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Analysis on β1 integrin and its associating molecules in the pathophysiology of Rheumatoid Arthritis and Progressive Systemic Sclerosis.

Research Project

Project/Area Number 17591031
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 膠原病・アレルギー・感染症内科学
Research InstitutionThe University of Tokyo

Principal Investigator

IWATA Satoshi  The University of Tokyo, Institute of Medical Science, Project Assistant Professor, 医科学研究所, 特任助手 (00396871)

Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
Keywordsintegrin / adhesion molecule / Cas-L / tetraspanin / cell migration / TGF-β / NF-κB / Smad / 細胞遊送 / integrin / rheumatoid arthritis / IKK / raft / PSS
Research Abstract

β1 integrin is key adhesion molecule possibly involving in pathogenesis of autoimmune inflammatory diseases such as rheumatoid arthritis (RA) and progressive systemic sclerosis (PSS). The aim of this study is investigating the biological roles of β1 integrin and its associating molecules Crk-associated substrate lymphocyte type (Cas-L) and tetraspanins (CD9 and CD82).
1) We showed that Cas-L localize in lipid raft through its c-terminal half domains, and that reduction of Cas-L expression by shRNAi retroviral vector resulted in significantly reduced cellular migration and IL-2 production, suggesting that localization of Cas-L in lipid raft is necessary for cellular migration and cytokine production.
2) We showed that Cas-L associated with IKK-α/β and TRAF6 that are important signaling molecules in NF-κB system. The associating domain of Cas-L for IKKs are tentatively determined as HLH domain. We further analyzed osteoclast differentiation using RAW264.7 cells, and find that mRNA of p130Cas, a Cas-L homologue, was up-regulated whereas that of Cas-L was down-regulated during RANKL-induced osteoclast differentiation.
3) By Two-Hybrid screening, we identified Smad6 and 7 as Cas-L binding molecules. We showed that Cas-L and Smad 6, 7 associate and co-localize each other in the cytoplasm. Furthermore, analysis on siRNA of Cas-L revealed that Cas-L positively regulates TGF-β-mediated signaling pathway.
4) To artificially regulate immune system in future, we generated potent shRNAi retroviral vector for Cas-L and recombinant extracellular loops of CD9 or CD82-IgG-Fc fusion proteins.

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (33 results)

All 2007 2006 2005

All Journal Article (33 results)

  • [Journal Article] Crk-associated substrate lymphocyte type regulates transforming growth factor-beta signaling by inhibiting Smad6 and Smad7.2007

    • Author(s)
      Inamoto S
    • Journal Title

      Oncogene 26(6)

      Pages: 893-904

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Crk-associated substrate lymphocyte type regulates transforming growth factor-beta signaling by inhibiting Smad6 and Smad7.2007

    • Author(s)
      Inamoto S, et al.
    • Journal Title

      Oncogene 26(6)

      Pages: 893-904

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Crk-associated substrate lmphocyte type regulates transforming growth factor-beta signaling by inhibiting Smad6 and Smad7.2007

    • Author(s)
      Inamoto S
    • Journal Title

      Oncogene 26(6)

      Pages: 893-904

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Anti-CD26 monoclonal antibody-mediated G1-S arrest of human renal clear cell carcinoma Caki-2 is associated with retinoblastom a substrate dephosphorylation, cyclin-dependent kinase 2 reduction, p27(kip1) enhancement, and disruption of binding to the extra cellular matrix.2006

    • Author(s)
      Inamoto T
    • Journal Title

      Clin Cancer Res 12 (11 Pt 1)

      Pages: 3470-3477

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Tyrosine phosphorylated Crk-associated substrate lymphocyte type associates with adaptor protein Nck : Role of Cas-L/Nck interaction in beta 1 integrin- and TCR-mediated signaling2006

    • Author(s)
      Hashizume Y
    • Journal Title

      日本免疫学会総会・学術集会記録 36

      Pages: 264-264

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] IFN-Y-stimulated human myeloid dendritic cells highly express multiple co-stimulatory molecules of the TNF family.2006

    • Author(s)
      Hashimoto M
    • Journal Title

      日本免疫学会総会・学術集会記録 36

      Pages: 129-129

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Anti-CD26 monoclonal antibody-mediated G1-S arrest of human renal clear carcinoma Caki-2 is associated with retinoblastoma substrate dephosphorylation, cyclin-dependent kinase 2 reduction, p27(kip1) enhancement, and disruption of binding to the extracellular matrix.2006

    • Author(s)
      Inamoto T, et al.
    • Journal Title

      Clin Cancer Res 12(11 pt 1)

      Pages: 3470-3477

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Tyrosine phosphorylated Crk-associated substrate lymphocyte type associates with adaptor protein Nck : Role of Cas-L/Nck interaction in beta 1 integrin- and TCR-mediated signaling2006

    • Author(s)
      Hashizume Y, et al.
    • Journal Title

      Proceedings of the Japanese Society for Immunology 36

      Pages: 264-264

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] IFN-γ-stimulated human myeliod dendritic cells highly express multiple co-stimulatory molecules of the TNF family.2006

    • Author(s)
      Hashimoto M, et al.
    • Journal Title

      Proceedings of the Japanese Society for Immunology 36

      Pages: 129-129

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Anti-CD26 monoclonal antibody-mediated G1-S arrest of human renal clear cell carcinoma Caki-2 is associated with retinoblastoma substrate dephosphorylation, cyclin-dependent kinase 2 reduction, p27(kip1) enhancement, and disruption of binding t the extracellular matrix.2006

    • Author(s)
      Inamoto T
    • Journal Title

      Clin Cancer Res 12(11 Pt1)

      Pages: 3470-7

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Tyrosine phosphorylated Crk-associated sbstrate lymphocyte type associates with adaptor protein Nck : Role of Cas-L/Nck interaction in beta 1 integrin- and TCR-mediated signaling2006

    • Author(s)
      Hashizume Y
    • Journal Title

      日本免疫学会総会・学術集会記録 36

      Pages: 264-264

    • Related Report
      2006 Annual Research Report
  • [Journal Article] IFN-y-stimulated human myeloid dendritic cells highly express multiple co-stimulatory molecultes of the TNF family.2006

    • Author(s)
      Hashimoto M
    • Journal Title

      日本免疫学会総会・学術集会記録 36

      Pages: 129-129

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Nedd9 protein, a Cas-L homologue, is upregulated after transient global ischemia in rats : possible involvement of Nedd9 in the differentiation of neurons after ischemia.2005

    • Author(s)
      Sasaki T
    • Journal Title

      Stroke 36(11)

      Pages: 2457-2462

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Roxithromycin specifically inhibits development of collagen induced arthritis and production of proinflammatory cytokines by human T cells and macrophages.2005

    • Author(s)
      Urasaki Y
    • Journal Title

      J Rheumatol 32(9)

      Pages: 1765-1774

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] CD26 mediates dissociation of Tollip and IRAK-1 from caveolin-1 and induces upregulation of CD86 on antigen-presenting cells.2005

    • Author(s)
      Ohnuma K
    • Journal Title

      Mol Cell Biol 25(17)

      Pages: 7743-7757

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] HTLV-I Tax induces and associates with Crk-associated substrate lymphocyte type (Cas-L).2005

    • Author(s)
      Iwata S
    • Journal Title

      Oncogene 24(7)

      Pages: 1262-1271

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Ro52によるIL-2産生機構の解析2005

    • Author(s)
      矢持忠徳
    • Journal Title

      日本リウマチ学会総会・学術集会抄録集 45

      Pages: 258-258

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] リウマチ性疾患の基礎 分子とシグナル CD26とCaveolin-1の相互作用を標的にしたリウマチ性疾患の治療の可能性2005

    • Author(s)
      大沼圭
    • Journal Title

      日本リウマチ学会総会・学術集会抄録集 45

      Pages: 110-110

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] β1インテグリン下流シグナル伝達分子Cas-LとSmad6及びSmad7との相互作用の解析2005

    • Author(s)
      岩田哲史
    • Journal Title

      日本リウマチ学会総会・学術集会抄録集 45

      Pages: 133-133

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Induction of Cas (Crk-associated substrate) family proteins, integrin-mediated signaling molecules, in the differentiation of osteoclasts by RANKL2005

    • Author(s)
      Urasaki Y
    • Journal Title

      日本免疫学会総会・学術集会記録 35

      Pages: 249-249

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Crk-associated substrate lymphocyte type (Cas-L) associates with Smad6 and Smad7 : Possible involvement of Cas-L in TGF-β-mediated signaling2005

    • Author(s)
      Hashizume Y
    • Journal Title

      日本免疫学会総会・学術集会記録 35

      Pages: 169-169

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Nedd9 protein, a Cas-L homologue, is upregulated after transient global ischemia in rats : possible involvement of Nedd9 in the differentiation of neurons after ischemia.2005

    • Author(s)
      Sasaki T, et al.
    • Journal Title

      Stroke 36(11)

      Pages: 2457-2462

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Roxithromycin specifically inhibits development of collagen induced arthritis and production of proinflammatory cytokines by human T cells and macrophages.2005

    • Author(s)
      Urasaki Y, et al.
    • Journal Title

      J Rheumatol 32(9)

      Pages: 1765-1774

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] CD26 mediates dissociation of Tollip and IRAK-1 from caveolin-1 and induces upregulation of CD86 on antigen-presenting cells.2005

    • Author(s)
      Ohnuma K, et al.
    • Journal Title

      Mol Cell Biol 25(17)

      Pages: 7743-7757

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] HTLV-1 Tax induces and associated with Crk-associated substrate lymphocyte type (Cas-L).2005

    • Author(s)
      Iwata S, et al.
    • Journal Title

      Oncogene 24(7)

      Pages: 1262-1271

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] 「研究成果報告書概要(欧文)」より2005

    • Author(s)
      Yamochi T, et al.
    • Journal Title

      The RYUMACHI Official Journal of Japan College of Rheumatology 45

      Pages: 258-258

    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] 「研究成果報告書概要(欧文)」より2005

    • Author(s)
      Ohnuma K, et al.
    • Journal Title

      The RYUMACHI Official Journal of Japan College of Rheumatology 45

      Pages: 110-110

    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] 「研究成果報告書概要(欧文)」より2005

    • Author(s)
      Iwata S, et al.
    • Journal Title

      The RYUMACHI Official Journal of Japan College of Rheumatology 45

      Pages: 133-133

    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Induction of Cas (Crk-associated substrate) family proteins, integrin-mediated signaling molecules, in the differentiation of osteoclasts by RANKL.2005

    • Author(s)
      Urasaki Y, et al.
    • Journal Title

      Proceedings of the Japanese Society for Immunology 35

      Pages: 249-249

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Crk-associated substrate lymphocyte type (Cas-L) associates with Smad6 and Smad7: Possible involvement of Cas-L in TGF-β-mediated signaling2005

    • Author(s)
      Hashizume Y, et al.
    • Journal Title

      Proceedings of the Japanese Society for Immunology 35

      Pages: 169-169

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Nedd9 protein, a Cas-L homologue, is upregulated after transient global ischemia in rats : possible involvement of Nedd9 in the differentiation of neurons after ischemia.2005

    • Author(s)
      Sasaki T, Iwata S, Okano HJ, Urasaki Y, Hamada J, Tanaka H, Dang NH, Okano H, Morimoto C.
    • Journal Title

      Stroke 36(11)

      Pages: 2457-2462

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Roxithromycin specifically inhibits development of collagen induced arthritis and production of proinflammatory cytokines by human T cells and macrophages.2005

    • Author(s)
      Urasaki Y, Nori M, Iwata S, Sasaki T, Hosono O, Kawasaki H, Tanaka H, Dang NH, Ikeda E, Morimoto C.
    • Journal Title

      J Rheumatol. 32(9)

      Pages: 1765-1774

    • Related Report
      2005 Annual Research Report
  • [Journal Article] HTLV-I Tax induces and associates with Crk-associated substrate lymphocyte type (Cas-L).2005

    • Author(s)
      Iwata S, Souta-Kuribara A, Yamakawa A, Sasaki T, Shimizu T, Hosono O, Kawasaki H, Tanaka H, Dang NH, Watanabe T, Arima N, Morimoto C.
    • Journal Title

      Oncogene 24(7)

      Pages: 1262-1271

    • Related Report
      2005 Annual Research Report

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Published: 2005-04-01   Modified: 2016-04-21  

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