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TACE-mediated ectodomain shedding of the type I TGF-beta receptor downregulates TGF-beta signaling.

Regulating TGF-beta receptor presentation provides an avenue to alter a cell's responsiveness to TGF-beta. We report that activation of the Erk MAP kinase pathway decreases the TGF-beta-induced Smad3 activation due to decreased cell surface levels of the type I receptor TbetaRI, but not the type II receptor. Inhibition of TACE activity or expression enhanced the cell surface TbetaRI levels and TGF-beta-induced Smad3 and Akt activation. Accordingly, silencing TACE expression in cancer cells enhanced the TbetaRI presentation and TGF-beta responsiveness, including the antiproliferative effect of TGF-beta, and epithelial-to-mesenchymal transition. These results establish a mechanism for downregulating TGF-beta signaling through TACE activation by the Erk MAP kinase pathway and a strategy for evasion of tumor suppression and modulation of epithelial-to-mesenchymal transition during cancer progression. The decreased growth inhibition by TGF-beta, due to elevated TACE activity, complements the growth stimulation resulting from increased release of TGF-alpha family ligands.

Pubmed ID: 19595713


  • Liu C
  • Xu P
  • Lamouille S
  • Xu J
  • Derynck R


Molecular cell

Publication Data

July 10, 2009

Associated Grants

  • Agency: NHLBI NIH HHS, Id: P01 HL060231
  • Agency: NHLBI NIH HHS, Id: P01 HL060231-100007
  • Agency: NHLBI NIH HHS, Id: P01 HL60231
  • Agency: NCI NIH HHS, Id: R01 CA063101
  • Agency: NCI NIH HHS, Id: R01 CA063101-14S1
  • Agency: NCI NIH HHS, Id: R01 CA63101

Mesh Terms

  • ADAM Proteins
  • Animals
  • Blotting, Western
  • Butadienes
  • CHO Cells
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation
  • Chromones
  • Cricetinae
  • Cricetulus
  • Down-Regulation
  • Enzyme Activation
  • HeLa Cells
  • Humans
  • Membrane Microdomains
  • Microscopy, Fluorescence
  • Mitogen-Activated Protein Kinase Kinases
  • Morpholines
  • Nitriles
  • Phosphorylation
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • RNA, Small Interfering
  • Receptors, Transforming Growth Factor beta
  • Signal Transduction
  • Smad3 Protein
  • Transfection
  • Transforming Growth Factor beta