YAP modulates TGF-β1-induced simultaneous apoptosis and EMT through upregulation of the EGF receptor

YAP is a transcriptional co-regulator that plays important roles in various patho-physiological processes, including the survival and death of cells. However, the effect of YAP on apoptosis and EMT, simultaneously mediated by TGF-β1, is not known. In this study, we demonstrate that YAP can modulate cell fate of apoptosis versus EMT by acting as a surviving factor. Overexpression of YAP in mouse mammary epithelial (NMuMG) cells suppressed TGF-β1-induced apoptosis, which shifted the cellular response predominantly toward EMT. In contrast, knockdown of YAP induced spontaneous apoptosis and enhanced TGF-β1-induced apoptosis, leading to a sharp decrease in the proportion of surviving cells that underwent EMT. These data suggest that YAP is an essential factor for modulating cellular responses to TGF-β1. Further investigation showed that YAP could regulate the expression level and activation of EGFR. Knockdown or inhibition of EGFR abolished the suppressive effect of YAP on apoptosis, whereas activation of EGFR by EGF significantly reduced apoptosis caused by the knockdown of YAP. The results indicate that EGFR and its activation are critical for YAP-mediated suppression of TGF-β1-induced apoptosis. This study provides a new understanding of the regulatory mechanism underlying the determination of cell fate in response to TGF-β1-mediated simultaneous apoptosis and EMT.