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

Miguel M Murillo1, Gaelle del Castillo, Aránzazu Sánchez

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

Oncogene
|April 28, 2005
PubMed

Insights

Transforming growth factor beta1 (TGF-beta1) impairs apoptosis in hepatocytes by activating epidermal growth factor receptor (EGFR) signaling. This EGFR activation is crucial for cell survival but not for epithelial-mesenchymal transition (EMT).

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • Transforming growth factor beta1 (TGF-beta1) has dual roles in cancer, acting as a tumor suppressor early on but potentially promoting oncogenesis in advanced stages.
  • TGF-beta1 can induce both pro- and anti-apoptotic signals in mammalian cells, with its anti-apoptotic mechanisms being less understood.
  • Hepatocytes are key cells in liver function and are susceptible to TGF-beta1 signaling pathways.

Purpose of the Study:

  • To elucidate the anti-apoptotic mechanism of TGF-beta1 in foetal rat hepatocytes.
  • To investigate the role of epidermal growth factor receptor (EGFR) and c-Src in TGF-beta1-mediated cell survival.
  • To determine whether EGFR signaling is essential for TGF-beta1-induced epithelial-mesenchymal transition (EMT).

Main Methods:

  • Investigated TGF-beta1 signaling pathways in foetal rat hepatocytes.
  • Utilized inhibitors to block EGFR and TACE (ADAM17) signaling.
  • Assessed Akt activation and phosphorylation status of c-Src.
  • Monitored apoptotic responses and EMT induction.

Main Results:

  • TGF-beta1 activates EGFR and phosphorylates c-Src, which is required for Akt activation and cell survival.
  • Blocking EGFR signaling potentiates the apoptotic effect of TGF-beta1.
  • TGF-beta1 rapidly activates TACE/ADAM17, leading to shedding of EGF-like ligands and subsequent EGF signaling activation.
  • EGFR activation is essential for inhibiting apoptosis but dispensable for TGF-beta1-induced EMT.

Conclusions:

  • TGF-beta1 promotes hepatocyte survival by activating a signaling cascade involving TACE/ADAM17, EGFR, c-Src, and Akt.
  • EGFR-mediated signaling is a critical anti-apoptotic mechanism of TGF-beta1 in hepatocytes.
  • The EGFR pathway is separable from the EMT pathway induced by TGF-beta1 in these cells.

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