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

Abstract

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.

Dual role of RACK1 in airway epithelial mesenchymal transition and apoptosis

“…On the other hand, to initiate tissue repair process, amounts of TGF‐β1 secreted from eosinophil and bronchial epithelial cell increase epithelial vulnerability to allergens and trigger the activation of EMT, which contributes to the subepithelial fibrosis in airway remodelling . Importantly, both of airway epithelial apoptosis and EMT are potently stimulated by TGF‐β, even simultaneously regulated by TGF‐β . Thus, a deeper understanding of TGF‐β1‐induced airway epithelial apoptosis and EMT may provide a new therapeutic asthma treatment in epithelial injury‐repair process.…”

The concomitant apoptosis and EMT underlie the fundamental functions of TGF-β

“…For instance, addition of EGF can strongly inhibit TGF-β-induced apoptosis, leading to a significant increase in the portion of cells that underwent EMT [43,47]. In this case, EGF can be mis-regarded as a required factor or co-inducing factor for TGF-β to induce EMT.…”

“…It has recently been shown that the extent of TGF-β-induced concomitant apoptosis and EMT can be profoundly influenced by YAP and EGF/EGFR signaling [43]. YAP is important for the survival of breast epithelial cells, which can significantly regulate the balance between apoptosis and EMT.…”

“…For instance, as mentioned previously, TGF-β-induced apoptosis concomitantly occurs with EMT in hepatocytes, breast cells, renal cells, and prostate cells [33,34,37,38,[44][45][46][47][48][49]. TGF-β can induce EMT without an apoptotic response in many cancer cells, including pancreatic cancer cells [53][54][55] and lung cancer cells [56][57][58], and in immortal non-cancer cell lines such as Mv1Lu [31,32], MDCK [35,59], MCF10A [43], and HMEC [60]. In addition to gaining uncontrolled proliferation and immortality, tumorigenesis can also be a process by which cells acquire the capacity to resist TGF-β-induced apoptosis.…”

“…1), including a mouse liver cell line and primary liver cells [34,42], mammary epithelial cells [43], fetal rat hepatocytes [44,45], medial edge epithelial (MEE) cells [38,46], renal tubular epithelial cells [47], and rabbit lens epithelial cells [48].…”