Utilization of Cdk5/p35 and its role as a negative modulator in signal transduction pathways in neurons.

2011 Fiscal Year Final Research Report

• Project Area: Cell Proliferation Control
• Project/Area Number: 19057007
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tokyo Metropolitan University
• Principal Investigator: HISANAGA Shin-ichi 首都大学東京, 大学院理工学研究科, 教授 (20181092)
• Project Period (FY): 2007 – 2011
• Keywords: サイクリン依存性キナーゼ / 分化 / 増殖 / 神経細胞 / 細胞死 / シグナル伝達

Research Abstract

Subcellular localization of Cdk5 is a molecular mechanism that prevents cell death of neurons even when Cdk5 is expressed in post-mitotic neurons. It was shown here that Cdk5 bound to membrane organelles in the cytoplasm through myristoylated p35 Cdk5 activator and Cdk5 activity promoted export of the active Cdk5-p35 complex from the nucleus. We confirmed that Cdk5 suppressed excitation of neurons. One of the molecular mechanisms is phosphorylation of Sept5, which inhibited interaction with syntaxin1 SNARE protein. We also found a novel function of Cdk5, which was suppression of neurite outgrowth through LMTK1 neuron abundant novel Ser/Thr protein kinase.

Research Products

• [Journal Article] Regulation of mitochondrial transport and inter-microtubule spacing by Tau phosphorylation at the sites hyperphosphorylated in Alzheimer’s disease. (2012)
  • Author(s): Shahpasand, S., Uemura, I., Saito, T., Asano, T., Hata, K., Shibata, K., Toyoshima, Y., Hasegawa, M., and Hisanaga, S.
  • Journal Title: J. Neurosci. Volume: 32 Pages: 2430-2441
• [Journal Article] Phos-tag を用いたCdk5制御サブユニットp35のin vivo リン酸化の定量的解析 (2012)
  • Author(s): 久永眞市
  • Journal Title: 生物物理化学 Volume: 56 Pages: s9
• [Journal Article] Calpastatin, an endogenous calpain-inhibitor protein, regulates the cleavage of the Cdk5 activator p35 to p25. (2011)
  • Author(s): Sato, K., Minegishi, S., Takano, J., Plattner, F., Saito, T., Asada, A., Kawahara, H., Iwata, N., Saido, T. C., Hisanaga, S.
  • Journal Title: J. Neurochem. Volume: 117 Pages: 504-515
• [Journal Article] Regulation and role of Cdk5 kinase activity in neuronal survival and death. (2010)
  • Author(s): Hisanaga, S., and Endo, E.
  • Journal Title: J. Neurochem. Volume: 115 Pages: 1309-1321
• [Journal Article] Membrane association facilitates degradation and cleavage of the cyclin-dependent kinase 5 activators p35 and p39. (2010)
  • Author(s): Minegishi, S., Asada, A., Miyauchi, S., Fuchigami, T., Saito, T., and Hisanaga, S.
  • Journal Title: Biochemistry Volume: 49 Pages: 5482-5493
• [Journal Article] Quantitative Measurement of In Vivo Phosphorylation States of Cdk5 Activator p35 by Phos-tag SDS-PAGE. (2010)
  • Author(s): Hosokawa, T., Saito, T., Asada, A., Fukunaga, K., and Hisanaga, S.
  • Journal Title: Mol. Cell. Proteomics. Volume: 9 Pages: 1133-1143
• [Journal Article] AATYK1A phosphorylation by Cdk5 regulates the recycling endosome pathway. (2010)
  • Author(s): Takano, T., Tsutsumi, K., Saito, T., Asada, A., Tomomura, M., Fukuda, M., Hisanaga, S.
  • Journal Title: Genes Cells Volume: 15 Pages: 783-797
• [Journal Article] Phosphorylation of AATYK1 by Cdk5 suppresses its tyrosine phosphorylation. (2010)
  • Author(s): Tsutsumi, K., Takano, T., Endo, R., Fukuda, M., Ohshima, T., Tomomura, M., and Hisanaga, S.
  • Journal Title: PLoS ONE Volume: 5 Pages: e10260
• [Journal Article] Commitment of MPP+-induced neuronal cell death by proteasome-mediated degradation of p35 Cdk5 activator. (2009)
  • Author(s): Endo, R., Saito, T., Asada, A., Kawahara, H., Ohshima, T., and Hisanaga, S.
  • Journal Title: J. Biol. Chem. Volume: 284 Pages: 26029-26039
• [Journal Article] Effect of pin1 or microtubule binding on dephosphorylation of FTDP-17 mutant tau. (2009)
  • Author(s): Yotsumoto, K., Saito, T., Asada, A., Oikawa, T., Kimura, T., Uchida, C., Ishiguro, K., Uchida, T., Hasegawa, M., and Hisanaga, S.
  • Journal Title: J. Biol. Chem. Volume: 284 Pages: 16840-16847
• [Journal Article] Novel axonal distribution of neurofilament-H phosphorylated at the GSK3β-phosphorylation site in its E-segment. (2009)
  • Author(s): Sasaki, T., Ishiguro, K., and Hisanaga, S.
  • Journal Title: J. Neurosci. Res. Volume: 87 Pages: 3088-3097
• [Journal Article] Suppression of mutant huntingtin aggregate formation by Cdk5/p35 through the effect on microtubule stability. (2008)
  • Author(s): Kaminosono, S., Saito, T., Oyama, F., Ohshima, T., Asada, A., Nagai, Y., Nukina, N., and Hisanaga, S.
  • Journal Title: J. Neurosci. Volume: 28 Pages: 8747-8755
• [Journal Article] Myristoylation of p39 and p35 is a determinant of cytoplasmic or nuclear localization of active cycline-dependent kinase 5 (Cdk5) complexes. (2008)
  • Author(s): Asada, A., Yamamoto, N., Gohda, M., Saito, T., Hayashi, N., and Hisanaga, S.
  • Journal Title: J. Neurochem. Volume: 106 Pages: 1325-1336
• [Journal Article] Palmitoylation-dependent endosomal localization of AATYK1A and its interaction with Src. (2008)
  • Author(s): Tsutsumi, K., Tomomura, M., Furuichi, T., and Hisanaga, S.
  • Journal Title: Genes to Cells Volume: 13 Pages: 949-964
• [Journal Article] p25/Cdk5 promotes the progression of cell death in nucleus of ER-stressed neurons. (2007)
  • Author(s): Saito, T., Konno, T., Asada, A. and Hisanaga, S.
  • Journal Title: J. Neurochem. Volume: 102 Pages: 133-140
• [Journal Article] Regulation of the interaction of Disabled-1 with CIN85 by phosphorylation with Cyclin-dependent kinase 5. (2007)
  • Author(s): Sato, Y., Taoka, M., Sugiyama, N., Kubo, K., Fuchigami, T., Asada, A., Saito, T., Nakajima, K., Isobe, T. and Hisanaga, S.
  • Journal Title: Genes Cells Volume: 12 Pages: 1315-1327
• [Journal Article] Regulation of the membrane association and kinase activity of Cdk5-p35 by phosphorylation of p35. (2007)
  • Author(s): Sato, K., Zhu, Y-S., Saito, T., Yotsumoto, K., Asada, A., Hasegawa, M. and Hisanaga, S.
  • Journal Title: J. Neurosci. Res. Volume: 85 Pages: 3071-3078
• [Journal Article] Phosphorylation of adult type sept5 (cdcrel-1) by cyclin-dependent kinase 5 inhibits interaction with syntaxin-1. (2007)
  • Author(s): Taniguchi, T., Taoka, M., Itakura, M., Asada, A., Saito, T., Kinoshita, M., Takahashi, M., Isobe, T., and Hisanaga, S.
  • Journal Title: J. Biol. Chem. Volume: 282 Pages: 7869-7876
• [Journal Article] Supression of calpain-dependent cleavage of the cdk5 activator p35 to p25 by site-specific phosphorylation. (2007)
  • Author(s): Kamei, H., Saito, T, Ozawa, O., Fujita, Y., Asada, A., Bibb, J. A., Saido, T. C., Sorimachi, S., and Hisanaga, S.
  • Journal Title: J. Biol. Chem. Volume: 282 Pages: 1687-1694
• [Journal Article] Subcellular localization of active Cdk5 is determined by its own kinase activity.
  • Author(s): Asada, A., Saito, T., and Hisanaga, S.
  • Journal Title: J. Cell Sci. Volume: (in press)
• [Journal Article] LMTK1/AATYK1 Is a Novel Regulator of Axonal Outgrowth That Acts via Rab11 in a Cdk5-Dependent Manner.
  • Author(s): Takano, T., Tomomura, M., Yoshioka, N., Tsutsumi, K., Terasawa, Y., Saito, T., Kawano, H., Kamiguchi, H., Fukuda, M., Hisanaga, S.
  • Journal Title: J. Neurosci. Volume: (in press)
• [Presentation] Regulation of the kinase activity and function of Cyclin-dependent kinase 5 in post-mitotic neurons. (2011)
  • Author(s): Hisanaga, S.
  • Organizer: 第23回国際神経化学会シンポジウム
  • Place of Presentation: アテネ
  • Year and Date: 20110800
• [Presentation] Phos-tag SDS-PAGEによって新しく出来たこと (2011)
  • Author(s): 久永眞市
  • Organizer: 日本生化学会フォーラム
  • Place of Presentation: 京都
  • Year and Date: 20110300
• [Presentation] Cdk5 and neuron cell death. (2011)
  • Author(s): Hisanaga, S., Asada, A., and Saito, T.
  • Organizer: Pep Con-2010
  • Place of Presentation: 北京
  • Year and Date: 20110300
• [Presentation] Normal and abnormal phosphorylation of Tau by Cyclin-dependent kinase 5. (2010)
  • Author(s): Hisanaga, S.
  • Organizer: Aging, Tau Protein and Dementias
  • Place of Presentation: 東京
  • Year and Date: 20101000
• [Presentation] Pro-survival and pro-apoptotic activity of neuron-specific protein kinase Cdk5. (2009)
  • Author(s): Hisanaga, S.
  • Organizer: 27th Annual conference of Indian Academy of Neuroscience
  • Place of Presentation: インド
  • Year and Date: 20091200
• [Presentation] タンパク質リン酸化研究へのフォスタグSDS-PAGEの応用 (2009)
  • Author(s): 久永眞市, 細川智永, 浅田明子, 斎藤太郎
  • Organizer: 第４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: 熊本
  • Year and Date: 20091100
• [Presentation] Effect of PIN1 and microtubules binding on dephosphorylation of FTDP-17 mutant Tau. (2009)
  • Author(s): Hisanaga, S.
  • Organizer: 2009 International Conference on Alzheimer’s Disease
  • Place of Presentation: ウィーン
  • Year and Date: 20090700
• [Presentation] Reconsideration of the activation mechanism of Cdk5 by p35 and p39. (2009)
  • Author(s): Hisanaga, S.
  • Organizer: 2^<nd> International Symposium on Cdk5
  • Place of Presentation: 東京
  • Year and Date: 20090600
• [Presentation] dk5 and Microtubules in Neurodegenerative Diseases. (2009)
  • Author(s): Hisanaga, S.
  • Organizer: The International Symposium on “Cell Cycle and Cell Architecture”
  • Place of Presentation: 名古屋
  • Year and Date: 2009-02-26
• [Presentation] サイクリン依存性キナーゼ５の活性制御と神経変性疾患 (2008)
  • Author(s): 久永眞市, 淺田明子, 斎藤太郎
  • Organizer: 第31回日本分子生物学会シンポジウム
  • Place of Presentation: 神戸
  • Year and Date: 20081200
• [Presentation] 神経細胞の生死を決めるCdk5の膜結合と核移行 (2007)
  • Author(s): 久永真市, 浅田明子, 斉藤太郎
  • Organizer: 第30回分子生物学会ワークショップ
  • Place of Presentation: 横浜
  • Year and Date: 20071200
• [Presentation] Filament assembly abnormality of neurofilament-L with Charcot-Marie-Tooth disease mutation (2007)
  • Author(s): Hisanaga, S., Gotow, T., Shiozaki, M., Sasaki, T., Asada, A., Saito, T., Uchiyama, Y., Yasuki, J.
  • Organizer: 第31回日本神経科学大会
  • Place of Presentation: 東京
  • Year and Date: 20070700
• [Presentation] フォスタグSDS-PAGEを用いたタンパク質リン酸化の解析-Cdk5活性化サブユニットp35の場合-
  • Author(s): 久永眞市, 細川智永, 浅田明子, 斎藤太郎
  • Organizer: 第7回ヒトプロテオーム学会
  • Place of Presentation: 東京
• [Presentation] サイクリン依存性キナーゼ５（Cdk5）の異常活性化と神経変性疾患
  • Author(s): 久永眞市
  • Organizer: 「筋萎縮性側索硬化症の病態に基づく画期的治療法の開発」班のワークショップ
  • Place of Presentation: 東京
• [Presentation] Neuronal development and neurodegeneration on Cdk5 and related signaling.
  • Author(s): Hisanaga, S.
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋
• [Presentation] アルツハイマー病でみられるタウの異常リン酸化とプロテインフォスファターゼ
  • Author(s): 久永眞市, 斎藤太郎
  • Organizer: 第82回日本生化学会
  • Place of Presentation: 神戸
• [Book] 細胞機能．「第３版分子生物学」第12章 田沼靖一編 (2011)
  • Author(s): 久永真市
  • Total Pages: 141-154
  • Publisher: 丸善
• [Book] Neurofilaments in aged amimals. Cytoskeleton of the Nervous System. pp325-345. Advances in Neurobiology 3. Eds. By R. Nixon and A Yuan. (2011)
  • Author(s): Hisanaga, S., Sasaki, T., and Uchida, A.
  • Publisher: Springer
• [Book] 神経細胞におけるCdk5-p35の活用戦略．「細胞周期フロンティア」, 佐方功幸, 稲垣昌樹, 岸本健雄 編集, pp242-247 (2010)
  • Author(s): 久永眞市, 遠藤良
  • Publisher: 共立出版
• [Book] Cyclin-dependent kinase 5: preparation and measurement of kinase activity. In Protein kinase technologies. Neuromethods (Ed., H. Mukai)
  • Author(s): Minegishi, S., Hisanaga, S.
  • Publisher: Springer(in press)
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