Regulatory mechanisms of cellular functions by integrins and their ligands

• Project/Area Number: 25291026
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Osaka University
• Principal Investigator: Sekiguchi Kiyotoshi 大阪大学, たんぱく質研究所, 寄附研究部門教授 (50187845)
• Co-Investigator(Kenkyū-buntansha): 山田 雅司 大阪大学, たんぱく質研究所, 助教 (90304055) ; 二木 杉子 大阪大学, たんぱく質研究所, 助教 (00403014)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2015: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2014: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2013: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: 細胞外マトリックス / 細胞接着 / 幹細胞 / 細胞増殖 / ニッチ / リンパ管

Outline of Final Research Achievements

Mice deficient of polydom, a newly identified integrin alpha9beta1 ligand, were generated to study the function of polydom. We found that i) polydom was secreted from mesenchymal cells and deposited around lymphatic vessels; ii) the lymphatic plexus failed to remodel into collecting lymphatic vessels in polydom-deficient mice and thereby died immediately after birth due to severe edema; iii) the expression of Foxc2, a transcription factor involved in lymphatic vessel remodeling, was reduced in polydom-deficient mice; iv) polydom was capable of binding to angiopoietin-2 that has been known to regulate lymphangiogenesis. These results indicate that polydom regulates lymphatic vessel remodeling through binding to angiopoietin-2, thereby promoting the expression of Foxc2.

Research Products

• [Int'l Joint Research] ヴェストファーレン・ヴィルヘルム大学(ドイツ)
• [Journal Article] Probing the acidic residue within the integrin binding site of laminin-511 that interacts with the metal ion-dependent adhesion site of α6β1 integrin. (2017)
  • Author(s): Taniguchi, Y., Li, S., Takizawa, M., Oonishi, E., Toga, J., Yagi, E., and Sekiguchi, K.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 291 Issue: 3 Pages: 525-531
  • DOI: 10.1016/j.bbrc.2017.04.051
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Polydom is an extracellular matrix protein involved in lymphatic vessel remodeling. (2017)
  • Author(s): Morooka, N., Futaki, S., Sato-Nishiuchi, R., Nishino, M., Totani, Y., Shimono, C., Nakano, I., Nakajima, H., Mochizuki, N., and Sekiguchi, K.
  • Journal Title: Circ. Res. Volume: 120 Issue: 8 Pages: 1276-1288
  • DOI: 10.1161/circresaha.116.308825
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] An evolutionarily conserved role for polydom/svep1 during lymphatic vessel formation. (2017)
  • Author(s): Karpanen, T., Padberg, Y., van de Pavert, SA., Dierkes, C., Morooka, N., Peterson-Maduro, J., van de Hoek, G., Adrian, M., Mochizuki, N., Sekiguchi, K., Kiefer, F., Schulte, D., and Schulte-Merker, S.
  • Journal Title: Circ. Res. Volume: 120 Issue: 8 Pages: 1263-1275
  • DOI: 10.1161/circresaha.116.308813
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] β1 integrin signaling promotes neuronal migration along vascular scaffolds in the post-stroke brain (2017)
  • Author(s): Fujioka T,Kaneko N, Ajioka I, Nakaguchi K, Omata T, Ohba H, Fassler R, Garcia-Verdugo JM, Sekiguchi K, Matsukawa N, Sawamoto K
  • Journal Title: EbioMedicine Volume: 16 Pages: 195-203
  • DOI: 10.1016/j.ebiom.2017.01.005
  • NAID: 120006626426
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Laminin-guided highly efficient endothelial commitment from human pluripotent stem cells. (2016)
  • Author(s): Ohta R., Niwa A., Taniguchi Y., Suzuki NM., Toga J., Yagi E., Saiki N., Nishinaka-Arai Y., Okada C., Watanabe A., Nakahata T., Sekiguchi K., Saito MK.
  • Journal Title: Scientific Reports Volume: - Issue: 1 Pages: 35680-35680
  • DOI: 10.1038/srep35680
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Co-ordinated ocular development from hiPSCs and recovery of anterior eye function. (2016)
  • Author(s): Hayashi R, Ishikawa Y, Sasamoto Y, Katori R, Nomura N, Ichikawa T, Araki S, Soma T, Kawasaki S, Sekiguchi K, Quantock A, Tsujikawa M, & Nishida K.
  • Journal Title: Nature Volume: 17;531(7594) Issue: 7594 Pages: 376-80
  • DOI: 10.1038/nature17000
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Molecular Basis of the Ligand-binding Specificity of αvβ8 Integrin. (2016)
  • Author(s): Ozawa, A., Sato, Y., Imabayashi, T., Uemura, T., Takagi, J., and Sekiguchi, K.
  • Journal Title: The Journal of Biological Chemisry Volume: 291 Issue: 22 Pages: 11551-11565
  • DOI: 10.1074/jbc.m116.719138
  • NAID: 120006585485
  • Peer Reviewed / Open Access
• [Journal Article] Molecular basis of laminin-integrin interactions. (2015)
  • Author(s): Yamada, M., Sekiguchi, K.
  • Journal Title: Curr. Top. Membr. Volume: 76 Pages: 197-229
  • DOI: 10.1016/bs.ctm.2015.07.002
  • ISBN: 9780128040157
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Isolation and characterization of sweat gland muyoepithelial cells from human skin. (2014)
  • Author(s): Kurata, Y., Futaki, S., Nakano, I., Tanemura, A., Murota, H., Katayama, I., and Sekiguchi, K.
  • Journal Title: Cell Struct. Funct. Volume: 89 Pages: 101-112
  • Peer Reviewed
• [Journal Article] In situ detection of integrin ligands. (2014)
  • Author(s): Kiyozumi, D., Sato-Nishiuchi, R., and Sekiguchi, K.
  • Journal Title: Curr. Protoc. Cell Biol. Volume: 65
  • Peer Reviewed
• [Journal Article] A novel efficient feeder-free culture system for the derivation of human induced pluripotent stem cells. (2014)
  • Author(s): Nakagawa M, Taniguchi Y, Senda S, Takizawa N, Ichisaka T, Asano K, Morizane A, Doi D, Takahashi J, Nishizawa M, Yoshida Y, Toyoda T, Osafune K, Sekiguchi K, YamanakaS.
  • Journal Title: Scientific Reports Volume: 4 Issue: 1 Pages: 3594-3594
  • DOI: 10.1038/srep03594
  • NAID: 120005357344
  • Peer Reviewed
• [Journal Article] Nephronectin binds to heparan sulfate proteoglycans via its MAM domain. (2013)
  • Author(s): Sato, Y., Shimono, C., Li, S., Nakano, I., Norioka, N., Sugiura, N., Kimata, K., Yamada, M., and Sekiguchi, K.
  • Journal Title: Matrix Biology Volume: 32 Pages: 188-195
  • Peer Reviewed
• [Journal Article] Substrate-attached materials are enriched with tetraspanins and are analogous to the structures associated with rear-end retraction in migrating cells. (2013)
  • Author(s): Yamada, M., Mugnai, G., Serada, S., Yagi, Y., Naka, T., and Sekiguchi, K.
  • Journal Title: Cell Adhesion and Migration Volume: 7 Pages: 304-314
  • Peer Reviewed
• [Journal Article] GPR56 functions together with α3β1 integrin in regulating cerebral cortical development. (2013)
  • Author(s): Jeong, S., Luo, R., Singer, K., Kreidberg, J., Shimono, C., Kiyozumi, D., Sekiguchi, K., and Piao, X.
  • Journal Title: PLoS One Volume: 8 Issue: 7 Pages: e68781-e68781
  • DOI: 10.1371/journal.pone.0068781
  • NAID: 120006626410
  • Peer Reviewed
• [Journal Article] Disease-associated single amino acid mutation in the calf-1 domain of integrin α3 leads to defects in its processing and cell surface expression. (2013)
  • Author(s): Yamada, M., and Sekiguchi, K.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 441 Pages: 988-993
  • Peer Reviewed
• [Presentation] Crystal structure of the integrin-binding fragment of laminin-511. (2016)
  • Author(s): Takizawa, M., Arimori, T., Kitago, Y., Taniguchi, Y., Takagi, J., and Sekiguchi, K.
  • Organizer: American Society for Matrix Biology Biennial Meeting 2016
  • Place of Presentation: Florida (U.S.A.)
  • Year and Date: 2016-11-13
  • Int'l Joint Research
• [Presentation] Polydom is an extracellular matrix protein essential for lymphatic vessel remodeling. (2016)
  • Author(s): Morooka, M., Futaki, S., Totani, Y., Sato-Nishiuchi, R., Nakano, I., and Sekiguchi, K.
  • Organizer: American Society for Matrix Biology Biennial Meeting 2016
  • Place of Presentation: Florida (U.S.A.)
  • Year and Date: 2016-11-13
  • Int'l Joint Research
• [Presentation] Probing the acidic residue within the integrin binding site of laminin-511 that directly interacts with the metal ion-dependent adhesion site of integrin β1 by comprehensive site-directed mutagenesis. (2016)
  • Author(s): Taniguchi, Y., Li, S., Yamashita, E., Takizawa, M., Oonishi, E., Toga, J., E Yagi, E., and Sekiguchi, K.
  • Organizer: American Society for Matrix Biology Biennial Meeting 2016
  • Place of Presentation: Florida (U.S.A.)
  • Year and Date: 2016-11-13
  • Int'l Joint Research
• [Presentation] Molecular basis of laminin recognition by integrins. (2015)
  • Author(s): Sekiguchi, K.
  • Organizer: 9th International Conference on Proteoglycans and 10th Pan-pacific Connective Tissue Societies Symposium
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2015-08-23
  • Int'l Joint Research / Invited
• [Presentation] The involvement of the extracellular matrix protein polydom in the regulation of mouse bone marrow mesenchymal stem cells. (2015)
  • Author(s): Yanada, M., Shitamichi, H., Sato-Nishiuchi, R., Kusumoto,K.,Morooka,N., Tamai, K., Ezoe, S., Futaki, S., and Sekiguchi, K.
  • Organizer: International Society for Stem Cell Reseach Annual Meeting 2015.
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2015-06-24
  • Int'l Joint Research
• [Presentation] Laminin E8 fragments as a versatile platform for fabrication of collagen-based matrices having basement membrane -like activities. (2015)
  • Author(s): Sekiguchi, K., Sato-Nishiuchi, R., Ebisu, F.,Shimono, C.,Taniguchi, Y.,and Li, S.
  • Organizer: International Society for Stem Cell Reseach Annual Meeting 2015.
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2015-06-24
  • Int'l Joint Research
• [Presentation] 基底膜ラミニンによるインテグリンおよびテトラスパニンを介した上皮細胞機能制御 (2014)
  • Author(s): 山田雅司、関口清俊
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-16
• [Presentation] The C-terminal Glu Residue of laminin γ1 chain that is essential for integrin binding is positioned at the junctional region of G1 and G2 domains of laminin-511 (2014)
  • Author(s): Taniguchi, Y., Toga, J., Yagi, E., Norioka, N., Iwasaki, K., Sekiguchi, K.
  • Organizer: American Society of Matrix Biology 2014
  • Place of Presentation: Cleveland, USA
  • Year and Date: 2014-10-13
• [Presentation] Polydom is an extracellular matrix protein involved in lymphatic vessel remodeling (2014)
  • Author(s): Morooka, N., Futaki, S., Sato-Nishiuchi, R., Nakano, I., Sekiguchi, K.
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: 京都
  • Year and Date: 2014-04-13
• [Presentation] Polydom is an extracellular matrix protein involved in lymphatic vessel remodeling. (2014)
  • Author(s): Morooka, N., Futaki, S., Sato-Nishiuchi, R., Nakano, I., Sekiguchi, K.
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: 京都
• [Presentation] コラーゲン結合活性を付加したラミニンフラグメントの作製
  • Author(s): 佐藤（西内）涼子、李紹良、関口清俊
  • Organizer: 第45回日本結合組織学会・第60回マトリックス研究会合同学術集会
  • Place of Presentation: 和歌山
• [Presentation] ほ乳類組織における基底膜ライブイメージングのためのプローブ開発
  • Author(s): 二木杉子、堀本絢乃、矢野真理子、下野知性、関口清俊
  • Organizer: 第45回日本結合組織学会・第60回マトリックス研究会合同学術集会
  • Place of Presentation: 和歌山
• [Presentation] Untangling the complexity of the extracellular matrix: From the matrixome detabase to the innovation of stem cell technology
  • Author(s): 関口清俊
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜
• [Book] バイオマテリアル：その基礎と先端研究への展開 (2015)
  • Author(s): 下野知性、関口清俊
  • Total Pages: 368
  • Publisher: 東京化学同人
• [Remarks] 大阪大学蛋白質研究所マトリクソーム科学（ニッピ）寄附研究部門
  • URL: http://www.protein.osaka-u.ac.jp/matrixome/
• [Remarks] 大阪大学蛋白質研究所細胞外マトリックス研究室
  • URL: http://protein.osaka-u.ac.jp/chemistry/