TACE-Mediated Ectodomain Shedding of the Type I TGF-β Receptor Downregulates TGF-β Signaling

• Published in: Molecular cell Vol. 35; no. 1; pp. 26 - 36
• Main Authors: Liu, Cheng, Xu, Pinglong, Lamouille, Samy, Xu, Jian, Derynck, Rik
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.07.2009
• Subjects: ADAM Proteins - genetics; ADAM Proteins - metabolism; ADAM17 Protein; Animals; Blotting, Western; Butadienes - pharmacology; Cell Line; Cell Line, Tumor; Cell Proliferation - drug effects; CHO Cells; Chromones - pharmacology; Cricetinae; Cricetulus; Down-Regulation - drug effects; Enzyme Activation - drug effects; HeLa Cells; Humans; HUMDISEASE; 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; PROTEINS; Proto-Oncogene Proteins c-akt - metabolism; Receptors, Transforming Growth Factor beta - genetics; Receptors, Transforming Growth Factor beta - metabolism; RNA, Small Interfering - genetics; Signal Transduction; SIGNALING; Smad3 Protein - metabolism; Transfection; Transforming Growth Factor beta - pharmacology; PROTEINS; HUMDISEASE; SIGNALING
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2009.06.018

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