We have previously reported that neutrophil elastase (NE) downregulates transforming growth factor- (TGF-) maintained tropoelastin mRNA levels in lung fibroblasts through transactivation of the epidermal growth factor receptor (EGFR)/Mek/Erk pathway, which is dependent on the NE-initiated release of soluble EGFR ligands. In the present study, we investigated the mechanism by which epidermal growth factor (EGF) downregulates tropoelastin expression. We found that EGF downregulates tropoelastin expression through inhibiton of TGF- signaling. We show that EGF does not prevent the TGF--induced nuclear accumulation of Smad2/3; rather, EGF stabilizes the short-lived Smad transcriptional corepressor TG-interacting factor (TGIF) via EGFR/Mek/Erk-mediated phosphorylation of TGIF. Elevated TGIF levels, either by overexpressing TGIF or by preventing its degradation, are sufficient to inhibit TGF--induced tropoelastin expression. Moreover, TGIF is essential for EGF to downregulate tropoelastin expression as siRNA knockdown of TGIF blocked EGF-induced downregulation of tropoelastin. Finally, we demonstrated that NE treatment, which releases EGF-like growth factors, causes stabilization of TGIF through the EGFR/Mek/Erk pathway. These results suggest that EGFR/Mek/Erk signaling specifically antagonizes the proelastogenic action of TGF- in lung fibroblasts by stabilizing the Smad transcriptional corepressor TGIF.