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

SummaryRegulating 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.