Regulation of signaling network and cellular responses by Wnt

• Project/Area Number: 21249017
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Osaka University
• Principal Investigator: KIKUCHI Akira 大阪大学, 医学系研究科, 教授 (10204827)
• Co-Investigator(Kenkyū-buntansha): YAMAMOTO Hideki 大阪大学, 大学院・医学系研究科, 准教授 (20372691) ; SATO Akira 大阪大学, 大学院・医学系研究科, 助教 (70464302)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥47,970,000 (Direct Cost: ¥36,900,000、Indirect Cost: ¥11,070,000); Fiscal Year 2011: ¥14,820,000 (Direct Cost: ¥11,400,000、Indirect Cost: ¥3,420,000); Fiscal Year 2010: ¥15,730,000 (Direct Cost: ¥12,100,000、Indirect Cost: ¥3,630,000); Fiscal Year 2009: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
• Keywords: Wnt / シグナル伝達 / 受容体 / エンドサイトーシス / 極性 / がん / 転移 / ヘパラン硫酸プロテオグリカン / グリピカン / β-カテニン依存性経路 / β-カテニン非依存性経路 / エクトドメイン / Wnt5a / Dvl / 細胞分裂期 / 前立腺癌 / MMP / 紡錘糸 / Dkkl / 接着斑 / インテグリン / リピッドラフト / クラスリン

Research Abstract

In this study we analyzed the molecular mechanism of the regulation of Wnt signaling and the pathogenesis of diseases due to its abnormalities. The following points were clarified.(1) The selective activation of Wnt signaling was regulated by receptor-mediated endocytosis.(2) Wnt5a regulated cell migration through the organization of microtubule stability by the binding of Dvl and APC.(3) Overexpression of Wnt5a promoted aggressiveness of gastric cancer through the induction of laminin 2.

Research Products

• [Journal Article] An Wnt5a-antibody suppresses metastasis of gastric cancer cells in vivo by inhibiting receptor-mediated endocytosis (2012)
  • Author(s): Hanaki, H., Yamamoto, H., Sakane, H., Matsumoto, S., Ohdan, H., Sato, A., and Kikuchi, A
  • Journal Title: Mol. Cancer Ther Volume: 11 Pages: 298-307
  • Peer Reviewed
• [Journal Article] Localization of glypican-4 in different membrane microdomains is involved in the regulation of Wnt signaling (2012)
  • Author(s): Sakane, H., Yamamoto, H., Matsumoto, S., Sato, A., and Kikuchi, A
  • Journal Title: J. Cell Sci Volume: 125 Pages: 449-460
  • Peer Reviewed
• [Journal Article] Regulation of focal adhesion dynamics by Wnt5a signaling (2012)
  • Author(s): Matsumoto, S., and Kikuchi, A
  • Journal Title: Methods in Mol. Biol Volume: 839 Pages: 215-227
  • Peer Reviewed
• [Journal Article] Wnt5a : its signaling, functions, and implication in diseases (2012)
  • Author(s): Kikuchi, A., Yamamoto, H., Sato, A., and Maysimoto, S
  • Journal Title: Acta physiol Volume: 204 Pages: 17-33
  • Peer Reviewed
• [Journal Article] An Wnt5a-antibody suppresses metastasis of gastric cancer cells in vivo by inhibiting receptor-mediated endocytosis (2012)
  • Author(s): Hanaki, H., et.al.
  • Journal Title: Mol.Cancer Ther. Volume: 11 Issue: 2 Pages: 298-307
  • DOI: 10.1158/1535-7163.mct-11-0682
  • Peer Reviewed
• [Journal Article] Localization of glypican-4 in different membrane microdomains is involved in the regulation of Wnt signaling (2012)
  • Author(s): Sakane, H., et.al.
  • Journal Title: J.Cell Sci. Volume: 125 Issue: 2 Pages: 449-460
  • DOI: 10.1242/jcs.091876
  • Peer Reviewed
• [Journal Article] Regulation of focal adhesion dynamics by Wnt5a signaling (2012)
  • Author(s): Matsumoto, S., et.al.
  • Journal Title: Methods Mol.Biol. Volume: 839 Pages: 215-27
  • DOI: 10.1007/978-1-61779-510-7_17
  • ISBN: 9781617795091, 9781617795107
  • Peer Reviewed
• [Journal Article] Wnt5a : its signaling, functions, and implication in diseases (2012)
  • Author(s): Kikuchi, A., et.al.
  • Journal Title: Acta Physiol. Volume: 204 Issue: 1 Pages: 17-33
  • DOI: 10.1111/j.1748-1716.2011.02294.x
  • Peer Reviewed
• [Journal Article] Insufficiency of BUBR1, a mitotic spindle checkpoint regulator, causes impaired ciliogenesis in vertebrates (2011)
  • Author(s): Miyamoto, T., Porazinski, S., Wang, H., Borovina, A., Ciruna, B., Shimizu, A., Kajii, T., Kikuchi, A., Furutani-Seiki, M., and Matsuura, S
  • Journal Title: Hum. Mol. Genet Volume: 20 Pages: 2058-2070
  • Peer Reviewed
• [Journal Article] The transmembrane protein Waif1/ 5T4 inhibits Wnt/β-catenin signaling and activates noncanonical Wnt pathways by modifying LRP6 subcellular localization (2011)
  • Author(s): Kagermeier-Schenk, B., Wehner, D., Ozhan-Kizil, G., Yamamoto, H., Jian Li, Kirchner, K., Hoffmann, C., Stern, P., Kikuchi, A., Schambony, A., and Weidinger, G
  • Journal Title: Dev. Cell Volume: 21 Pages: 1129-1143
  • Peer Reviewed
• [Journal Article] MMP-10/ Stromelysin-2 Promotes Invasion of Head and Neck Cancer (2011)
  • Author(s): Deraz, E. M., Kudo, Y., Yoshida, M., Obayashi, M., Tsunematsu, T., Tani, H., Siriwardena, S., Keikhaee, M. R., Qi, G., Iizuka, S., Ogawa, I., Campisi, G., Lo Muzio, L., Abiko, Y., Kikuchi, A., Takata, T
  • Journal Title: PLoS ONE Volume: 6
  • NAID: 120005300499
  • Peer Reviewed
• [Journal Article] New insights into the mechanism of Wnt signaling pathway activation (2011)
  • Author(s): Kikuchi, A., Yamamoto, H., Sato, A., Mastumoto, S
  • Journal Title: Int. Rev. Cell. Mol. Biol Volume: 291 Pages: 21-71
  • Peer Reviewed
• [Journal Article] Insufficiency of BUBR1, a mitotic spindle checkpoint regulator, causes impaired ciliogenesis in vertebrates (2011)
  • Author(s): Miyamoto, T., et.al.
  • Journal Title: Human Molcular Genetics Volume: 20 Issue: 10 Pages: 2058-2070
  • DOI: 10.1093/hmg/ddr090
  • Peer Reviewed
• [Journal Article] Waif1/5T4 inhibits Wnt/β-catenin signaling and activates noncanonical Wnt pathways by modifying LRP6 subcellular localization (2011)
  • Author(s): Kagermeier-Schenk, B., et.al.
  • Journal Title: Dev.Cell. Volume: 21 Issue: 6 Pages: 1129-1143
  • DOI: 10.1016/j.devcel.2011.10.015
  • Peer Reviewed
• [Journal Article] MMP10/stromelysin-2 promotes invasion of head and neck cancer (2011)
  • Author(s): Deraz EM, Kudo Y, Yoshida M, Tani H, Tsunematsu T, et al
  • Journal Title: PLos ONE Volume: (電子媒体) Issue: 10 Pages: e25438-e25438
  • DOI: 10.1371/journal.pone.0025438
  • Peer Reviewed
• [Journal Article] New insights into the mechanism of Wnt signaling pathway activation (2011)
  • Author(s): Kikuchi, A
  • Journal Title: Int Rev Cell Mol Biol. Volume: 291 Pages: 21-71
  • DOI: 10.1016/b978-0-12-386035-4.00002-1
  • ISBN: 9780123860354
  • Peer Reviewed
• [Journal Article] Regulation of focal adhesion dynamics by WNt5a signaling. (2011)
  • Author(s): Matsumoto, S., Kikuchi, A.
  • Journal Title: Methods in Mol.Biol. Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Insufficiency of BUBR1, a mitotic spindle checkpoint regulator, causes impaired ciliogenesis in vertebrates. (2011)
  • Author(s): Miyamoto, T., Kikuchi, A.
  • Journal Title: Hum.Mol.Genet. Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Dishevelled, a Wnt signaling component, is involved in mitotic progression with Plk1 (2010)
  • Author(s): Kikuchi, K., Niikura, Y., Kitagawa, K., and Kikuchi, A
  • Journal Title: EMBO J Volume: 29 Pages: 3470-3483
  • Peer Reviewed
• [Journal Article] Ror2/ Frizzled complex mediates Wnt5a-induced AP-1 activation by regulating Dishevelled polymerization (2010)
  • Author(s): Nishida, M., Itsukushima, S., Nomachi, A., Endo, M., Wang, Z., Inaba, D., Qiao, S., Takada, S., Kikuchi, A., and Minami, Y
  • Journal Title: Mol. Cell. Biol Volume: 30 Pages: 3610-3619
  • Peer Reviewed
• [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., and Kikuchi, A
  • Journal Title: EMBO J Volume: 29 Pages: 1192-1204
  • Peer Reviewed
• [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., and Kikuch, A
  • Journal Title: Oncogene Volume: 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., and Kikuchi, A
  • Journal Title: J. Cell Sci Volume: 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., and Kikuchi, A
  • Journal Title: EMBO J Volume: 29 Pages: 41-54
  • Peer Reviewed
• [Journal Article] Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase. (2010)
  • Author(s): Yamamoto, H., Kikuchi, A..
  • Journal Title: Oncogene Volume: 29 Pages: 2036-2046
  • Peer Reviewed
• [Journal Article] Binding of APC and disheveled mediates Wnt5a-regulated focal adhesion dynamics in migrating cells. (2010)
  • Author(s): Matsumoto, S., Kikuchi, A.
  • Journal Title: EMBO J. Volume: 29 Pages: 1192-1204
  • Peer Reviewed
• [Journal Article] Dishevelled, a Wnt signaling component, is involved in mitotic progression with Plk1. (2010)
  • Author(s): Kikuchi, K., Kikuchi, A.
  • Journal Title: EMBO J. Volume: 29 Pages: 3470-3483
  • Peer Reviewed
• [Journal Article] Ror2/Frizzled complex mediates Wnt5a-induced AP-1 activation by regulating Dishevelled polymerization. (2010)
  • Author(s): Nishida, M., Kikuchi, A.
  • Journal Title: Mol.Cell.Biol. Volume: 30 Pages: 3610-3619
  • 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., Kikuchi, A.
  • Journal Title: J.Cell Sci. Volume: 123 Pages: 360-368
  • Peer Reviewed
• [Journal Article] GSK3 regulates expression of human and mouse c-Myb via different mechanisms. (2010)
  • Author(s): Kitagawa, K.Kikuchi, A.
  • Journal Title: Cell Div. Volume: 5 Pages: 27-27
  • NAID: 120005305355
  • Peer Reviewed
• [Journal Article] Wnt5a regulates distinct signaling pathways by binding to Frizzled2. (2010)
  • Author(s): Sato, A., et.al.
  • Journal Title: EMBO J. Volume: 29 Pages: 41-54
  • Peer Reviewed
• [Journal Article] LPR6 is internalized by Dkk1 to suppress its phosphorylation in the lipid raft and is recycled for reuse. (2010)
  • Author(s): Sakane, H., et.al.
  • Journal Title: J.Cell Sci. Volume: 123 Pages: 360-368
  • Peer Reviewed
• [Journal Article] Axin localizes to the centrosome and is involved in microtubule nucleation (2009)
  • Author(s): Fumoto, K., Kadono, M., Izumi, N., and Kikuchi, A
  • Journal Title: EMBO R Volume: 10 Pages: 606-613
  • 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., and Kikuchi, A
  • Journal Title: Gastroenterology Volume: 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., Fan Y., Kikuchi, A., Skoultchi, A. I., and Nakayama, K
  • Journal Title: Nat. Cell Biol Volume: 11 Pages: 172-182
  • Peer Reviewed
• [Journal Article] Retinoic acid induces discrete Wnt-signaling-dependent differentiation in F9 cells (2009)
  • Author(s): Inoue, A., Nagafuchi, A., Kikuchi, A
  • Journal Title: Biophys. Biochem., Res. Commun Volume: 390 Pages: 564-569
  • NAID: 120005955237
  • Peer Reviewed
• [Journal Article] Fbw7promotes ubiquitin-dependent degradation of c-Myb : involvement of GSK3-mediated phosphorylation of Thr-572 in mouse c-Myb (2009)
  • Author(s): Kitagawa K, Hiramatsu Y, Uchida C, Isobe T, Hattori T, Oda T, Shibata K, Nakamura S, Kikuchi A., Kitagawa M
  • Journal Title: Oncogene Volume: 28 Pages: 2393-2405
  • Peer Reviewed
• [Journal Article] Wnt-Ryk signaling mediates axon growth inhibition andlimits functional recovery after spinal cord injury (2009)
  • Author(s): Miyashita, T., Koda, M., Kitajo, K., Yamazaki, M., Takahashi, K., Kikuchi, A. and Yamashita, T
  • Journal Title: J Neurotrauma Volume: 26 Pages: 955-964
  • Peer Reviewed
• [Journal Article] Selective activation mechanisms of Wnt signaling pathways (2009)
  • Author(s): Kikuchi, A., Yamamoto, H., and Sato, A
  • Journal Title: Trends Cell Biol Volume: 19 Pages: 119-129
  • Peer Reviewed
• [Journal Article] Laminin γ2 Mediates Wnt5a-induced Invasion of Gastric Cancer Cells. (2009)
  • Author(s): Yamamoto, H., et.al.
  • Journal Title: Gastroenterology Volume: 137 Pages: 242-252
  • Peer Reviewed
• [Journal Article] Axin localizes to the centrosome and is involved in microtubule nucleation. (2009)
  • Author(s): Fumoto, K., et.al.
  • Journal Title: EMBO R. Volume: 10 Pages: 606-613
  • Peer Reviewed
• [Journal Article] CHD8 suppresses p53-mediated apoptosis through histone H1 recruitment during early embryogenesis. (2009)
  • Author(s): Nishiyama, M., et.al.
  • Journal Title: Nat.Cell Biol. Volume: 11 Pages: 172-182
  • Peer Reviewed
• [Journal Article] Retinoic acid induces discrete Wnt-signaling-dependent differentiation in F9 cells. (2009)
  • Author(s): Inoue, A., et.al.
  • Journal Title: Biophys.Biochem., Res.Commun. Volume: 390 Pages: 564-569
  • Peer Reviewed
• [Journal Article] Fbw7 promotes ubiquitin-dependent degradation of c-Myb : involvement of GSK3-mediated phosphorylation of Thr-572 in mouse c-Myb. (2009)
  • Author(s): Kitagawa K., et.al.
  • Journal Title: Oncogene. Volume: 28 Pages: 2393-2405
  • Peer Reviewed
• [Journal Article] Wnt-Ryk signaling mediates axon growth inhibition andlimits functional recovery after spinal cord injury. (2009)
  • Author(s): Miyashita, T., et.al.
  • Journal Title: J Neurotrauma. Volume: 26 Pages: 955-964
  • Peer Reviewed
• [Presentation] Growth factor-dependent regulation of cell polarity during tubulogenesis (2011)
  • Author(s): Kikuchi, A
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-15
• [Presentation] Growth factor-dependent regulation of cell polarity during tubulogenesis (2011)
  • Author(s): Kikuchi, A., et.al.
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 神奈川県(招待講演)
  • Year and Date: 2011-12-15
• [Presentation] Wnt5a ; its signaling and implication in tumorigenesis (2011)
  • Author(s): Kikuchi, A., et.al.
  • Organizer: 13^<th> Japanese-German Cancer Workshop
  • Place of Presentation: 広島県(招待講演)
  • Year and Date: 2011-11-19
• [Presentation] Wntシグナルによる上皮形態形成制御とその異常による病態 (2011)
  • Author(s): 菊池章
  • Organizer: 第84回内分泌学会学術総会
  • Place of Presentation: 神戸
  • Year and Date: 2011-04-22
• [Presentation] Wnt5a ; its signaling and implication in tumorigenesis (2011)
  • Author(s): Kikuchi, A
  • Organizer: 13th Japanese-German Cancer Workshop
  • Place of Presentation: Hiroshima
• [Presentation] Epithelial morphogenesis regulated by cell polarity in three-dimensional culture (2010)
  • Author(s): Kikuchi, A
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-07
• [Presentation] Epithelial morphogenesis regulated by cell polarity in three-dimensional culture. (2010)
  • Author(s): Kikuchi, A.
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-07
• [Presentation] Wnt5a, its signaling, functions and diseases. (2010)
  • Author(s): Kikuchi, A.
  • Organizer: Wnt meeting 2010
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2010-10-27
• [Presentation] Dishevelled is involved in mitotic progression in cooperation with Polo-like kinase 1. (2010)
  • Author(s): Kikuchi, A.
  • Organizer: Wnt symposium 2010
  • Place of Presentation: Heidelberg, Germany
  • Year and Date: 2010-10-26
• [Presentation] Wnt5a : Its Signaling, Cellular Functions, and Disease (2010)
  • Author(s): Kikuchi, A
  • Organizer: Cellular Signaling and Translational Research, Korea Global
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2010-05-07
• [Presentation] Wnt5a : Its Signaling, Cellular Functions, and Disease. (2010)
  • Author(s): Kikuchi, A.
  • Organizer: Cellular Signaling and Translational Research, Korea Grobal
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2010-05-07
• [Presentation] Wnt5a : Its Signaling, Cellular Functions, and Diseases (2010)
  • Author(s): Kikuchi, A
  • Organizer: 16th ISD meeting
  • Place of Presentation: Nara
• [Presentation] Wnt5a, its signaling, functions and diseases (2010)
  • Author(s): Kikuchi, A
  • Organizer: Wnt meeting 2010
  • Place of Presentation: Stockholm, Sweden
• [Presentation] Dishevelled is involved in mitotic progression in cooperation with Polo-like kinase 1 (2010)
  • Author(s): Kikuchi, A
  • Organizer: Wnt symposium 2010
  • Place of Presentation: Heidelberg, Germany
• [Presentation] Wnt5a : Its Signaling, Cellular Functions, and Diseases (2010)
  • Author(s): Kikuchi, A
  • Organizer: 7th Meeting of Bone Biology Forum
  • Place of Presentation: Shizuoka, Japan
• [Presentation] Wnt5a Signaling and Cancer (2010)
  • Author(s): Kikuchi, A
  • Organizer: Sapporo International Cancer Symposium 2010
  • Place of Presentation: Sapporo, Japan
• [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] Regulation of cell adhesion and migration by Wnt5a signaling (2009)
  • Author(s): Kikuchi, A.
  • Organizer: 第32回日本分子生物学会
  • Place of Presentation: 横浜市
  • 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: I1Ciocco, Italy
  • Year and Date: 2009-11-09
• [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: Switzerland
  • Year and Date: 2009-08-28
• [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
• [Book] 遺伝情報の発現制御-転写機構からエピジェネティクスまで- (2012)
  • Author(s): 菊池章(分担翻訳)
  • Total Pages: 30
  • Publisher: メディカル・サイエンス・インターナショナル
• [Remarks] ホームページ
  • URL: http://www.med.osaka-u.ac.jp/pub/molbiobc/index.html
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/molbiobc/