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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM Proteins / genetics
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ADAM Proteins / metabolism*
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ADAM17 Protein
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Animals
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Blotting, Western
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Butadienes / pharmacology
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CHO Cells
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Cell Line
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Chromones / pharmacology
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Cricetinae
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Cricetulus
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Down-Regulation / drug effects
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Enzyme Activation / drug effects
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HeLa Cells
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Humans
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Membrane Microdomains / drug effects
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Membrane Microdomains / metabolism*
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Microscopy, Fluorescence
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Morpholines / pharmacology
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Nitriles / pharmacology
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Phosphorylation / drug effects
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Protein-Serine-Threonine Kinases / genetics
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Protein-Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Small Interfering / genetics
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / metabolism*
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Signal Transduction*
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Smad3 Protein / metabolism
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Transfection
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Transforming Growth Factor beta / pharmacology*
Substances
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Butadienes
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Chromones
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Morpholines
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Nitriles
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RNA, Small Interfering
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Receptors, Transforming Growth Factor beta
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Smad3 Protein
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Transforming Growth Factor beta
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U 0126
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Protein-Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Receptor, Transforming Growth Factor-beta Type I
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Mitogen-Activated Protein Kinase Kinases
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ADAM Proteins
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ADAM17 Protein
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ADAM17 protein, human