Involvement of EGF receptor and c-Src in the survival signals induced by TGF-β1 in hepatocytes

Transforming growth factor beta1 (TGF- β 1) belongs to a family of polypeptide factors, whose cytostatic and apoptotic functions help restrain the growth of mammalian cells. Although solid data established the role of TGF- β 's as suppressor factors in tumorigenic processes, in the context of an advanced stage of disease, TGF- β 's could also play a pro-oncogenic role. We have previously shown that TGF- β 1 induces both pro- and antiapoptotic signals in foetal rat hepatocytes. In this work, we have focused on its antiapoptotic mechanism. We show that TGF- β 1 activates the epidermal growth factor receptor (EGFR) and phosphorylates c-Src. EGFR is required for Akt activation. Blocking EGFR signalling amplifies the apoptotic response to TGF- β 1. TGF- β 1 induced a rapid activation of the tumour necrosis factor- α -converting enzyme (TACE/ADAM (a disintegrin and metalloprotease) 17). Inhibitors of TACE considerably attenuated Akt activation, which suggests that TGF- β 1 activates EGF signalling in hepatocytes by promoting shedding of EGF-like ligands. The activation of c-Src by TGF- β 1 is EGFR dependent and is required for full Akt phosphorylation and cell survival. Inhibition of EGFR does not block the epithelial–mesenchymal transition (EMT) induced by TGF- β 1 in hepatocytes, which indicates that activation of EGFR plays an essential role in impairing apoptosis, but it is dispensable for the EMT process.