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 RIS Download
ADAM Proteins | ADAM17 Protein | 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