TMEPAI/PMEPA1 (transmembrane prostate androgen induced-RNA/prostate transmembrane protein, androgen induced 1) is a pro-tumorigenic factor induced by TGF-beta signaling and constitutive TMEPAI expression in lung cancer cells depends on activated autocrine TGF-beta signaling. Here we demonstrate a novel mechanism of TMEPAI transcriptional co-regulation by EGF signaling. Interestingly, we found that ELK-1, downstream of EGFR/Ras/MAPK pathway, modulates TMEPAI expression. ELK-1 binds to the first intron (+1037 to +1294) of the TMEPAI gene together with TGF-beta activated Smad3 and enhances the transcription of TMEPAI. Furthermore, TMEPAI gene activation by EGF and TGF-beta signaling was reduced by the MEK inhibitor U0126. Together, EGF signaling collaboratively regulates TGF-beta-induced TMEPAI expression. (C) 2014 Elsevier Inc. All rights reserved.