Involvement of EGF receptor and c-Src in the survival signals induced by TGF-beta1 in hepatocytes

Oncogene. 2005 Jun 30;24(28):4580-7. doi: 10.1038/sj.onc.1208664.


Transforming growth factor beta1 (TGF-beta1) 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-beta's as suppressor factors in tumorigenic processes, in the context of an advanced stage of disease, TGF-beta's could also play a pro-oncogenic role. We have previously shown that TGF-beta1 induces both pro- and anti-apoptotic signals in foetal rat hepatocytes. In this work, we have focused on its anti-apoptotic mechanism. We show that TGF-beta1 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-beta1. TGF-beta1 induced a rapid activation of the tumour necrosis factor-alpha-converting enzyme (TACE/ADAM (a disintegrin and metalloprotease) 17). Inhibitors of TACE considerably attenuated Akt activation, which suggests that TGF-beta1 activates EGF signalling in hepatocytes by promoting shedding of EGF-like ligands. The activation of c-Src by TGF-beta1 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-beta1 in hepatocytes, which indicates that activation of EGFR plays an essential role in impairing apoptosis, but it is dispensable for the EMT process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins
  • ADAM17 Protein
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Caspase 3
  • Caspases / metabolism
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • Class Ib Phosphatidylinositol 3-Kinase
  • Epithelial Cells / metabolism
  • ErbB Receptors / metabolism*
  • Hepatocytes / cytology*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Isoenzymes / metabolism
  • Liver / cytology
  • Liver / embryology
  • Mesoderm / metabolism
  • Metalloendopeptidases / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins pp60(c-src) / drug effects
  • Proto-Oncogene Proteins pp60(c-src) / metabolism*
  • Rats
  • Rats, Wistar
  • Signal Transduction
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta / pharmacology
  • Transforming Growth Factor beta1
  • Tumor Necrosis Factor-alpha / metabolism


  • Isoenzymes
  • Proto-Oncogene Proteins
  • Tgfb1 protein, rat
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Tumor Necrosis Factor-alpha
  • Phosphatidylinositol 3-Kinases
  • Class Ib Phosphatidylinositol 3-Kinase
  • Pik3cg protein, rat
  • ErbB Receptors
  • Proto-Oncogene Proteins pp60(c-src)
  • Akt1 protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Casp3 protein, rat
  • Caspase 3
  • Caspases
  • ADAM Proteins
  • Metalloendopeptidases
  • ADAM17 Protein
  • Adam17 protein, rat