK1

• Project/Area Number: 16K07060
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Tokyo Metropolitan University
• Principal Investigator: Hisanaga Shin-ichi 首都大学東京, 理学研究科, 教授 (20181092)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2018: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 神経細胞 / 軸索 / スパイン / 小胞輸送 / 自閉症 / リン酸化 / マウス / エンドソーム / LMTK1 / 脳 / 神経 / 認知症 / Rab / ノックアウトマウス / 膜輸送 / 行動解析 / 発現解析 / タンパク質 / 酵素 / 神経科学 / 神経突起 / Cdk5 / 脳・神経 / 細胞・組織 / 神経突起伸長

Outline of Final Research Achievements

Lemur kinase 1 (LMTK1) is a novel Ser/Thr protein kinase expressed highly in mammalian brains. We reported previously that LMTK1 plays a role in axon outgrowth and spine formation in primary neurons. Here, we investigated the molecular mechanism of LMTK1 regulation of axon outgrowth, and a function of LMTK1B, another isoform of LMTK1 different from LMTK1A, and properties of LMTK1 knockout mouse. We found that (1) LMTK1 regulated Rab11 small GTPase by activating TBC1D9B Rab11 GAP, (2) the kinase negative form of LMTK1B was different from kinase negative LMTK1A in the axon outgrowth and spine formation whereas wild types of them localized at the perinuclear region, and (3) LMTK1 KO mice exhibited hyper locomotive activity, reduced anxiety and anti-depressant behaviors.

Academic Significance and Societal Importance of the Research Achievements

神経細胞の軸索伸長やスパイン形成には細胞骨格構造が重要な役割を果たしていることは知られていたが、細胞膜成分がどのようにして供給されるかは殆どわかっていなかった。本研究により、LMTK1という新規キナーゼが過剰な小胞輸送を抑えていること、その仕組みとしてRab11をそのGAPを介して、制御していることが明らかになった。さらにLMTK1の欠失は自閉症様の症状を示すことが明らかとなった。

Research Products

• [Int'l Joint Research] Universidad de Chile(チリ)
• [Int'l Joint Research] Universidad de Chile(チリ)
• [Journal Article] Cyclin-dependent kinase 5 promotes proteasomal degradation of the 5-HT1A receptor via phosphorylation. (2019)
  • Author(s): Takahashi, M. et al
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 510 Pages: 370-375
  • Peer Reviewed / Open Access
• [Journal Article] Cytoplasmic control of Rab family small GTPases through BAG6 (2019)
  • Author(s): Takahashi Toshiki、Minami Setsuya、Tsuchiya Yugo、Tajima Kazu、Sakai Natsumi、Suga Kei、Hisanaga Shin‐ichi、Ohbayashi Norihiko、Fukuda Mitsunori、Kawahara Hiroyuki
  • Journal Title: EMBO reports Volume: 20 Issue: 4
  • DOI: 10.15252/embr.201846794
  • NAID: 120007127921
  • Peer Reviewed / Open Access
• [Journal Article] otent prion-like behaviors of pathogenic α-synuclein and evaluation of inactivation methods. (2018)
  • Author(s): Tarutani A, Arai T, Murayama S, Hisanaga SI, Hasegawa M
  • Journal Title: Acta Neuropathol Commun Volume: 6 Issue: 1 Pages: 29-29
  • DOI: 10.1186/s40478-018-0532-2
  • Peer Reviewed / Open Access
• [Journal Article] Isoform-independent and -dependent phosphorylation of microtubule-associated protein tau in mouse brain during postnatal development. (2018)
  • Author(s): Tuerde, D., Kimura, T., Miyasaka, T., Furusawa, K., Shimozawa, A., Hasegawa, M., Ando, A., Hisanaga, S.
  • Journal Title: J. Biol, Chem. Volume: 293 Issue: 5 Pages: 1781-1793
  • DOI: 10.1074/jbc.m117.798918
  • Peer Reviewed / Open Access
• [Journal Article] Phospho-Tau Bar Code: Analysis of Phosphoisotypes of Tau and Its Application to Tauopathy. (2018)
  • Author(s): Kimura T, Sharma G, Ishiguro K, Hisanaga SI.
  • Journal Title: Front Neurosci. Volume: 12 Pages: 44-44
  • DOI: 10.3389/fnins.2018.00044
  • Peer Reviewed / Open Access
• [Journal Article] Cdk5 regulation of the GRAB-mediated Rab8-Rab11 cascade in axon outgrowth. (2017)
  • Author(s): Furusawa, K., Asada, A., Urrutia, P., Gonzalez-Billault, C., Fukuda, M. and Hisanaga, S. I.
  • Journal Title: J. Neurosci. Volume: 37 Issue: 4 Pages: 790-806
  • DOI: 10.1523/jneurosci.2197-16.2017
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] In vivo regulation of glycogen synthase kinase 3β activity in neurons and brains. (2017)
  • Author(s): Krishnankutty, A., Kimura, T., Saito, T., Aoyagi, K., Asada, A., Takahashi, S., Ando, K., Ohara-Imaizumi, M., Ishiguro, K., Hisanaga, S.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 8602-8602
  • DOI: 10.1038/s41598-017-09239-5
  • Peer Reviewed / Open Access
• [Journal Article] Quantitative and combinatory determination of in situ phosphorylation of tau and its FTDP-17 mutants. (2016)
  • Author(s): Kimura T, Hosokawa T, Taoka M, Tsutsumi K, Ando K, Ishiguro K, Hosokawa M, Hasegawa M, Hisanaga S.
  • Journal Title: Sci. Rep. Volume: 6 Issue: 1 Pages: 33479-33479
  • DOI: 10.1038/srep33479
  • Peer Reviewed / Open Access
• [Journal Article] The kinase activity of endosomal kinase LMTK1A regulates its cellular localization and interactions with cytoskeletons. (2016)
  • Author(s): Sharma S, Tsutsumi K, Saito T, Asada A, Ando K, Tomomura T, Hisanaga S.
  • Journal Title: Genes Cells. Volume: 21 Issue: 10 Pages: 1080-1094
  • DOI: 10.1111/gtc.12404
  • Peer Reviewed / Open Access
• [Journal Article] Two degradation pathways of the p35 Cdk5 activation subunit, dependent and independent of ubiquitination. (2016)
  • Author(s): Takasugi et al.,
  • Journal Title: J. Biol. Chem. Volume: 291 Issue: 9 Pages: 4649-4657
  • DOI: 10.1074/jbc.m115.692871
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Abundance of Nonphosphorylated Tau in Mouse and Human Tauopathy Brains Revealed by the Use of Phos-Tag Method (2016)
  • Author(s): Kimura T, Hatsuta H, Masuda-Suzukake M, Hosokawa M, Ishiguro K, Akiyama H, Murayama S, Hasegawa M, Hisanaga S
  • Journal Title: American Journal of Pathology Volume: 186 Issue: 2 Pages: 398-409
  • DOI: 10.1016/j.ajpath.2015.10.009
  • Peer Reviewed / Open Access
• [Presentation] CD2-associated protein (CD2AP) sorts amyloid precursor protein (APP) to late endosomes from early endosomes. (2019)
  • Author(s): Furusawa, K. et al.,
  • Organizer: AD/PD 2019
  • Int'l Joint Research
• [Presentation] In vivo phosphorylation of tau in brains of Marmoset, a non-human Primate. (2018)
  • Author(s): Hisanaga, S., et al.
  • Organizer: 15 meeting of APSN
  • Int'l Joint Research
• [Presentation] The role of Thr231 phosphorylation of tau on its localization into the nucleus. (2018)
  • Author(s): Zhu, Y. et al.
  • Organizer: 15 meeting of APSN
  • Int'l Joint Research
• [Presentation] Lemur kinase 1 (LMTK1A) regulates dendritic spine formation through the TBC1D9B Rab11 GAP and Rab11 cascade. (2018)
  • Author(s): Nishino, H. et al.,
  • Organizer: 第69回日本細胞生物学会
• [Presentation] エンドソームのトラッフィキング制御と軸索形成及び維持 (2018)
  • Author(s): 久永眞市
  • Organizer: SAM研究会シンポジウム
  • Invited
• [Presentation] Cyclin-dependent kinase 5, its role in neuronal differentiation, synaptic activity and neurodegeneration. (2018)
  • Author(s): Hisanaga, S.
  • Organizer: Royan International Conference
  • Int'l Joint Research / Invited
• [Presentation] Phospho-tau bar code－死後脳でのタウリン酸化解析はタウオパチーの診断に役立つか？ (2018)
  • Author(s): 久永眞市
  • Organizer: 新学術領域研究「コホート・生体試料支援プラットフォーム」研究者対象シンポジウム
  • Invited
• [Presentation] 複雑怪奇なリン酸化タンパク質タウのPhos-tag解析 (2018)
  • Author(s): 木村妙子、久永眞市
  • Organizer: 電気泳動学会シンポジウム
  • Invited
• [Presentation] Cdk5-dependent phosphorylation of GRAB, a guanine nucleotide exchange factor for Rab8, regulates neuronal migration in the developing cerebral cortex. (2018)
  • Author(s): Furusawa, K., Asada, A., Urrutia, P., Gonzalez-Billault, C., Fukuda, M., Hisanaga, S.
  • Organizer: ASCB/EMBO 2017 Meeting
  • Int'l Joint Research
• [Presentation] Cdk5-dependent phosphorylation of GRAB, a guanine nucleotide exchange factor for Rab8, regulates axon outgrowth by directing Rab8A to Rab11A-positive endosomes. (2016)
  • Author(s): Furusawa, K., Asada, A., Urrutia, P., Gonzalez-Billault, C., Fukuda, M., Hisanaga, S
  • Organizer: American Society for Cell Biology 20162016
  • Place of Presentation: サンフランシスコ、アメリカ
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] 小胞体輸送を制御する脳キナーゼLMTK1の膜貫通型と非膜貫通型アイソフォームの発現と機能解析 (2016)
  • Author(s): 杉山亜梨華、高橋路佳、魏冉、福田公子、友村美根子、安藤香奈絵、久永眞市.
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30
• [Presentation] In vivo regulation of GSK3b activity unveiled by the quantitative measurement of its phospho-isotypes (2016)
  • Author(s): Krishnankutty, K., Kimura, T., Saito, T., Aoyagi, K.,Asada, A., Ando, K., Ohara-Imaizumi, M., Ishiguro, K., Hisanaga, S.
  • Organizer: 46th annual meeting of Society for Neuroscience
  • Place of Presentation: サンディエゴ、アメリカ
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Phosphorylation and Isoform Expression of Microtubule-Associated Protein Tau are Regulated Independently during Brain Development. (2016)
  • Author(s): Tuerde, D., Kimura, T., Miyasaka, T., Asada, A., Saito1, T.,Ando, K., Hisanaga, S.
  • Organizer: 14th Asian-Pacific Society for Neurochemistry
  • Place of Presentation: クアラルンプール、マレーシア
  • Year and Date: 2016-08-26
  • Int'l Joint Research
• [Presentation] 樹状突起スパイン形成におけるLemur kinase1A(LMTK1A) の役割. (2016)
  • Author(s): 西野尋紀, 堤弘次, 浅田明子, 斎藤太郎, 久永眞市
  • Organizer: 第68回日本細胞生物学会大会
  • Place of Presentation: 京都
  • Year and Date: 2016-06-15
• [Remarks] 首都大学東京 生命科学専攻 神経分子機能研究室
  • URL: http://www.biol.se.tmu.ac.jp/labo.asp?ID=neumol
• [Remarks] 神経分子機能研究室
  • URL: http://www.comp.tmu.ac.jp/mns/