dc.contributor |
Universitat de Barcelona |
dc.contributor.author |
Moreno Càceres, Joaquim |
dc.contributor.author |
Caja Puigsubirà, Laia |
dc.contributor.author |
Mainez Villoro, Jessica |
dc.contributor.author |
Mayoral, R. |
dc.contributor.author |
Martín Sánz, P. |
dc.contributor.author |
Moreno Vicente, Roberto |
dc.contributor.author |
Pozo, Miguel A. del |
dc.contributor.author |
Dooley, Steven |
dc.contributor.author |
Egea Guri, Gustavo |
dc.contributor.author |
Fabregat Romero, Isabel |
dc.date |
2016-04-20T13:59:39Z |
dc.date |
2016-04-20T13:59:39Z |
dc.date |
2014-07 |
dc.date |
2016-04-20T13:59:44Z |
dc.identifier.citation |
2041-4889 |
dc.identifier.citation |
648204 |
dc.identifier.uri |
http://hdl.handle.net/2445/97701 |
dc.format |
11 p. |
dc.format |
application/pdf |
dc.language.iso |
eng |
dc.publisher |
Nature Publishing Group |
dc.relation |
Reproducció del document publicat a: http://dx.doi.org/10.1038/cddis.2014.294 |
dc.relation |
Cell Death and Disease, 2014, vol. 5, p. e1326 |
dc.relation |
http://dx.doi.org/10.1038/cddis.2014.294 |
dc.rights |
cc-by-nc-sa (c) Moreno Càceres et al., 2014 |
dc.rights |
info:eu-repo/semantics/openAccess |
dc.rights |
http://creativecommons.org/licenses/by-nc-sa/3.0/es |
dc.subject |
Factor de creixement epidèrmic |
dc.subject |
Apoptosi |
dc.subject |
Fosforilació |
dc.subject |
Epidermal growth factor |
dc.subject |
Apoptosis |
dc.subject |
Phosphorylation |
dc.title |
Caveolin-1 is required for TGF-β-induced transactivation of the EGF receptor pathway in hepatocytes through the activation of the metalloprotease TACE/ADAM17 |
dc.type |
info:eu-repo/semantics/article |
dc.type |
info:eu-repo/semantics/publishedVersion |
dc.description.abstract |
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. |