Abnormal Differentiation in Cancer Cells and Intracellular Signaling

2009 Fiscal Year Final Research Report

• Project/Area Number: 17014066
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Hiroshima University
• Principal Investigator: KIKUCHI Akira Hiroshima University, 医学系研究科, 教授 (10204827)
• Co-Investigator(Kenkyū-buntansha): YAMAMOTO Hideki 大阪大学, 医学系研究科, 准教授 (20372691) ; SATO Akira 大阪大学, 医学系研究科, 助教 (70464302) ; HINO Shin-ichirou 広島大学, 医歯薬学総合研究科, 助手 (00372699) ; KISHIDA Michiko 広島大学, 医歯薬学総合研究科, 助手 (40274089)
• Project Period (FY): 2005 – 2009
• Keywords: がん / Wnt / シグナル伝達 / 分化 / 極性 / 接着 / 転移

Research Abstract

In this study we focused in Wnt signaling among many intracellular signaling pathways involved in tumorigenesis. We analyzed the molecular mechanisms of tumorigenesis by abnormality in Wnt signaling in the light of differentiation and polarity. The following points are clarified. (1) Wnt proteins were purified and the roles of their post-translational modifications were clarified. (2) Receptor-mediated endocytic routes played a role in the selective activation of multiple Wnt signaling. (3) Wnt5a signaling regulated cell migration and cell polarity. (4) Abnormalities in Wnt5a signaling were involved in aggressiveness of human cancer. (5) Novel binding proteins to GSK-3, a protein kinase, were identified, and they were involved in the regulation of microtubule dynamics and focal adhesion. (6) Dvl regulated spindle dynamics and spindle assemble dynamics in mitosis.

Research Products

• [Journal Article] Binding of APC and disheveled mediates Wnt5a-regulated focal adhesion dynamics in migrating cells. (2010)
  • Author(s): Matsumoto,S., Fumoto,K. Okamoto,T. Kaibuchi,K., Kikuchi,A
  • Journal Title: EMBO J. 29 Pages: 1192-1204
• [Journal Article] Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase. (2010)
  • Author(s): Yamamoto,H., Oue,N., Sato,A., Hasegawa,Y., Matsubara,A., Yamamoto,H., Yasui,W., Kikuch,A
  • Journal Title: Oncogene 29 Pages: 2036-2046
  • Peer Reviewed
• [Journal Article] LRP6 is internalized by Dkk1 to suppress its phosphorylation in the lipid raft and is recycled for reuse. (2010)
  • Author(s): Sakane,H., Yamamoto,H., Kikuchi,A
  • Journal Title: J.Cell Sci. 123 Pages: 360-368
  • Peer Reviewed
• [Journal Article] Wnt5a regulates distinct signaling pathways by binding to Frizzled2. (2010)
  • Author(s): Sato,A., Yamamoto,H., Sakane,H., Koyama,H., Kikuchi,A
  • Journal Title: EMBO J. 29 Pages: 41-54
  • Peer Reviewed
• [Journal Article] Axin localizes to the centrosome and is involved in microtubule nucleation. (2009)
  • Author(s): Fumoto,K., Kadono,M., Izumi,N., Kikuchi,A
  • Journal Title: EMBO R. 10 Pages: 606-613
  • Peer Reviewed
• [Journal Article] Selective activation mechanisms of Wnt signaling pathways. (2009)
  • Author(s): Kikuchi,A., Yamamoto,H., Sato,A
  • Journal Title: Trends Cell Biol. 19 Pages: 119-129
  • Peer Reviewed
• [Journal Article] Laminin・2 mediates Wnt5a-induced invasion of gastric cancer cells. (2009)
  • Author(s): Yamamoto,H., Kitadai,.Y., Yamamoto,H., Oue,N., Ohdan,H., Yasui,W., Kikuchi,A
  • Journal Title: Gastroenterology 137 Pages: 242-252
  • Peer Reviewed
• [Journal Article] CHD8 suppreses p53-mediated apoptosis through histone H1 recruotment during early embryogenesis. (2009)
  • Author(s): Nishiyama,M., Oshikawa,K., Tukada,Y., Nakagawa,T., Iemura,S., Natsume,T., FanY., Kikuchi,A., Skoultchi,A.I., Nakayama,K
  • Journal Title: Nat.Cell Biol. 11 Pages: 172-182
  • Peer Reviewed
• [Journal Article] Polycomb-group complex 1 acts as an E3 ubiquitin ligase for Geminin to sustain hematopoietic stem cell activity. (2008)
  • Author(s): Ohtsubo,M., Yasunaga,S., Ohno,Y., Tsumura,M., Okada,S., Ishikawa,N., Shirao,K., Kikuchi,A., Nishitani,H., Kobayashi,M., Takihara,Y
  • Journal Title: Proc.Natl.Acad.Sci.USA. 105 Pages: 10396-10401
  • Peer Reviewed
• [Journal Article] AIP regulates stability of Aurora-A at early mitotic phase coordinately with GSK-3・. (2008)
  • Author(s): Fumoto,K., Lee, P-C., Saya,H., Kikuchi,A
  • Journal Title: Oncogene 27 Pages: 4478-4487
  • Peer Reviewed
• [Journal Article] Tumor formation due to abnormalities in the ・-catenin-independent pathway of Wnt signaling. (2008)
  • Author(s): Kikuchi,A. Yamamoto,H
  • Journal Title: Cancer Sci. 99 Pages: 202-208
  • Peer Reviewed
• [Journal Article] GSK-3・ regulates proper mitotic spindle formation in cooperation with a component of the がγ-tubulin ring complex, GCP5. (2008)
  • Author(s): Izumi,N., Fumoto,K., Izumi,S., Kikuchi,A
  • Journal Title: J.Biol.Chem. 283 Pages: 12981-12991
  • Peer Reviewed
• [Journal Article] IGFBP-4 is a canonical Wnt inhibitor that promotes cardiac myogenesis. (2008)
  • Author(s): Zhu,W., Shiojima,I., Ito,Y., Li,Z., Ikeda,H., Yoshida,M., Naito,A., Nishi,J., Ueno,H., Umezawa,A., Minamino1,T., Nagai,T., Kikuchi,A., Asashima,M., Komuro,I
  • Journal Title: Nature 454 Pages: 345-349
  • Peer Reviewed
• [Journal Article] Wnt3a and Dkk1 regulate distinct internalization pathways of LRP6 to tune the activation of ・-catenin signaling. (2008)
  • Author(s): Yamamoto,H., Sakane,H., Yamamoto,H., Michiue,T., Kikuch,A
  • Journal Title: Dev. Cell 15 Pages: 37-48
• [Journal Article] Glycosylation and palmitoylation of Wnt-3a are coupled to produce an active form of Wnt-3a. (2007)
  • Author(s): Komekado,H., Yamamoto,H., Chiba,T., Kikuchi,A
  • Journal Title: Genes Cells 12 Pages: 521-534
  • Peer Reviewed
• [Journal Article] Regulation of Wnt signaling by receptor-mediated endocytosis. (2007)
  • Author(s): Kikuchi,A. Yamamoto,H
  • Journal Title: J.Biochem. 141 Pages: 443-451
  • Peer Reviewed
• [Journal Article] Dvl regulates endo- and exocytotic processes through binding to synaptotagmin. (2007)
  • Author(s): Kishida,S., Hamao,K., Inoue,M., Hasegawa,M., Matsuura,Y., Mikoshiba,K., Fukuda,M., Kikuchi,A
  • Journal Title: Genes Cells 12 Pages: 49-61
  • Peer Reviewed
• [Journal Article] Post-translational palmitoylation and glycosylation of Wnt-5a are necessary for its signaling. (2007)
  • Author(s): Kurayoshi,M., Yamamoto,H., Takada,S., Izumi,S., Kikuchi,A
  • Journal Title: Biochem.J. 402 Pages: 515-523
  • Peer Reviewed
• [Journal Article] Non-covalent binding of SUMO protease to SUMO is necessary for enzymatic activities and cell growth. (2007)
  • Author(s): Ihara,M., Koyama,H., Uchimura,Y., Saitoh,H., Kikuchi,A
  • Journal Title: J.Biol.Chem. 282 Pages: 16465-16475
  • Peer Reviewed
• [Journal Article] The DIX domain of Dishevelled confers Wnt signaling by dynamic polymerization. (2007)
  • Author(s): Schwarz-Romond,T., Fiedler1,M., Shibata,N., Butler,P.J.G., Kikuchi,A., Higuchi,Y., Bienz,M.
  • Journal Title: Nat.Strut.Mol.Biol. 14 Pages: 484-492
  • Peer Reviewed
• [Journal Article] Multiplicity of the interactions of Wnt proteins and their receptors. (2007)
  • Author(s): Kikuchi,A., Kishida,S., Yamamoto,H
  • Journal Title: Cell.Signal. 19 Pages: 659-671
  • Peer Reviewed
• [Journal Article] Developmemtal stage-specific, biphasic roles of Wnt/・-catenin signaling in cardiomyogenesis and hematopoiesis. (2006)
  • Author(s): Naito,A., Shiojima,I., Akazawa,H., Hidaka,K., Morisaki,T., Kikuchi,A., Komuro,I
  • Journal Title: Proc.Natl.Acad.Sci.USA. 103 Pages: 19812-19817
  • Peer Reviewed
• [Journal Article] Filopodia formation mediated by receptor tyrosine kinase Ror2 is required for Wnt5a-induced cell migration. (2006)
  • Author(s): Nishita,M., Yoo,S-K., Nomachi,A., Kani,S., Sougawa,N., Ohta,Y., Takada,S., Kikuchi,A., Minami,Y
  • Journal Title: J.Cell Biol. 175 Pages: 555-562
  • Peer Reviewed
• [Journal Article] Expression of Wnt-5a is correlated with aggressiveness of gastric cancer by stimulating cell migration and invasion. (2006)
  • Author(s): Kurayoshi,M., Oue,N., Yamamoto,H., Kishida,M., Inoue,A., Asahara,T., Yasui,W., Kikuchi,A
  • Journal Title: Cancer Res. 66 Pages: 10439-10448
  • Peer Reviewed
• [Journal Article] GSK-3・-regulated interaction of BICD with dynein is involved in microtubule anchorage at centrosome. (2006)
  • Author(s): Fumoto,K., Hoogenraad,C.C., Kikuchi,A
  • Journal Title: EMBO J. 25 Pages: 5670-5682
  • Peer Reviewed
• [Journal Article] Regulation of Wnt signaling by protein-protein interaction and post-translational modifications. (2006)
  • Author(s): Kikuchi,A., Kishida,S., Yamamoto,H
  • Journal Title: Experi.&Mol.Med. 38 Pages: 1-10
  • Peer Reviewed
• [Journal Article] Caveolin is necessary for Wnt-3a-induced internalization of LRP6 and accumulation of ・-catenin. (2006)
  • Author(s): Yamamoto,H., Komekado,H., Kikuchi,A
  • Journal Title: Dev.Cell 11 Pages: 213-223
  • Peer Reviewed
• [Journal Article] Glycogen synthase kinase-3 And h-prune regulate cell migration by modulating focal adhesions. Mol. (2006)
  • Author(s): Kobayashi,T., Hino,S., Oue,N., Asahara,T., Zollo,M., Yasui,W., Kikuchi,A
  • Journal Title: Cell.Biol. 26 Pages: 898-911
  • Peer Reviewed
• [Journal Article] GSK-3 regulates phosphorylation of CRMP-2 and neuronal polarity. (2005)
  • Author(s): Yoshimura,T., Kawano,Y., Arimura,N., Kawabata,S., Kikuchi,A., KaibuchiK
  • Journal Title: Cell. 120 Pages: 137-149
  • Peer Reviewed
• [Journal Article] Phosphorylation of ・-catenin by cyclic AMP-dependent protein kinase stabilizes ・-catenin through inhibition of its ubiquitination. (2005)
  • Author(s): Hino,S-I., Tanji,C., Nakayama,K-I., Kikuchi,A
  • Journal Title: Mol.Cell.Biol. 25 Pages: 9063-9072
  • Peer Reviewed
• [Journal Article] SUMO-1 modification of PIASy, an E3 ligase, is necessary for PIASy-dependent activation of Tcf-4. (2005)
  • Author(s): Ihara,M., Yamamoto,H., Kikuchi,A
  • Journal Title: Mol.Cell.Biol. 25 Pages: 3506-3518
  • Peer Reviewed
• [Presentation] Regulation of Cell adhesion and Migration byWnt5a signaling (2009)
  • Author(s): 菊池章
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2009-12-12
• [Presentation] Wnt signaling and receptor-mediated endocytosis (2009)
  • Author(s): Kikuchi, A.
  • Organizer: Endotrack on the tracks of signalling
  • Place of Presentation: Il Ciocco, Italy
  • Year and Date: 2009-11-09
• [Presentation] Regulation of cell adhesion and migration by Wnt5a signaling (2009)
  • Author(s): Kikuchi, A.
  • Organizer: EMBO Workshop : Wnt Signalling in Development and Disease
  • Place of Presentation: Arolla, Switzerland
  • Year and Date: 2009-08-28
• [Presentation] Wntシグナルによる細胞運動制御とその異常による癌の悪性化 (2008)
  • Author(s): 菊池章
  • Organizer: 第31回日本分子生物学会年会、第81回日本生化学会大会シンポジウム
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-12
• [Presentation] β-カテニン非依存性のWntシグナルによる細胞応答とがん (2008)
  • Author(s): 菊池章
  • Organizer: 第67回日本癌学会学術総会モーニングレクチャー
  • Place of Presentation: 横浜
  • Year and Date: 2008-10-29
• [Presentation] Spatial and temporal regulation of Glycogen Synthase kinase-3 and Cellular function. (2007)
  • Author(s): Kikuchi, A.
  • Organizer: 2007 Annual meeting of Korean Society of Medical Biochemistry and Molecular Biology.
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2007-10-25
• [Presentation] Wntシグナルによるがんの悪性化 (2007)
  • Author(s): 菊池章
  • Organizer: 第66回日本癌学会学術総会モーニングレクチャー
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-05
• [Presentation] Wnt-5aによる細胞運動能の促進と胃癌の悪性化 (2007)
  • Author(s): 菊池章
  • Organizer: 第65回日本癌学会学術総会シンポジウム
  • Place of Presentation: 横浜
  • Year and Date: 2007-09-30
• [Presentation] Regulation of Wnt signaling by receptor-mediated endocytosis. (2007)
  • Author(s): Kikuchi, A.
  • Organizer: Wnt Signaling in Development and Disease.
  • Place of Presentation: Berlin, Germany
  • Year and Date: 2007-09-13
• [Presentation] Expression of Wnt5a is correlated with aggressiveness of gastric and prostate cancer by stimulating cell migration and invasion. (2007)
  • Author(s): Kikuchi, A., Yamamoto,H
  • Organizer: Traditional Wnt meeting.
  • Place of Presentation: La Jolla. California, USA
  • Year and Date: 2007-06-22
• [Presentation] Caveolin-mediated endocytosis of LRP6 is required for activation of Wnt/・-catenin pathway. (2006)
  • Author(s): Kikuchi, A.
  • Organizer: Keystone symposia, Wnt and・-Catenin Signaling in Development and Disease.
  • Place of Presentation: Snowbird Resort, Snowbird, Utah, USA
  • Year and Date: 20060407-20060412
• [Presentation] Regulation of Cellular functions by Wnt signaling. (2006)
  • Author(s): Kikuchi, A.
  • Organizer: Cell Signaling and Protein Networking.
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2006-05-18
• [Remarks] ホームページ等
  • URL: http://www.med.osaka-u.ac.jp/pub/molbiobc/