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Caveolin-1 is required for TGF-β-induced transactivation of the EGF receptor pathway in hepatocytes through the activation of the metalloprotease TACE/ADAM17 Moreno Càceres, Joaquim Caja Puigsubirà, Laia Mainez Villoro, Jessica Mayoral, R. Martín Sánz, P. Moreno Vicente, Roberto Pozo, Miguel Ángel del Dooley, Steven Egea Guri, Gustavo Fabregat Romero, Isabel Factor de creixement epidèrmic Apoptosi Fosforilació Epidermal growth factor Apoptosis Phosphorylation Transforming growth factor-beta (TGF-β) 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-β in these cells. Caveolin-1 (Cav1) is a structural protein of caveolae linked to TGF-β receptors trafficking and signaling. Previous results have indicated that in hepatocytes, Cav1 is required for TGF-β-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-β, 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-β-induced survival signals in Cav1−/− hepatocytes, such as AKT and ERK1/2 phosphorylation and NFκ-B activation. Transactivation of the EGFR pathway by TGF-β 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-β treatment. In conclusion, in hepatocytes, Cav1 is required for TGF-β-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-β pro-apoptotic effects. Therefore, Cav1 contributes to the pro-tumorigenic effects of TGF-β in liver cancer cells. 2016-04-20T13:59:39Z 2016-04-20T13:59:39Z 2014-07 2016-04-20T13:59:44Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion 2041-4889 https://hdl.handle.net/2445/97701 648204 25032849 eng Reproducció del document publicat a: http://dx.doi.org/10.1038/cddis.2014.294 Cell Death and Disease, 2014, vol. 5, p. e1326 http://dx.doi.org/10.1038/cddis.2014.294 info:eu-repo/grantAgreement/EC/FP7/316549/EU//IT-LIVER cc-by-nc-sa (c) Moreno Càceres et al., 2014 http://creativecommons.org/licenses/by-nc-sa/3.0/es info:eu-repo/semantics/openAccess 11 p. application/pdf Nature Publishing Group Articles publicats en revistes (Ciències Fisiològiques)