Caveolin-1 is Required for TGF-β-induced Transactivation of the EGF Receptor Pathway in Hepatocytes Through the Activation of the Metalloprotease TACE/ADAM17

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2014 Jul 18

PMID 25032849

Citations 22

Authors

J Moreno-Caceres

L Caja

J Mainez

R Mayoral

P Martin-Sanz

R Moreno-Vicente

M A Del Pozo

S Dooley

G Egea

I Fabregat

Affiliations

Soon will be listed here.

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.

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References

Di Guglielmo G, Le Roy C, Goodfellow A, Wrana J . Distinct endocytic pathways regulate TGF-beta receptor signalling and turnover. Nat Cell Biol. 2003; 5(5):410-21. DOI: 10.1038/ncb975. View

Valdes F, Murillo M, Valverde A, Herrera B, Sanchez A, Benito M . Transforming growth factor-beta activates both pro-apoptotic and survival signals in fetal rat hepatocytes. Exp Cell Res. 2004; 292(1):209-18. DOI: 10.1016/j.yexcr.2003.08.015. View

Lu Z, Ghosh S, Wang Z, Hunter T . Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion. Cancer Cell. 2004; 4(6):499-515. DOI: 10.1016/s1535-6108(03)00304-0. View

Vizan P, Miller D, Gori I, Das D, Schmierer B, Hill C . Controlling long-term signaling: receptor dynamics determine attenuation and refractory behavior of the TGF-β pathway. Sci Signal. 2013; 6(305):ra106. DOI: 10.1126/scisignal.2004416. View

Meyer C, Godoy P, Bachmann A, Liu Y, Barzan D, Ilkavets I . Distinct role of endocytosis for Smad and non-Smad TGF-β signaling regulation in hepatocytes. J Hepatol. 2010; 55(2):369-78. DOI: 10.1016/j.jhep.2010.11.027. View

Sancho P, Bertran E, Caja L, Carmona-Cuenca I, Murillo M, Fabregat I . The inhibition of the epidermal growth factor (EGF) pathway enhances TGF-beta-induced apoptosis in rat hepatoma cells through inducing oxidative stress coincident with a change in the expression pattern of the NADPH oxidases (NOX) isoforms. Biochim Biophys Acta. 2008; 1793(2):253-63. DOI: 10.1016/j.bbamcr.2008.09.003. View

Mineo C, Gill G, Anderson R . Regulated migration of epidermal growth factor receptor from caveolae. J Biol Chem. 1999; 274(43):30636-43. DOI: 10.1074/jbc.274.43.30636. View

Murillo M, del Castillo G, Sanchez A, Fernandez M, Fabregat I . Involvement of EGF receptor and c-Src in the survival signals induced by TGF-beta1 in hepatocytes. Oncogene. 2005; 24(28):4580-7. DOI: 10.1038/sj.onc.1208664. View

Couet J, Sargiacomo M, Lisanti M . Interaction of a receptor tyrosine kinase, EGF-R, with caveolins. Caveolin binding negatively regulates tyrosine and serine/threonine kinase activities. J Biol Chem. 1997; 272(48):30429-38. DOI: 10.1074/jbc.272.48.30429. View

10.

Martin-Sanz P, Callejas N, Casado M, Bosca L . Expression of cyclooxygenase-2 in foetal rat hepatocytes stimulated with lipopolysaccharide and pro-inflammatory cytokines. Br J Pharmacol. 1998; 125(6):1313-9. PMC: 1565703. DOI: 10.1038/sj.bjp.0702196. View

11.

Caja L, Ortiz C, Bertran E, Murillo M, Miro-Obradors M, Palacios E . Differential intracellular signalling induced by TGF-beta in rat adult hepatocytes and hepatoma cells: implications in liver carcinogenesis. Cell Signal. 2006; 19(4):683-94. DOI: 10.1016/j.cellsig.2006.09.002. View

12.

Pol A, Calvo M, Enrich C . Isolated endosomes from quiescent rat liver contain the signal transduction machinery. Differential distribution of activated Raf-1 and Mek in the endocytic compartment. FEBS Lett. 1999; 441(1):34-8. DOI: 10.1016/s0014-5793(98)01517-8. View

13.

Pol A, Lu A, Pons M, Peiro S, Enrich C . Epidermal growth factor-mediated caveolin recruitment to early endosomes and MAPK activation. Role of cholesterol and actin cytoskeleton. J Biol Chem. 2000; 275(39):30566-72. DOI: 10.1074/jbc.M001131200. View

14.

Parr-Sturgess C, Rushton D, Parkin E . Ectodomain shedding of the Notch ligand Jagged1 is mediated by ADAM17, but is not a lipid-raft-associated event. Biochem J. 2010; 432(2):283-94. DOI: 10.1042/BJ20100321. View

15.

Murillo M, Carmona-Cuenca I, del Castillo G, Ortiz C, Roncero C, Sanchez A . Activation of NADPH oxidase by transforming growth factor-beta in hepatocytes mediates up-regulation of epidermal growth factor receptor ligands through a nuclear factor-kappaB-dependent mechanism. Biochem J. 2007; 405(2):251-9. PMC: 1904531. DOI: 10.1042/BJ20061846. View

16.

Tang Y, Zeng X, He F, Liao Y, Qian N, Toi M . Caveolin-1 is related to invasion, survival, and poor prognosis in hepatocellular cancer. Med Oncol. 2011; 29(2):977-84. DOI: 10.1007/s12032-011-9900-5. View

17.

Grande-Garcia A, Echarri A, de Rooij J, Alderson N, Waterman-Storer C, Valdivielso J . Caveolin-1 regulates cell polarization and directional migration through Src kinase and Rho GTPases. J Cell Biol. 2007; 177(4):683-94. PMC: 2064213. DOI: 10.1083/jcb.200701006. View

18.

Caja L, Sancho P, Bertran E, Fabregat I . Dissecting the effect of targeting the epidermal growth factor receptor on TGF-β-induced-apoptosis in human hepatocellular carcinoma cells. J Hepatol. 2010; 55(2):351-8. DOI: 10.1016/j.jhep.2010.10.041. View

19.

Valdes F, Alvarez A, Locascio A, Vega S, Herrera B, Fernandez M . The epithelial mesenchymal transition confers resistance to the apoptotic effects of transforming growth factor Beta in fetal rat hepatocytes. Mol Cancer Res. 2002; 1(1):68-78. View

20.

Takaguri A, Shirai H, Kimura K, Hinoki A, Eguchi K, Carlile-Klusacek M . Caveolin-1 negatively regulates a metalloprotease-dependent epidermal growth factor receptor transactivation by angiotensin II. J Mol Cell Cardiol. 2010; 50(3):545-51. PMC: 3035769. DOI: 10.1016/j.yjmcc.2010.12.009. View