Roles and modes of action of nectins in heterotypic cell-cell adhesions

• Project/Area Number: 26251013
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Kobe University
• Principal Investigator: Takai Yoshimi 神戸大学, 医学研究科, 特命教授 (60093514)
• Co-Investigator(Kenkyū-buntansha): 下野 洋平 神戸大学, 医学(系)研究科(研究院), 准教授 (90594630) ; 水谷 清人 神戸大学, 医学(系)研究科(研究院), 講師 (50559177) ; 宮田 宗明 神戸大学, 医学(系)研究科(研究院), 助教 (90582007) ; 溝口 明 三重大学, 医学(系)研究科(研究院), 教授 (90181916)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥40,820,000 (Direct Cost: ¥31,400,000、Indirect Cost: ¥9,420,000); Fiscal Year 2016: ¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000); Fiscal Year 2015: ¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000); Fiscal Year 2014: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
• Keywords: 細胞接着・運動 / 細胞シグナル伝達機構 / 異種細胞間接着 / 細胞膜受容体 / ネクチン / アファディン / 細胞情報伝達機構

Outline of Final Research Achievements

The roles and modes of action of nectins in heterotypic cell-cell adhesions were investigated. We identified a novel cell adhesion apparatus formed by the heterophilic trans-interaction between nectin-4 and nectin-1, which were expressed in the luminal and basal cells in the mammary gland, respectively. Nectin-4 in this apparatus enhanced the prolactin receptor signaling. Moreover, we showed that nectin-2 and nectin-3 expressed in olfactory and supporting cells, respectively, interacted in trans and recruited cadherin to the heterotypic cell junctions, resulting in the formation of the mosaic pattern in the olfactory epithelium. Further, we showed that nectin-2δ was localized on the plasma membranes of astrocytic perivascular endfoot processes facing the basement membrane of blood vessels in the brain. Genetic ablation of nectin-2 caused degeneration of the astrocytic perivascular endfoot processes and neurons, indicating that nectin- 2 is required to maintain the brain structures.

Research Products

• [Journal Article] Nectin-4 co-stimulates the prolactin receptor by interacting with SOCS1 and inhibiting its activity on the JAK2-STAT5a signaling pathway. (2017)
  • Author(s): Maruoka, M., Kedashiro, S., Ueda, Y., Mizutani, K., and Takai, Y.
  • Journal Title: Journal of Biological Chemistry Volume: 292 Issue: 17 Pages: 6895-6909
  • DOI: 10.1074/jbc.m116.769091
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Roles of afadin in the formation of the cellular architecture of the mouse hippocampus and dentate gyrus. (2017)
  • Author(s): Miyata M, Maruo T, Kaito A, Wang S, Yamamoto H, Fujiwara T, Mizoguchi A, Mandai K, Takai Y
  • Journal Title: Mol Cell Neurosci Volume: 79 Pages: 34-44
  • DOI: 10.1016/j.mcn.2016.12.007
  • Peer Reviewed
• [Journal Article] Aging-dependent expression of synapse-related proteins in the mouse brain. (2017)
  • Author(s): Shiotani, H., Maruo, T., Sakakibara, S., Miyata, M., Mandai, K., Mochizuki, H., Takai, Y.
  • Journal Title: Genes to Cells Volume: 印刷中 Issue: 5 Pages: 472-484
  • DOI: 10.1111/gtc.12489
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Multiple roles of afadin in the ultrastructural morphogenesis of mouse hippocampal mossy fiber synapses. (2017)
  • Author(s): Sai, K., Wang, S., Kaito, A., Fujiwara, T., Maruo, T., Itoh, Y., Miyata, M., Sakakibara, S., Miyazaki, N., Murata, K., Yamaguchi, Y., Haruta, T., Nishioka, H., Motojima, Y., Komura, M., Kimura, K., Mandai, K., Takai, Y., and Mizoguchi, A.
  • Journal Title: J Comp Neurol Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The active zone protein CAST regulates synaptic vesicle recycling and quantal size in the mouse hippocampus. (2016)
  • Author(s): Kobayashi S, Hida Y, Ishizaki H, Inoue E, Tanaka-Okamoto M, Yamasaki M, Miyazaki T, Masahiro F, Kitajima I, Takai Y, Watanabe M, Ohtsuka T, Manabe T
  • Journal Title: Eur J Neurosci. Volume: 44 Issue: 5 Pages: 2272-2284
  • DOI: 10.1111/ejn.13331
  • Peer Reviewed / Open Access
• [Journal Article] Localization of nectin-2δ at perivascular astrocytic endfoot processes and degeneration of astrocytes and neurons in nectin-2 knockout mouse brain. (2016)
  • Author(s): Miyata M, Mandai K, Maruo T, Sato J, Shiotani H, Kaito A, Itoh Y, Wang S, Fujiwara T, Mizoguchi A, Takai Y, Rikitake Y
  • Journal Title: Brain Res Volume: 1649 Pages: 90-101
  • DOI: 10.1016/j.brainres.2016.08.023
  • Peer Reviewed
• [Journal Article] Nectin spot: a novel type of nectin-mediated cell adhesion apparatus. (2016)
  • Author(s): Mizutani, K., and Takai, Y.
  • Journal Title: Biochemical Journal Volume: 473 Issue: 18 Pages: 2691-2715
  • DOI: 10.1042/bcj20160235
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Regulatory role of the cell adhesion molecule nectin-1 in GABAergic inhibitory synaptic transmission in the CA3 region of mouse hippocampus. (2016)
  • Author(s): Geng, X., Mandai, K., Maruo, T., Wang, S., Fujiwara, T., Mizoguchi, A., Takai, Y., and Mori, M.
  • Journal Title: Genes Cells Volume: 21 Issue: 1 Pages: 88-98
  • DOI: 10.1111/gtc.12322
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Synergistic action of nectins and cadherins generates the mosaic cellular pattern of the olfactory epithelium. (2016)
  • Author(s): Sayaka Katsunuma, Hisao Honda, Tomoyasu Shinoda, Yukitaka Ishimoto, Takaki Miyata, Hiroshi Kiyonari, Takaya Abe, Ken-ichi Nibu, Yoshimi Takai, and Hideru Togashi.
  • Journal Title: The Journal of Cell Biology Volume: 212 Issue: 5 Pages: 561-75
  • DOI: 10.1083/jcb.201509020
  • NAID: 120005766825
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A Novel Nectin-mediated Cell Adhesion Apparatus Which Is Implicated in Prolactin Receptor Signaling for Mammary Gland Development (2016)
  • Author(s): Kitayama M, Mizutani K, Maruoka M, Mandai K, Sakakibara S, Ueda Y, Komori T, Shimono Y, Takai Y
  • Journal Title: Journal of Biological Chemistry Volume: 291 Issue: 11 Pages: 5817-5831
  • DOI: 10.1074/jbc.m115.685917
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Activity-dependent alteration of the morphology of a hippocampal giant synapse. (2016)
  • Author(s): Maruo, T., Mandai, K., Takai, Y., and Mori, M.
  • Journal Title: Mol Cell Neurosci Volume: 71 Pages: 25-33
  • DOI: 10.1016/j.mcn.2015.12.005
  • Peer Reviewed
• [Journal Article] Nectin-1 spots regulate the branching of olfactory mitral cell dendrites. (2015)
  • Author(s): Fujiwara, T., Inoue, T., Maruo, T., Rikitake, Y., Ieki, N., Mandai, K., Kimura, K., Kayahara, T., Wang, S., Itoh, Y., Sai, K., Mori, M., Mori, K., Takai, Y., and Mizoguchi, A.
  • Journal Title: Mol Cell Neurosci Volume: 68 Pages: 143-150
  • DOI: 10.1016/j.mcn.2015.07.003
  • Peer Reviewed
• [Journal Article] Nectin-1 spots as a novel adhesion apparatus that tethers mitral cell lateral dendrites in a dendritic meshwork structure of the developing mouse olfactory bulb. (2015)
  • Author(s): Inoue, T., Fujiwara, T., Rikitake, Y., Maruo, T., Mandai, K., Kimura, K, Kayahara, T, Wang, S., Itoh, Y., Sai, K., Mori, M., Mori, K., Mizoguchi, A., and Takai, Y.
  • Journal Title: J Comp Neurol Volume: 523 Issue: 12 Pages: 1824-1839
  • DOI: 10.1002/cne.23762
  • Peer Reviewed
• [Journal Article] Impairment of radial glial scaffold-dependent neuronal migration and formation of double cortex by genetic ablation of afadin. (2015)
  • Author(s): Yamamoto H, Mandai K, Konno D, Maruo T, Matsuzaki F, Takai Y
  • Journal Title: Brain Res Volume: 43 Pages: 775-86
  • DOI: 10.1016/j.brainres.2015.05.012
  • Peer Reviewed
• [Journal Article] Downregulation of CXCR4 in Metastasized Breast Cancer Cells and Implication in Their Dormancy (2015)
  • Author(s): Nobutani K, Shimono Y, Mizutani K, Ueda Y, Suzuki T, Kitayama M, Minami A, Momose K, Miyawaki K, Akashi K, Azuma T, Takai Y
  • Journal Title: PLoS One Volume: 10 Issue: 6 Pages: e0130032-e0130032
  • DOI: 10.1371/journal.pone.0130032
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The cell adhesion molecule necl-4/cadm4 serves as a nobel regulator for contact inhibition of cell movement and proliferation. (2015)
  • Author(s): Yamana S, Tokiyama A, Mizutani K, Hirata K, Takai Y, Rikitake Y.
  • Journal Title: PloS One. Volume: 10 Issue: 4 Pages: e0124259-e0124259
  • DOI: 10.1371/journal.pone.0124259
  • Peer Reviewed / Open Access
• [Journal Article] Nectin-1 spots as a novel adhesion apparatus that tethers mitral cell lateral dendrites in a dendritic meshwork structure of the developing mouse olfactory bulb. (2015)
  • Author(s): Inoue T, Fujiwara T, Rikitake Y, Maruo T, Mandai K, Kimura K, Kayahara T, Wang S, Ioth Y, Sai K, Mori M, Mori K, Mizoguchi A, Takai Y.
  • Journal Title: J Comp Neurol. Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Human T-cell leukemia virus type 1 (HTLV-1) tax requires CADM1/TSLC1 for inactivation of the NF-κB inhibitor A20 and constitutive NF-κB signaling. (2015)
  • Author(s): Pujari R, Hunte R, Thomas R, van der Weyden L, Rauch D, Ratner L, Nyborg JK, Ramos JC, Takai Y, Shembade N.
  • Journal Title: PLoS Pathog. Volume: 16 Issue: 3 Pages: e1004721-e1004721
  • DOI: 10.1371/journal.ppat.1004721
  • Peer Reviewed / Open Access
• [Journal Article] Nectins and nectin-like molecules in development and disease. (2015)
  • Author(s): Mandai K, Rikitake Y, Mori M, Takai Y.
  • Journal Title: Curr Top Dev Biol. Volume: 112 Pages: 197-231
  • DOI: 10.1016/bs.ctdb.2014.11.019
  • ISBN: 9780124077584
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Crystal structure of afadin PDZ domain-nectin-3 complex shows the structural plasticity of the ligand-binding site. (2015)
  • Author(s): Fujiwara Y, Goda N, Tamashiro T, Narita H, Satomura K, Tenno T, Nakagawa A, Oda M, Suzuki M, Sakisaka T, Takai Y, Hiroaki H.
  • Journal Title: Protein Sci. Volume: 24 Issue: 3 Pages: 376-385
  • DOI: 10.1002/pro.2628
  • Peer Reviewed / Open Access
• [Journal Article] Quantitative analysis of the cellular composition in seminiferous tubules in normal and genetically modified infertile mice. (2015)
  • Author(s): Nakata H, Wakayama T, Takai Y, Iseki S.
  • Journal Title: J Histochem Cytochem. Volume: 63 Issue: 2 Pages: 99-113
  • DOI: 10.1369/0022155414562045
  • NAID: 120005593935
  • Peer Reviewed / Open Access
• [Journal Article] Genetic ablation of afadin causes mislocalization and deformation of Paneth cells in the mouse small intestinal epithelium. (2014)
  • Author(s): Tanaka-Okamoto M, Itoh Y, Miyoshi J, Mizoguchi A, Mizutani K, Takai Y, Inoue M.
  • Journal Title: PLoS One. Volume: 9 Issue: 10 Pages: e110549-e110549
  • DOI: 10.1371/journal.pone.0110549
  • Peer Reviewed / Open Access
• [Journal Article] Afadin requirement for cytokine expressions in keratinocytes during chemically induced inflammation in mice. (2014)
  • Author(s): Yoshida T, Iwata T, Takai Y, Birchmeier W, Yamato M, Okano T.
  • Journal Title: Genes Cells. Volume: 19 Issue: 11 Pages: 842-852
  • DOI: 10.1111/gtc.12184
  • Peer Reviewed / Open Access
• [Journal Article] s-Afadin binds more preferentially to the cell adhesion molecules nectins than l-afadin. (2014)
  • Author(s): Kobayashi R, Kurita S, Miyata M, Maruo T, Mandai K, Rikitake Y, Takai Y.
  • Journal Title: Genes Cells. Volume: 19 Issue: 12 Pages: 853-863
  • DOI: 10.1111/gtc.12185
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Syntaxin-binding protein STXBP5 inhibits endothelial exocytosis and promotes platelet secretion. (2014)
  • Author(s): Zhu Q, Yamakuchi M, Ture S, de la Luz Garcia-Hernandez M, Ko KA, Modjeski KL, LoMonaco MB, Johnson AD, O'Donnell CJ, Takai Y, Morrell CN, Lowenstein CJ.
  • Journal Title: J Clin Invest. Volume: 124 Issue: 10 Pages: 4503-4516
  • DOI: 10.1172/jci71245
  • Peer Reviewed / Open Access
• [Journal Article] Platelet secretion and hemostasis require syntaxin-binding protein STXBP5. (2014)
  • Author(s): Ye S, Huang Y, Joshi S, Zhang J, Yang F, Zhang G, Smyth SS, Li Z, Takai Y, Whiteheart SW.
  • Journal Title: J Clin Invest. Volume: 124 Issue: 10 Pages: 4517-4528
  • DOI: 10.1172/jci75572
  • Peer Reviewed / Open Access
• [Journal Article] Suppression of the TGF-β1-induced protein expression of SNAI1 and N-cadherin by miR-199a. (2014)
  • Author(s): Suzuki T, Mizutani K, Minami A, Nobutani K, Kurita S, Nagino M, Shimono Y, Takai Y.
  • Journal Title: Genes Cells. Volume: 19 Issue: 9 Pages: 667-675
  • DOI: 10.1111/gtc.12166
  • Peer Reviewed / Open Access
• [Presentation] Roles of afadin in the development of the cellular architecture of the hippocampus. (2016)
  • Author(s): 宮田宗明、丸尾知彦、山本昆明、垣内愛加、王淑杰、藤原武志、溝口明、萬代研二、高井義美
  • Organizer: 第３９回日本神経科学大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-07-20
• [Presentation] ネクチン-2αとマウス手綱核 (2016)
  • Author(s): 塩谷元、萬代研二、宮田宗明、丸尾知彦、垣内愛加、王淑杰、藤原武志、溝口明、望月秀樹、高井義美
  • Organizer: 第３９回日本神経科学大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-07-20
• [Presentation] 海馬苔状線維シナプス分化における２つのアファディンスプライスバリアントの役割 (2016)
  • Author(s): 丸尾知彦、萬代研二、榊原正太郎、伊藤優、藤原武志、王淑杰、崔煌植、垣内愛加、耿瀟奇、森正弘
  • Organizer: 第３９回日本神経科学大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-07-20
• [Presentation] 細胞の接着とシグナル伝達 (2015)
  • Author(s): 高井義美
  • Organizer: 第３８回日本分子生物学会年会・第８８回日本生化学会大会 合同大会 (BMB2015)
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] 乳腺分化を制御する新規のネクチン依存性細胞間接着装置 (2015)
  • Author(s): 圓岡真宏、北山-吉田美登里、水谷清人、高井義美
  • Organizer: 第３８回日本分子生物学会年会・第８８回日本生化学会大会 合同大会 (BMB2015)
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-01
• [Presentation] 転移乳がん細胞におけるCXCR4の発現低下とがん休眠との関連 (2015)
  • Author(s): 上田悠貴、信谷健太郎、下野洋平、水谷清人、鈴木俊裕、北山美登里、南晶洋、百瀬健次、宮脇恒太、赤司浩一、東健、高井義美
  • Organizer: 第７４回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-10-08
• [Presentation] AdAMS: Activith-dependent alteration of morphology of a hippocampal mossy fiber bouton. (2015)
  • Author(s): Maruo Tomohiko, Mandai Kenji, Takai Yoshimi, Mori Masahiro
  • Organizer: 第３８回日本神経科学大会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2015-07-28
• [Presentation] SBF-SEM 3D reconstitution analysis reveals alterations in composition and morphology of mouse hippocampal mossy fiber synapses by afadin knockout (2015)
  • Author(s): Takeshi Fujiwara, Shujie Wang, Yu Itoh, Kousyoku Sai, Aika Kaito, Naoyuki Miyazaki, Kazuyoshi Murata, Tomohiko Maruo, Hideaki Yamamoto, Kenji Mandai, Yoshimi Takai, Akira Mizoguchi
  • Organizer: 第120回日本解剖学会総会・全国学術集会・第92回日本生理学会大会合同大会
  • Place of Presentation: 神戸国際会議場・展示場
  • Year and Date: 2015-03-21
• [Presentation] Afadin plays an important role in formation of puncta adherentia junction and differentiation of presynapses in hippocampal neurons. (2014)
  • Author(s): Daisaku Toyoshima, Kenji Mandai, Tomohiko Maruo, Irwan Supriyanto, Hideru Togashi, Takahito Inoue, Masahiro Mori, Yoshimi Takai
  • Organizer: Neuroscience 2014
  • Place of Presentation: Washington, DC, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] マイクロRNA-199aはTGFβ－1で誘導されるSNAI1とN-cadherinの発現を 抑制する (2014)
  • Author(s): 鈴木俊裕、水谷清人、南晶洋、信谷健太郎、梛野正人、下野洋平、 高井義美
  • Organizer: 第７３回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Afadin-deficiency leads to the formation of double cortex by abnormal radial glial scaffold and cell-autonomous impairment of neuronal migration during development. (2014)
  • Author(s): Hideaki Yamamoto, Kenji Mandai, Daijiro Konno, Tomohiko Maruo, Fumio Matsuzaki, Yoshimi Takai
  • Organizer: 2014 CSHL Conference on Glia in Health & Disease
  • Place of Presentation: New York, NY, USA
  • Year and Date: 2014-07-17 – 2014-07-21
• [Presentation] シグナル伝達と細胞接着―研究の歴史と展望― (2014)
  • Author(s): 高井義美
  • Organizer: 第１００回日本消化器病学会総会
  • Place of Presentation: 東京国際フォーラム
  • Year and Date: 2014-04-23 – 2014-04-26
  • Invited
• [Patent(Industrial Property Rights)] ErbB3活性化に伴うシグナルの伝達抑制物質及びそのスクリーニング方法 (2016)
  • Inventor(s): 高井義美、水谷清人、慶田城迅
  • Industrial Property Rights Holder: 高井義美、水谷清人、慶田城迅
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-096427
  • Filing Date: 2016-05-12