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Caveolin-1 is required for TGF-ß-induced transactivation of the EGF receptor pathway in hepatocytes through the activation of the metalloprotease TACE/ADAM17

AuthorsCaja, Laia; Mayoral, Rafael ; Martín-Sanz, Paloma ; Egea, Gustavo; Fabregat, Isabel
Issue Date2014
PublisherNature Publishing Group
CitationCell Death and Disease 5: e1326 (2014)
AbstractTransforming growth factor-beta (TGF-b) plays a dual role in hepatocytes, inducing both pro- and anti-apoptotic responses, whose balance decides cell fate. Survival signals are mediated by the epidermal growth factor receptor (EGFR) pathway, which is activated by TGF-ß in these cells. Caveolin-1 (Cav1) is a structural protein of caveolae linked to TGF-ß receptors trafficking and signaling. Previous results have indicated that in hepatocytes, Cav1 is required for TGF-ß-induced anti-apoptotic signals, but the molecular mechanism is not fully understood yet. In this work, we show that immortalized Cav1-/- hepatocytes were more sensitive to the pro-apoptotic effects induced by TGF-ß, showing a higher activation of caspase-3, higher decrease in cell viability and prolonged increase through time of intracellular reactive oxygen species (ROS). These results were coincident with attenuation of TGF-ß-induced survival signals in Cav1-/- hepatocytes, such as AKT and ERK1/2 phosphorylation and NFj-ß activation. Transactivation of the EGFR pathway by TGF-ß was impaired in Cav1 -/- hepatocytes, which correlated with lack of activation of TACE/ADAM17, the metalloprotease responsible for the shedding of EGFR ligands. Reconstitution of Cav1 in Cav1-/- hepatocytes rescued wild-type phenotype features, both in terms of EGFR transactivation and TACE/ADAM17 activation. TACE/ADAM17 was localized in detergent-resistant membrane (DRM) fractions in Cav1+/+ cells, which was not the case in Cav1-/- cells. Disorganization of lipid rafts after treatment with cholesterol-binding agents caused loss of TACE/ADAM17 activation after TGF-ß treatment. In conclusion, in hepatocytes, Cav1 is required for TGF-ß-mediated activation of the metalloprotease TACE/ADAM17 that is responsible for shedding of EGFR ligands and activation of the EGFR pathway, which counteracts the TGF-ß pro-apoptotic effects. Therefore, Cav1 contributes to the pro-tumorigenic effects of TGF-ß in liver cancer cells.
DescriptionThis work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.-- et al.
Publisher version (URL)http://dx.doi.org/10.1038/cddis.2014.294
Identifiersdoi: 10.1038/cddis.2014.294
issn: 2041-4889
Appears in Collections:(IIBM) Artículos
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