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

Abstract

Transforming growth factor beta1 (TGF-b1) 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-b's as suppressor factors in tumorigenic processes, in the context of an advanced stage of disease, TGF-b's could also play a pro-oncogenic role. We have previously shown that TGF-b1 induces both pro-and antiapoptotic signals in foetal rat hepatocytes. In this work, we have focused on its antiapoptotic mechanism. We show that TGF-b1 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-b1. TGF-b1 induced a rapid activation of the tumour necrosis factor-a-converting enzyme (TACE/ADAM (a disintegrin and metalloprotease) 17). Inhibitors of TACE considerably attenuated Akt activation, which suggests that TGF-b1 activates EGF signalling in hepatocytes by promoting shedding of EGF-like ligands. The activation of c-Src by TGF-b1 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-b1 in hepatocytes, which indicates that activation of EGFR plays an essential role in impairing apoptosis, but it is dispensable for the EMT process.

EGFR is dispensable for c-Met-mediated proliferation and survival activities in mouse adult liver oval cells

“…Furthermore, EGFR is activated and required for TGF-β-induction of antiapoptotic signals, such as AKT [22], constituting a part of the mechanism induced by TGF-β to confer resistance to apoptosis in fetal hepatocytes after an EMT process [37]. Consistent with these data, we see an increased apoptotic index under serum deprivation as well as TGF-β treatment in the presence of AG1478 (Fig.…”

“…A fluorometric assay in the presence of Ac-DEVD-AMC as fluorogenic Caspase-3 substrate was used following a previously described procedure [22].…”

High glucose activates PKC-ζ and NADPH oxidase through autocrine TGF-β1 signaling in mesangial cells

“…Non-Smad, TGF-␤ 1 effectors include MAPKs such as ERK, PI3 kinase, Akt, NADPH oxidase, p21-activated kinase-2, Ras, and Src (5,6,17,19,36,37,50,60). Many of these poorly understood, non-Smad TGF-␤ 1 effects may be indirectly mediated by Smads, but some appear to arise independently of Smads, as illustrated in cells lacking Smads or by mutant TGF-␤ receptors (2,6,50,60).…”

“…PI3 kinase phosphorylates the D-3 position of the inositol ring of phosphoinositides, recruiting proteins with pleckstrin homology domains to membranes, such as PKB/kt and PKC-/ . TGF-␤ 1 is reported to stimulate PI3 kinase in mesangial cells (14,30,46) and fibroblasts (6,37,60). We previously reported that primary cultured rat mesangial cells express predominantly PKC-with little or undetectable PKC-.…”

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

“…Indeed, ADAM-17 contributes to EGFRligand release and induction of cell proliferation and invasion [137]. A link has been established between TGF-β1 and cell proliferation since TGF-β1 induces a rapid activation of ADAM-17 leading in turn to EGFR signalling [138]. In activated hepatic stellate cells, TGF-βl induces ADAM-12 expression which might also participate in tumour progression [139].…”