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

Mol Cell. 2009 Jul 10;35(1):26-36. doi: 10.1016/j.molcel.2009.06.018.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / genetics
  • ADAM Proteins / metabolism*
  • ADAM17 Protein
  • Animals
  • Blotting, Western
  • Butadienes / pharmacology
  • CHO Cells
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chromones / pharmacology
  • Cricetinae
  • Cricetulus
  • Down-Regulation / drug effects
  • Enzyme Activation / drug effects
  • HeLa Cells
  • Humans
  • Membrane Microdomains / drug effects
  • Membrane Microdomains / metabolism*
  • Microscopy, Fluorescence
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Morpholines / pharmacology
  • Nitriles / pharmacology
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Small Interfering / genetics
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Signal Transduction*
  • Smad3 Protein / metabolism
  • Transfection
  • Transforming Growth Factor beta / pharmacology*

Substances

  • Butadienes
  • Chromones
  • Morpholines
  • Nitriles
  • RNA, Small Interfering
  • Receptors, Transforming Growth Factor beta
  • Smad3 Protein
  • Transforming Growth Factor beta
  • U 0126
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Receptor, Transforming Growth Factor-beta Type I
  • Mitogen-Activated Protein Kinase Kinases
  • ADAM Proteins
  • ADAM17 Protein
  • ADAM17 protein, human