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Caveolin-1 is requi...
Caveolin-1 is required for TGF-β-induced transactivation of the EGF receptor pathway in hepatocytes through the activation of the metalloprotease TACE/ADAM17
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Moreno-Càceres, J (author)
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- Caja, Laia (author)
- Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
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Mainez, J (author)
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Mayoral, R (author)
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Martín-Sanz, P (author)
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Moreno-Vicente, R (author)
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Del Pozo, M Á (author)
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Dooley, S (author)
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Egea, G (author)
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Fabregat, I (author)
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(creator_code:org_t)
- 2014-07-17
- 2014
- English.
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In: Cell Death and Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 5
- Related links:
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https://www.nature.c...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- 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.
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- art (subject category)
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- By the author/editor
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Moreno-Càceres, ...
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Caja, Laia
-
Mainez, J
-
Mayoral, R
-
Martín-Sanz, P
-
Moreno-Vicente, ...
-
show more...
-
Del Pozo, M Á
-
Dooley, S
-
Egea, G
-
Fabregat, I
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show less...
- Articles in the publication
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Cell Death and D ...
- By the university
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Uppsala University