ERK-Smurf1-RhoA signaling is critical for TGFß-drived EMT and tumor metastasis.

Epithelial-mesenchymal transition (EMT) has fundamental roles in various biological processes. However, there are still questions pending in this fast-moving field. Here we report that in TGFß-induced EMT, ERK-mediated Smurf1 phosphorylation is a prerequisite step for RhoA degradation and the consequent mesenchymal state achievement. Upon TGFß treatment, activated ERK phosphorylates Thr223 of Smurf1, a member of HECT family E3 ligase, to promote Smurf1-mediated polyubiquitination and degradation of RhoA, thereby leading to cell skeleton rearrangement and EMT. Blockade of phosphorylation of Smurf1 inhibits TGFß-induced EMT, and accordingly, dramatically blocks lung metastasis of murine breast cancer in mice. Hence, our study reveals an unknown role of ERK in TGFß-induced EMT and points out a potential strategy in therapeutic intervention.