Signal transduction by centrosome-associated protein kinases

• Project/Area Number: 24590396
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Aichi Cancer Center Research Institute
• Principal Investigator: GOTO Hidemasa 愛知県がんセンター(研究所), 腫瘍医化学部, 室長 (20393126)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 分裂期 / キナーゼ / Plk1 / 14-3-3 / PI3キナーゼ / Akt / 中心体 / 14-3-3ガンマ

Outline of Final Research Achievements

Polo-like kinase 1 (Plk1) controls multiple aspects of mitosis. Here, we identified Ser99 on Plk1 as a novel mitosis-specific phosphorylation site. Plk1-Ser99 phosphorylation creates a docking site for 14-3-3gamma and this interaction stimulates the catalytic activity of Plk1. 14-3-3gamma knockdown or replacement of wild-type Plk1 by a Ser99-phospho-blocking mutant leads to a prometaphase/metaphase-like arrest due to the activation of the spindle assembly checkpoint. Inhibition of PI3K and Akt significantly reduces the level of Plk1-Ser99 phosphorylation and delays metaphase to anaphase transition. Mitotic Plk1 activity is regulated by Plk1 binding to 14-3-3gamma following Plk1-Ser99 phosphorylation downstream of the PI3K-Akt signalling pathway. This novel Plk1 activation pathway controls proper progression from metaphase to anaphase. Our study paves the way for future studies elucidating the relationship between PI3K-Akt pathway and Plk1 in carcinogenesis.

Research Products

• [Journal Article] Novel Insights into Chk1 Regulation by Phosphorylation (2015)
  • Author(s): Goto, H., Kasahara, K., and Inagaki, M.
  • Journal Title: Cell Structure and Function Volume: 40 Issue: 1 Pages: 43-50
  • DOI: 10.1247/csf.14017
  • NAID: 130004885867
  • ISSN: 0386-7196, 1347-3700
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Inhibition of endocytic vesicle fusion by Plk1-mediated phosphorylation of vimentin during mitosis. (2014)
  • Author(s): Ikawa, K.
  • Journal Title: Cell Cycle Volume: 13 Issue: 1 Pages: 126-137
  • DOI: 10.4161/cc.26866
  • Peer Reviewed
• [Journal Article] Plk1 Phosphorylates CLIP-170 and Regulates Its Binding to Microtubules for Chromosome Alignment (2014)
  • Author(s): Kaneko M., Matsuzawa K., Matsui T., Akita H., Sugiyama I., Ishidate F., Nakano A., Takashima S., Goto H., Inagaki M., Kaibuchi K., and Watanabe T.
  • Journal Title: Cell Structure and Function Volume: 39 Issue: 1 Pages: 45-59
  • DOI: 10.1247/csf.14001
  • NAID: 130004053900
  • ISSN: 0386-7196, 1347-3700
  • Peer Reviewed / Open Access
• [Journal Article] Cdk1 Coordinates Timely Activation of MKlp2 Kinesin with Relocation of the Chromosome Passenger Complex for Cytokinesis. (2014)
  • Author(s): Kitagawa, M.
  • Journal Title: Cell Rep. Volume: 7 Issue: 1 Pages: 166-179
  • DOI: 10.1016/j.celrep.2014.02.034
  • Peer Reviewed / Open Access
• [Journal Article] Direct interaction of Plk4 with STIL ensures formation of a single procentriole per parental centriole, Nature Communications (2014)
  • Author(s): Midori Ohta, Tomoko Ashikawa, Yuka Nozaki, Hiroko Kozuka-Hata, Hidemasa Goto, Masaki Inagaki, Masaaki Oyama and Daiju Kitagawa
  • Journal Title: Nature communications Volume: 5:5267 Issue: 1 Pages: 1-12
  • DOI: 10.1038/ncomms6267
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cyclin A/Cdk2 regulates Cdh1 and claspin during late S/G2 phase of the cell cycle. (2014)
  • Author(s): Oakes, V., Wang, W., Harrington, B., Lee, W.J., Beamish, H., Chia, K.M., Pinder, A., Goto, H., Inagaki, M., Pavey, S., and Gabrielli, B.
  • Journal Title: Cell Cycle Volume: 13 Issue: 20 Pages: 3302-3311
  • DOI: 10.4161/15384101.2014.949111
  • Peer Reviewed
• [Journal Article] New Insights into Roles of Intermediate Filament Phosphorylation and Progeria Pathogenesis. (2014)
  • Author(s): Goto, H.
  • Journal Title: IUBMB Life Volume: 66 Issue: 3 Pages: 195-200
  • DOI: 10.1002/iub.1260
  • Peer Reviewed / Open Access
• [Journal Article] Defect of mitotic vimentin phosphorylation causes microophthalmia and cataract via aneuploidy and senescence in lens epithelial cells. (2013)
  • Author(s): Matsuyama, M.
  • Journal Title: J. Biol. Chem. Volume: 288 Issue: 50 Pages: 35626-35635
  • DOI: 10.1074/jbc.m113.514737
  • Peer Reviewed
• [Journal Article] The p90 ribosomal S6 kinase (RSK) inhibitor BI-D1870 prevents gamma irradiation-induced apoptosis and mediates senescence via RSK- and p53-independent accumulation of p21WAF1/CIP1. (2013)
  • Author(s): Neise, D.
  • Journal Title: Cell Death Dis. Volume: 4 Issue: 10 Pages: e859-e859
  • DOI: 10.1038/cddis.2013.386
  • Peer Reviewed
• [Journal Article] PI 3-kinase-dependent phosphorylation of Plk1-Ser99 promotes association with 14-3-3γ and is required for metaphase-anaphase transition (2013)
  • Author(s): Kasahara, K., Goto, H., Izawa, I., Kiyono, T., Watanabe, N., Elowe, S., Nigg, E.A. and Inagaki, M.
  • Journal Title: Nat. Commun. Volume: 4 Issue: 1 Pages: 1882-1882
  • DOI: 10.1038/ncomms2879
  • Peer Reviewed / Open Access
• [Journal Article] Cell cycle progression by the repression of primary cilia formation in proliferating cells. (2013)
  • Author(s): Goto, H.
  • Journal Title: Cell. Mol. Life Sci. Volume: 70 Issue: 20 Pages: 3893-3905
  • DOI: 10.1007/s00018-013-1302-8
  • Peer Reviewed
• [Journal Article] Trichoplein and Aurora A block aberrant primary cilia assembly in proliferating cells. (2012)
  • Author(s): Inoko, A., …., Inagaki, M.
  • Journal Title: J. Cell Biol. Volume: 197 Issue: 3 Pages: 391-405
  • DOI: 10.1083/jcb.201106101
  • Peer Reviewed
• [Journal Article] P90 RSK arranges Chk1 in the nucleus for monitoring of genomic integrity during cell proliferation (2012)
  • Author(s): Li, P., Goto, H., Kasahara, K., Matsuyama, M., Wang, Z., Yatabe, Y., Kiyono, T., Inagaki, M.
  • Journal Title: Mol. Biol. Cell Volume: 23 Issue: 8 Pages: 1582-1592
  • DOI: 10.1091/mbc.e11-10-0883
  • Peer Reviewed
• [Journal Article] Novel regulation of checkpoint kinase 1 : Is checkpoint kinase 1 a good candidate for anti-cancer therapy? (2012)
  • Author(s): Goto, H., Izawa, I., Li, P. and Inagaki, M.
  • Journal Title: Cancer Sci. Volume: (in press) Issue: 7 Pages: 1195-1200
  • DOI: 10.1111/j.1349-7006.2012.02280.x
  • Peer Reviewed
• [Presentation] Defect of Vimentin Phosphorylation Cause Aging via Aneuploidy and Cellular Senescence (2014)
  • Author(s): Tanaka H., Goto H., Inoko A., Izawa I., and Inagaki M.
  • Organizer: 第73回日本癌学会総会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2014-09-27
• [Presentation] Screening of novel Aurora-A-associated proteins to prevent primary cilia assembly at the centrosome in proliferating cells.
  • Author(s): Goto H. and Inagaki M.
  • Organizer: 第65回日本細胞生物学会大会
  • Place of Presentation: ウィンク愛知（名古屋市）
  • Invited
• [Presentation] Screening of novel Aurora-A-associated proteins
  • Author(s): Goto H., Era S., Li P., Kasahara K., Inoko A., Izawa I., Mochizuki H., Togashi T., Kawamura Y., Kawakami Y., Goshima N., Kiyono T., and Inagaki M.
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: パシフィコ横浜（横浜市）
• [Presentation] Novel mitotic signaling crosstalk between PI3K-Akt pathway and Plk1
  • Author(s): Goto H.
  • Organizer: 1st International Symposium on Protein Modifications in Pathogenic Dysregulation of Signaling
  • Place of Presentation: 東京大学医科学研究所（東京）
  • Invited
• [Presentation] P90 RSK arranges Chk1 in the nucleus for monitoring of genomic integrity during cell proliferation
  • Author(s): 後藤英仁
  • 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大会
  • Place of Presentation: 神戸国際会議場（神戸）
• [Book] Monoclonal Antibodies: Methods and Protocols, Second Edition (2014)
  • Author(s): Goto H. and Inagaki M.
  • Publisher: Humana Press
• [Book] ヒトと医学のステージへ拡大する細胞周期 中山敬一編、実験医学増刊号、31巻、２号 (2013)
  • Author(s): 後藤英仁、稲垣昌樹.
  • Publisher: 羊土社
• [Book] ヒトと医学のステージへ拡大する細胞周期、実験医学増刊号、31巻、２号 (2013)
  • Author(s): 後藤英仁
  • Publisher: 羊土社
• [Remarks] 腫瘍医化学部／部門紹介／愛知県がんセンター研究所
  • URL: http://www.pref.aichi.jp/cancer-center/ri/01bumon/08hatsugan_seigyo/index.html