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2004 Fiscal Year Final Research Report Summary

Regulation of molecular interaction between TGF-β and Wnt signalings

Research Project

Project/Area Number 15390101
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionTokyo Medical and Dental University

Principal Investigator

SHIBUYA Hiroshi  Tokyo Medical and Dental University, Medical Research Institute, Professor, 難治疾患研究所, 教授 (30261324)

Co-Investigator(Kenkyū-buntansha) URUSHIYAMA Seiichi  Tokyo Medical and Dental University, Medical Research Institute, Assistant Professor, 難治疾患研究所, 助手 (30334428)
SHIRAKABE Kyoko  Tokyo Medical and Dental University, Medical Research Institute, Assistant Professor, 難治疾患研究所, 助手 (00345315)
Project Period (FY) 2003 – 2004
KeywordsWnt signaling / NLK / Sox 11 / HMG2L1 / STAT3 / TGF-β signaling / mcb-1
Research Abstract

TGF-β signaling regulates cell growth, differentiation, morphogenesis and apoptosis. TGF-β activated kinase 1 (TAK1) and Nemo-like kinase (NLK) function in Xenopus, Drosophila and C.elegans developments. Here we report that serine phosphorylation of STAT3 induced by TAK1-NLK cascade is essential for TGF-β-mediated mesoderm induction in Xenopus embryo. Depletion of TAK1, NLK or STAT3 blocks TGF-β-mediated mesoderm induction. Co-expression of NLK and STAT3 induces mesoderm by a mechanism that requires serine phosphorylation of STAT3. Activin activates NLK, which in turn directly phosphorylates STAT3. Moreover, depletion of either TAK1 or NLK inhibits endogenous serine phosphorylation of STAT3. These results provide the first evidence that TAK1-NLK-STAT3 cascade participates in TGF-β-mediated mesoderm induction.
MAFbx/Atrogin-1 has been identified as a regulator for skeletal muscle atrophy, and encodes an F-box-type E3 ubiquitin ligase. However, little is known about how MAFbx/Atrogin-1 regulates cellular signaling. Here we identify and genetically characterize MFB-1, a MAFbx/Atrogin-1 homologue from Caenorhabditis elegans. The mfb-1 deletion mutant significantly enhanced the dauer constitutive (Daf-c) phenotype caused by mutations in the DAF-7/TrGF-β-like signaling pathway, but not the DAF-2/insulin receptor-like signaling pathway. Conversely, the Daf-c phenotypes of DAF-7 pathway mutants were partially suppressed by mfb-1 cDNA transgenes. Thus, MFB-1 acts genetically downstream in the DAF-7 pathway. A mfb-1 :: GFP fusion was found to be expressed in the nervous system, hypodermis and intestine, and overlapped expression of many DAF-7 pathway genes. We propose that MFB-1 is a novel F-box protein that negatively regulates dauer formation in concert with the DAF-7 signaling pathway in C.elegans.

  • Research Products

    (8 results)

All 2004 2003

All Journal Article (8 results)

  • [Journal Article] Role of the TAK1-NLK-STAT3 pathway in TGF-β-mediated mesoderm induction.2004

    • Author(s)
      Ohkawara et al.
    • Journal Title

      Genes & Development 18

      Pages: 381-386

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] MFB-1, an F-box-type ubiquitin ligase, regulates TGF-β signaling.2004

    • Author(s)
      Aoyama et al.
    • Journal Title

      Genes Cells 9

      Pages: 1093-1101

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Manipulation of alternative splicing by a newly developed inhibitor of Clks.2004

    • Author(s)
      Muraki et al.
    • Journal Title

      J.Biol.Chem. 279

      Pages: 24246-24254

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Role of the TAK1-NLK-STAT3 pathway in TGF-β-mediated mesoderm induction2004

    • Author(s)
      Ohkawara et al.
    • Journal Title

      Genes & Development 18

      Pages: 381-386

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling.2003

    • Author(s)
      Ishitani et al.
    • Journal Title

      EMBO J. 22

      Pages: 6277-6288

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Cytokines suppress adipogenesis and PPAR-γ function through the TAK1/TAB1/NIK cascade.2003

    • Author(s)
      Suzawa et al.
    • Journal Title

      Nature Cell Biol. 5

      Pages: 224-230

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Negative regulation of Wnt signalling by HMG2L1, a novel NLK-binding protein.2003

    • Author(s)
      Yamada et al.
    • Journal Title

      Genes Cells 8

      Pages: 677-684

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Negative regulation of Wnt signaling by HMG2L1, a novel NLK-binding protein2003

    • Author(s)
      Yamada et al.
    • Journal Title

      Genes Cells 8

      Pages: 677-384

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2006-07-11  

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