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Analyses of a Novel Signaling Molecule, Cas

Research Project

Project/Area Number 09044271
Research Category

Grant-in-Aid for international Scientific Research

Allocation TypeSingle-year Grants
SectionJoint Research
Research Field Molecular biology
Research InstitutionUniversity of Tokyo

Principal Investigator

HIRAI Hisamaru  University of Tokyo Hospital, Internal Medicine, Associate Professor, 医学部附属病院, 助教授 (90181130)

Co-Investigator(Kenkyū-buntansha) KUROKAWA Mineo  Research Fellow of the Japan Society for the Promotion of Science (University of, 医学部附属病院), 特別研究員
SASAKI Ko  University of Tokyo Hospital, Internal Medicine, Assistant Professor, 医学部附属病院, 助手 (60282638)
HONDA Hiroaki  University of Tokyo Hospital, Internal Medicine, Assistant Professor, 医学部附属病院, 助手 (40245064)
CHIBA Shigeru  University of Tokyo Hospital, Internal Medicine, Assistant Professor, 医学部附属病院, 助手 (60212049)
MITAMI Kinuko  University of Tokyo Hospital, Internal Medicine, Assistant Professor, 医学部附属病院, 助手 (50251244)
山形 哲也  日本学術振興会, 特別研究員
小川 誠司  東京大学, 医学部・附属病院, 助手
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥8,500,000 (Direct Cost: ¥8,500,000)
Fiscal Year 1998: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 1997: ¥4,500,000 (Direct Cost: ¥4,500,000)
KeywordsCas / SH3 / subcellular localization / focal adhesion / knockout mouse / myofibril / シグナル伝達 / チロシンリン酸化
Research Abstract

p13OCas is an adapter protein that has an SH3 domain followed by multiple SH2 binding motifs in the substrate domain. It also contains a tyrosine residue and a proline-rich sequence near the C terminus, which are the binding sites for the SH2 and SH3 domains of Src kinase, respectively. Cas was shown to be inducibly tyrosine phosphorylated upon integrin stimulation. We examined the subcellular localization of Gas and determined the regions required for its localization to focal adhesions. In nontransformed cells, Cas was localized predominantly to the cytoplasm and partially to focal adhesions. However, in 527F-c-Src-transformed cells, Gas was localized mainly to podosomes. The localization of Cas to focal adhesions was observed in cells expressing the kinase-negative 527F/295M-c-Src. The SH3 domain of Cas is necessary for its localization to focal adhesions in nontransformed cells while both the SH3 domain and the C-terminal Src binding domain of Cas are required in 527F-c-Src-transfo … More rmed cells and fibronectin-stimulated cells. In addition, the localization of Gas to focal adhesions was abolished in Src-negative cells. These results demonstrate that the SH3 domain of Cas and the association of Cas with Src kinase play a pivotal role in the localization of Gas to focal adhesions. To determine its role in vivo, we generated mice lacking Gas. Gas-deficient embryos died in utero showing marked systemic congestion and growth retardation. Histologically, the heart was poorly developed and blood vessels were prominently dilated. Electron microscopic analysis of the heart revealed disorganization of myofibrils and disruption of Z-disks. In addition, actin stress fiber formation was severely impaired in Cas-deficient primary fibroblasts. Moreover, expression of activated Src in Cas-deficient primary fibroblasts did not induce a fully transformed phenotype, possibly owing to insufficient accumulation of actin cytoskeleton in podosomes. These findings have defined Gas function in cardiovascular development, actin filament assembly and Src-induced transformation. Less

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] Sakai R: "Characterization of the kinase activity essential for tyrosine phosphorylation of p130Cas in mouse fibroblasts." Oncogene. 14. 1419-1426 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Nakamoto T: "Requirements for the localization of p130Cas to Focal Adhesions." Mol.Cell.Biol.17. 3884-3897 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Manie SN: "Regulation of Integrin-Mediated p130Cas Tyrosine Phosphorylation in Human B Cells : a Role for p59fn and SHP2." J.Biol.Chem.272. 15636-15〓 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Astier A: "The related adhesion focal tyrosine kinase differentially phosphorylates p130Cas and the Cas-like protein, p105HEF1." J.Biol.Chem.272. 4230-4236 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kanda H: "Ligation of the T cell antigen receptor induces tyrosine phosphorylation of p105CasL, a member of the p130Cas-related docking protein family, and its subsequent binding to the Src homology 2 domain of c-Crk." Eur.J.Immunol.27. 2113-2117 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Honda H: "Cardiovascular anomaly, impaired actin bundling and resistance to Src-induced transformation in mice lacking p130Cas." Nature Genet. 19. 361-365 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Sakai R,Nakamoto T,Ozawa K,Aizawa S,Hirai H.: "Characterization of the kinase activity essential for tyrosine phosphorylation of p130Cas in mouse fibroblasts." Oncogene. 14. 1419-1426 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Nakamoto T,Sakai R,Honda H,Ogawa S,Ueno H,Suzuki T,Aizawa S-I,Yazaki Y,Hirai H: "Requirements for the localization of p130Cas to focal adhesions." Mol.Cell.Biol.17. 3884-3897 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Manie SN,Astier A,Haghayegi N,Canty T,Hirai H: "Freedman A.Regulation of Integrin-Mediated p130Cas Tyrosine Phosphorylation in Human B Cells : a Role for p59fyn and SHP2." J.Biol.Chem.272. 15636-15641 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Astier A,Serge N,Mani SN,Avraham H,Hirai H,Law SF,Zhang Y,Golemis EA,Fu Y Druker BJ,Haghayegi N,Freedman A,Avraham S.: "The related adhesion focal tyrosine kinase differentially phosphorylates p130Cas and the Cas-like protein, p105HEF1." J.Biol.Chem.272. 4230-4236 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kanda H,Mimura T,Morino N,Hamasaki K,Nakamoto T,Hirai H,Morimoto C,Yazaki Y,Nojima Y: "Ligation of the T cell antigen receptor induces tyrosine phosphorylation of p105CasL,a member of the p130Casrelated docking protein family, and its subsequent binding to the Src homology 2 domain of c-Crk." Eur.J.Immunol.27. 2113-2117 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Honda H,Oda H,Nakamoto T,Honda Z,Sakai R,Suzuki T,Saito T,Nakamura K,Nakao K,Ishikawa T,Katsuki M,Yazaki Y,Hirai H.: "Cardiovascular anomaly, impaired actin bundling and resistance to Src-induced transformation in mice lacking p130Cas." Nature Genet. 19. 361-365 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Sakai R: "Characterization of the kinase activity essential for tyrosine phosphorylation of p130Cas in mouse fibroblasts." Oncogene. 14. 1419-1426 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nakamoto T: "Requirements for the localization of p130Cas to Focal Adhesions." Mol.Cell.Biol.17. 3884-3897 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Manie SN: "Regulation of Integrin-Mediated p130Cas Tyrosine Phosphorylation in Human B Cells:a Role for p59fyn and SHP2." J.Biol.Chem.272. 15636-15641 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Astier A: "The related adhesion focal tyrosine kinase differentially phosphorylates p130Cas and the Cas-like protein,p105HEF1." J.Biol.Chem.272. 4230-4236 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kanda H: "Ligation of the T cell antigen receptor induces tyrosine phosphorylation of p105CasL,a member of the p130Cas-rejated docking protein family,and its subsequent binding to the Src homology 2 domain of c-Crk." Eur.J.Immunol.27. 2113-2117 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Honda H: "Cardiovascular anomaly,impaired actin bundling and resistance to Src-induced transformation in mice lacking p130Cas." Nature Genet. 19. 361-365 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Manie SN: "Involvement of p130Cas and p105HEF1, a novel Cas-like docking protein, in a cytoskeleton-dependent signaling pathway initiated by ligation of intergrin or antigen receptor on human B cells." J. Biol. Chem.272. 4230-4236 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Sakai R: "Characterization of the kinase activity essential for tyrosine phosphorylation of p130Cas in mouse fibroblasts." Oncogene. 14. 1419-1426 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Nakamoto T: "Requirements for the localization of p130Cas to Focal Adhesions." Mol. Cell. Biol.17. 3884-3897 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Manie SN: "Regulation of Integrin-Mediated p130Cas Tyrosine Phosphorylation in Human B Cells : a Role for p59fyn and SHP2." J. Biol. Chem.272. 15636-15641 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Astier A: "The related adhesion focal tyrosine kinase differentially phosphorylates p130Cas and the Cas-like protein, p105HEF1." J. Biol. Chem.272. 4230-4236 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] da Silva AJ: "Rosenfield JM. Mueller I. Bouton A. Hirai H. Rudd CE. Biochemical analysis of p120 / 130 a protein-tyrosine kinase substrate restricted to T and myeloid cells." J. Immunol.158. 2007-2016 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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