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Involvement of EGF receptor and c-Src in the survival signals induced by TGF-β1 in hepatocytes

Oncogene volume 24, pages 4580–4587 (2005)Cite this article

Abstract

Transforming growth factor beta1 (TGF-β1) belongs to a family of polypeptide factors, whose cytostatic and apoptotic functions help restrain the growth of mammalian cells. Although solid data established the role of TGF-β's as suppressor factors in tumorigenic processes, in the context of an advanced stage of disease, TGF-β's could also play a pro-oncogenic role. We have previously shown that TGF-β1 induces both pro- and antiapoptotic signals in foetal rat hepatocytes. In this work, we have focused on its antiapoptotic mechanism. We show that TGF-β1 activates the epidermal growth factor receptor (EGFR) and phosphorylates c-Src. EGFR is required for Akt activation. Blocking EGFR signalling amplifies the apoptotic response to TGF-β1. TGF-β1 induced a rapid activation of the tumour necrosis factor-α-converting enzyme (TACE/ADAM (a disintegrin and metalloprotease) 17). Inhibitors of TACE considerably attenuated Akt activation, which suggests that TGF-β1 activates EGF signalling in hepatocytes by promoting shedding of EGF-like ligands. The activation of c-Src by TGF-β1 is EGFR dependent and is required for full Akt phosphorylation and cell survival. Inhibition of EGFR does not block the epithelial–mesenchymal transition (EMT) induced by TGF-β1 in hepatocytes, which indicates that activation of EGFR plays an essential role in impairing apoptosis, but it is dispensable for the EMT process.

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Abbreviations

TGF:

transforming growth factor

EMT:

epithelial mesenchymal transition

PI-3K:

phosphatidylinositol-3-kinase

EGF:

epidermal growth factor

TACE:

tumour necrosis factor-α-converting enzyme

ADAM:

a disintegrin and metalloprotease

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Acknowledgements

We acknowledge Drs J Gil and MA Nieto for helpful discussions and A Vázquez for assistance in the flow cytometer. This work was supported by Grants from the Ministerio de Educación y Ciencia, Spain (BMC03-524) and the Comunidad Autónoma de Madrid (CAM 08.1/0003.1/2003). M Murillo and G del Castillo are the recipients of fellowships from the Ministerio de Educación y Ciencia, Spain.

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  1. Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, 28040, Spain

    Miguel M Murillo, Gaelle del Castillo, Aránzazu Sánchez, Margarita Fernández & Isabel Fabregat

  2. IDIBELL-Institut de Recerca Oncològica, Gran Via s/n, Km 2.7, L'Hospitalet, Barcelona, Spain

    Isabel Fabregat

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  1. Miguel M Murillo
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Correspondence to Isabel Fabregat.

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Murillo, M., Castillo, G., Sánchez, A. et al. Involvement of EGF receptor and c-Src in the survival signals induced by TGF-β1 in hepatocytes. Oncogene 24, 4580–4587 (2005). https://doi.org/10.1038/sj.onc.1208664

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