Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/7521
Título
Caveolin-1 is required for TGF-β-induced transactivation of the EGF receptor pathway in hepatocytes through the activation of the metalloprotease TACE/ADAM17
Autor(es)
Moreno-Càceres, J | Caja, L | Mainez, J | Mayoral, R | Martín-Sanz, P | Moreno-Vicente, Roberto CNIC | del Pozo, Miguel Angel CNIC | Dooley, S | Egea, G | Fabregat, I
Fecha de publicación
2014-07-17
Cita
Cell Death Dis. 2014; 5:e1326
Idioma
Inglés
Tipo de documento
journal article
Resumen
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.
MESH
ADAM Proteins | ADAM17 Protein | Animals | Apoptosis | Caveolin 1 | Cells, Cultured | Enzyme Activation | ErbB Receptors | Female | Hepatocytes | Male | Mice | Mice, Knockout | Phosphorylation | Reactive Oxygen Species | Signal Transduction | Transforming Growth Factor beta | Transcriptional Activation
Versión en línea
DOI
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