TACE-mediated ectodomain shedding of the type I TGF-beta receptor downregulates TGF-beta signaling.
Journal:
Mol. Cell 2009 JulAuthors:
Liu C, Xu P, Lamouille S, Xu J, Derynck R
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 enhan
...[more]ced 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.[less]
Mesh Headings:
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