Epidermal growth factor up-regulates transforming growth factor-β receptor type II in human dermal fibroblasts via p38 mitogen-activated protein kinase pathway

TGF-β receptors (TβRs) are serine/threonine kinase receptors that bind to TGF-β and propagate intracellular signaling through Smad proteins. TβRs are repressed in some human cancers and expressed at high levels in several fibrotic diseases. We demonstrated that epidermal growth factor (EGF) up-regulates type II TGF-β receptor (TβRII) expression in human dermal fibroblasts. EGF-mediated induction of TβRII expression was inhibited by the treatment of fibroblasts with a specific p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, whereas MEK inhibitor PD98059 did not block the up-regulation of TβRII by EGF. EGF induced the TβRII promoter activity, and this induction was significantly blocked by SB203580, but not by PD98059. The overexpression of the dominant negative form of p38α or p38β significantly reduced the induction of TβRII promoter activity by EGF. These results indicate that the EGF-mediated induction of TβRII expression involves the p38 MAPK signaling pathway. The EGF-mediated induction of TβRII expression may participate in a synergistic interplay between EGF and TGF-β signaling pathway.