Analysis of molecular mechanisms of Wnt5a-Ror signaling in repair after tissue damage, inflammation, and cancer progression

• Project/Area Number: 16H05152
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Kobe University
• Principal Investigator: Minami Yasuhiro 神戸大学, 医学研究科, 教授 (70229772)
• Co-Investigator(Kenkyū-buntansha): 内匠 透 国立研究開発法人理化学研究所, 脳神経科学研究センター, チームリーダー (00222092) ; 西田 満 神戸大学, 医学研究科, 准教授 (30379359) ; 遠藤 光晴 神戸大学, 医学研究科, 講師 (90436444) ; 林 真琴 神戸大学, 医学研究科, 助教 (50722930)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2018: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2016: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: Wnt5a-Rorシグナル / 神経損傷修復 / 神経炎症 / がんの浸潤 / 骨格筋損傷修復 / 組織損傷修復 / 遺伝子発現制御 / 神経損傷・神経炎症 / 顎下腺炎症モデル

Outline of Final Research Achievements

It has been well established that Ror1 and Ror2 receptor tyrosine kinases play important roles in developmental morphogenesis and tissue-/organo-genesis by acting as receptors for Wnt5a. In this study, we have shown that Ror1 and Ror2 play important roles in regulating repair and inflammatory responses after damage of brain neocortex and skeletal muscle by using experimental animal models. Furthermore, we show that Ror2 as well as Ror1 are expressed at high levels in various types of cancer cells, including osteosarcoma cells, breast cancer cells, malignant pleural mesotheliomas, and colo-rectal cancer cells, thereby promoting invasion of these cancer cells by activating similar and/or different signaling pathways.

Academic Significance and Societal Importance of the Research Achievements

本研究により、受容体型チロシンキナーゼRor1、Ror2は組織損傷修復において重要な役割を担うことが明らかとなり、今後Ror1、Ror2の発現・機能を制御することにより、損傷組織の修復や再生医療に応用できると予想される。また、Ror1、Ror2はがんの進展・増悪における浸潤過程において重要な役割を担うことが見出され、がんの新たな診断・治療法の開発における分子標的となることが期待される。

Research Products

• [Int'l Joint Research] ミュンスター大学 筋骨格医学研究所(ドイツ)
• [Int'l Joint Research] カリフォルニア大学デービス校 医学部(米国)
• [Int'l Joint Research] ハーバード大学(米国)
• [Int'l Joint Research] ハーバード大学/マサチューセッツ医科大学/カリフォルニア大学(米国)
• [Journal Article] Intraflagellar transport 20 promotes collective cancer cell invasion H. by regulating polarized organization of Golgi-associated microtubules (2019)
  • Author(s): Aoki, T., Nishita, M., Sonoda, J., Ikeda, T., Kakeji, Y., Minami, Y.
  • Journal Title: Cancer Sci. Volume: 110 Issue: 4 Pages: 1306-1316
  • DOI: 10.1111/cas.13970
  • Peer Reviewed / Open Access
• [Journal Article] Genetic interactions between Ror2 and Wnt9a, Ror1 and Wnt9a and Ror2 and Ror1: Phenotypic analysis of the limb skeleton and palate in compound mutants (2019)
  • Author(s): Weissenbock, M., Latham, R., Nishita, M., Wolff, L. I., Ho, H., Minami, Y., Hartmann, C.
  • Journal Title: Genes Cells Volume: 24 Issue: 4 Pages: 307-317
  • DOI: 10.1111/gtc.12676
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Temporal requirement of dystroglycan glycosylation during brain development and rescue of severe cortical dysplasia via gene delivery in the fetal stage (2018)
  • Author(s): Sudo Atsushi、Kanagawa Motoi、Kondo Mai、Ito Chiyomi、Kobayashi Kazuhiro、Endo Mitsuharu、Minami Yasuhiro、Aiba Atsu、Toda Tatsushi
  • Journal Title: Human molecular genetics Volume: 27 Issue: 7 Pages: 1174-1185
  • DOI: 10.1093/hmg/ddy032
  • NAID: 120006459805
  • Peer Reviewed / Open Access
• [Journal Article] Critical role of the Ror-family of receptor tyrosine kinases in invasion and proliferation of malignant pleural mesothelioma cells (2018)
  • Author(s): Saji Takeshi、Nishita Michiru、Ogawa Hiroyuki、Doi Takefumi、Sakai Yasuhiro、Maniwa Yoshimasa、Minami Yasuhiro
  • Journal Title: Genes to Cells Volume: 23 Issue: 7 Pages: 606-613
  • DOI: 10.1111/gtc.12599
  • Peer Reviewed / Open Access
• [Journal Article] Synchronized mesenchymal cell polarization and differentiation shape the formation of the murine trachea and esophagus (2018)
  • Author(s): Kishimoto, K., Tamura, M., Nishita, M., Minami, Y., Matsuoka, A., Abe, T., Shigeta, M., Morimoto, M.
  • Journal Title: Nat. Commun. Volume: 9 Issue: 1 Pages: 2816-2816
  • DOI: 10.1038/s41467-018-05189-2
  • NAID: 120006496738
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Diverse roles for the Ror-family Receptor Tyrosine Kinases in Neurons and Glial Cells during Development and Repair of the Nervous System. (2017)
  • Author(s): Endo, M., Minami, Y.
  • Journal Title: Developmental Dynamics Volume: 印刷中 Issue: 1 Pages: 24-32
  • DOI: 10.1002/dvdy.24515
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Ror1 receptor tyrosine kinase plays a critical role in regulating satellite cell proliferation during regeneration of injured muscle (2017)
  • Author(s): Kamizaki Koki、Doi Ryosuke、Hayashi Makoto、Saji Takeshi、Kanagawa Motoi、Toda Tatsushi、Fukada So-ichiro、Ho Hsin-Yi Henry、Greenberg Michael Eldon、Endo Mitsuharu、Minami Yasuhiro
  • Journal Title: Journal of Biological Chemistry Volume: 292 Issue: 38 Pages: 15939-15951
  • DOI: 10.1074/jbc.m117.785709
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Protein kinase N3 promotes bone resorption by osteoclasts in response to Wnt5a-Ror2 signaling. (2017)
  • Author(s): Uehara S, Udagawa N, Mukai H, Ishihara A, Maeda K, Yamashita T, Murakami K, Nishita M, Nakamura T, Kato S, Minami Y, Takahashi N and Kobayashi Y
  • Journal Title: Sci Signal Volume: 10 Issue: 494
  • DOI: 10.1126/scisignal.aan0023
  • Peer Reviewed / Open Access
• [Journal Article] Expression of Ror2 Associated with Fibrosis of the Submandibular Gland (2017)
  • Author(s): Takahashi, D., Suzuki, H., Kakei, Y., Yamakoshi, K., Minami, Y., Komori, T., Nishita, M.
  • Journal Title: Cell Structure and Function Volume: 42 Issue: 2 Pages: 159-167
  • DOI: 10.1247/csf.17019
  • NAID: 130006258840
  • ISSN: 0386-7196, 1347-3700
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Critical role of Ror2 receptor tyrosine kinase in regulating cell cycle progression of reactive astrocytes following brain injury. (2017)
  • Author(s): Endo, M., Ubulkasim, G., Kobayashi, C., Onishi, R., Minami, Y.
  • Journal Title: Glia Volume: 65 Issue: 1 Pages: 182-197
  • DOI: 10.1002/glia.23086
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Ror2 signaling regulates Golgi structure and transport through IFT20 for tumor invasiveness. (2017)
  • Author(s): Nishita, M., Park, S.-Y., Nishio, T., Kamizaki, K., Wang, Z., Tamada, K., Takumi, T., Hashimoto, R., Otani, H., Pazour, G.J., Hsu, V.W., and Minami, Y.
  • Journal Title: Sci. Rep. 7: 1, 2017. Volume: 7 Issue: 1 Pages: 1-1
  • DOI: 10.1038/s41598-016-0028-x
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Diverse regulation of mammary epithelial growth and branching morphogenesis through non-canonical Wnt signaling. (2017)
  • Author(s): Kessenbrock, K., Smith, P., Steenbeek, S., Pervolarakis, N., Kumar, R., Minami, Y., Goga, A., Hinck, L., Werb, Z.
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 114 Issue: 12 Pages: 3121-3126
  • DOI: 10.1073/pnas.1701464114
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Regulatory mechanisms and cellular functions of non-centrosomal microtubules. (2017)
  • Author(s): Nishita M, Satake T, Minami Y, Suzuki A.
  • Journal Title: J Biochem. Volume: - Issue: 1 Pages: 1-10
  • DOI: 10.1093/jb/mvx018
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice. (2016)
  • Author(s): Diaz-Horta, O., Abad, C., Sennaroglu, L., Foster II, J., DeSmidt, A., Bademci, G., Tokgoz-Yilmaz, S., Duman, D., Cengiz, F. B., Grati, M., Fitoz, S., Liu, X-Z., Farooq, A., Imtiaz, F., Currall, B. B., Morton, C. C., Nishita, M., Minami, Y., Lu, Z., Walz, K., Tekin, M.
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 113 Issue: 21 Pages: 5993-5998
  • DOI: 10.1073/pnas.1522512113
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Role of Ror family tyrosine kinases in skeletal muscle (2019)
  • Author(s): Koki Kamizaki, Ayano Yamamoto, Ryosuke Doi, Motoi Kanagawa, Tatsushi Toda, Akiyoshi Uezumi, So-ichiro Fukada, Mitsuharu Endo, Yasuhiro Minami
  • Organizer: 第9回アジア・オセアニア生理学会連合大会
  • Int'l Joint Research
• [Presentation] The role of Ror2 tyrosine kinase in neural stem/progenitor cells and reactive astrocytes (2018)
  • Author(s): Mitsuharu Endo, Yuki Tanaka, Mako Otsuka, Yashuhiro Minami
  • Organizer: Japanese-German YoungGlia collaborative meeting for mutual research exchange
  • Int'l Joint Research
• [Presentation] Ror1はSmgGDS-Rif経路を介して肺腺がん細胞の糸状突起形成と浸潤を促進する (2018)
  • Author(s): 西田 満、松本 邦夫、南 康博
  • Organizer: 日本癌学会学術総会
• [Presentation] IFT20は微小管ダイナミックスを制御することで大腸癌細胞の浸潤能亢進に寄与する (2018)
  • Author(s): 青木 丈明、西田 満、掛地 吉弘、南 康博
  • Organizer: 日本癌学会学術総会
• [Presentation] Ror2 regulates adipogenic differentiation of mesenchymal progenitor cells in the skeletal muscle (2018)
  • Author(s): Koki Kamizaki, Ayano Yamamoto, Ryosuke Doi, Motoi Kanagawa, Tatsushi Toda, Akiyoshi Uezumi, So-ichiro Fukada, Mitsuharu Endo, Yasuhiro Minami
  • Organizer: ASCB/EMBO meeting
  • Int'l Joint Research
• [Presentation] 受容体型チロシンキナーゼRor2による炎症応答制御機構の解析 (2017)
  • Author(s): 遠藤 光晴、大田 絢斗、大西 怜子、南 康博
  • Organizer: 日本細胞生物学会
• [Presentation] 脳の損傷修復における増殖性アストロサイトの役割 (2017)
  • Author(s): 遠藤 光晴、大田 絢斗、南 康博
  • Organizer: 日本組織細胞化学会
  • Invited
• [Presentation] Rorファミリー受容体型チロシンキナーゼによる骨格筋再生制御 (2017)
  • Author(s): 紙崎 孝基、土井 亮助、金川 基、戸田 達史、深田 宗一郎、遠藤 光晴、南 康博
  • Organizer: 骨格筋細胞研究会
• [Presentation] がん細胞浸潤突起の伸長・成熟におけるKIF1Cの機能 (2017)
  • Author(s): 佐事 武、西田 満、岡田 康志、南 康博
  • Organizer: 日本分子生物学会、日本生化学会
• [Presentation] Wnt5a依存的・非依存的なRorファミリー受容体型チロシンキナーゼの機能 (2017)
  • Author(s): 南 康博
  • Organizer: Wnt研究会
  • Invited
• [Presentation] Rorファミリー受容体型チロシンキナーゼは脳損傷に伴うアストロサイトの応答を制御する (2016)
  • Author(s): 遠藤 光晴、大田 絢斗、小林 千穂、大西 怜子、南 康博
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2016-11-30
• [Presentation] IFT20はゴルジ体における微小管形成を促進することでRor2シグナル依存的ながん細胞浸潤を制御する (2016)
  • Author(s): 西田 満、西尾 忠、紙崎 孝基、内匠 透、大谷 浩、南 康博
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2016-11-30
  • Invited
• [Presentation] がん細胞浸潤におけるRor2受容体型チロシンキナーゼの新たな機能 (2016)
  • Author(s): 佐事 武、西尾 忠、紙崎 孝基、西田 満、南 康博
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2016-11-30
• [Presentation] Ror2受容体型チロシンキナーゼのがんー胎児タンパク質としての機能 (2016)
  • Author(s): 南 康博、西田 満
  • Organizer: 第75回日本癌学会総会学術総会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2016-10-06
  • Invited
• [Presentation] エピジェネティック機構を介した受容体型チロシンキナーゼRor2の発現誘導によるアストロサイトの細胞周期制御 (2016)
  • Author(s): 遠藤 光晴、小林 千穂、グリジャハン オブリカスム、南 康博
  • Organizer: 第59回日本神経化学会大会
  • Place of Presentation: 福岡国際会議場（福岡）
  • Year and Date: 2016-09-08
• [Remarks] 神戸大学大学院医学研究科 生理学・細胞生物学講座 細胞生理学分野
  • URL: http://www.med.kobe-u.ac.jp/medzoo/index.html
• [Remarks] http://www.med.kobe-u.ac.jp/medzoo/
• [Remarks] 細胞生理学分野研究室ホームページ
  • URL: http://www.med.kobe-u.ac.jp/medzoo/