EGFR is dispensable for c-Met-mediated proliferation and survival activities in mouse adult liver oval cells

• Published in: Cellular signalling Vol. 24; no. 2; pp. 505 - 513
• Main Authors: Martínez-Palacián, A., del Castillo, G., Herrera, B., Fernández, M., Roncero, C., Fabregat, I., Sánchez, A.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.02.2012
• Subjects: Animals; Apoptosis - drug effects; c-Met; Cell Proliferation - drug effects; Cell Survival - drug effects; EGFR; Enzyme Inhibitors - pharmacology; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Deletion; Gene Expression; Heparin-binding EGF-like Growth Factor; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - metabolism; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Liver - cytology; Liver - drug effects; Liver - metabolism; Mice; Mice, Knockout; Oval cell; Phosphorylation - drug effects; Proliferation; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-met - deficiency; Proto-Oncogene Proteins c-met - genetics; Quinazolines - pharmacology; Signal Transduction - genetics; Signalling; Stem Cells - cytology; Stem Cells - drug effects; Stem Cells - metabolism; Survival; Transforming Growth Factor alpha - genetics; Transforming Growth Factor alpha - metabolism; Tyrphostins - pharmacology; AKT/PKB; EGF; HB-EGF; HGF; PLC-γ; STAT3; RTK; HCC; Proliferation; MAPK; Signalling; Survival; 2-AAF/PH; EGFR; DMEM; Oval cell; PI3K; FBS; ERK 1/2; TGF-β; c-Met; RLEC
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2011.09.031

Liver progenitor cells rise as potential critical players in hepatic regeneration but also carcinogenesis. It is therefore mandatory to define the signals controlling their activation and expansion. Recently, by using a novel in vitro model of oval cell lines expressing a mutant tyrosine kinase-inactive form of c-Met we demonstrated that autocrine c-Met signalling plays an essential role in promoting oval cell survival. Here, we investigated the significance of the epidermal growth factor receptor (EGFR) signalling in oval cell proliferation and survival, as well as a potential functional crosstalk between the c-Met and the EGFR pathways. We found an autocrine activation of the EGFR-triggered pathway in Metflx/flx and Met−/− oval cells as judged by constitutive expression of the EGFR ligands, transforming growth factor-alpha (TGF-α) and heparin-binding EGF like growth factor (HB-EGF), and activation of EGFR. On the other hand, treatment with AG1478, a specific inhibitor of EGFR, effectively blocked endogenous and EGF-induced proliferation, while increased serum withdrawal and transforming growth factor-beta (TGF-β)-induced apoptosis. These results suggest that constitutively activated EGFR might promote oval cell proliferation and survival. We found that hepatocyte growth factor (HGF) does not transactivate EGFR nor EGF transactivates c-Met. Furthermore, treatment with AG1478 or EGFR gene silencing did not interfere with HGF-mediated activation of target signals, such as protein kinase B (AKT/PKB), and extracellular signal-regulated kinases 1/2 (ERK 1/2), nor did it have any effect on HGF-induced proliferative and antiapoptotic activities in Metflx/flx cells, showing that HGF does not require EGFR activation to mediate such responses. EGF induced proliferation and survival equally in Metflx/flx and Met−/− oval cells, proving that EGFR signalling does not depend on c-Met tyrosine kinase activity. Together, our results provide strong evidence that in normal, untransformed oval cells, c-Met and EGFR represent critical molecular players to control proliferation and survival that function independent of one another. [Display omitted] ► Constituvely activated EGFR promotes mouse oval cell proliferation and survival. ► EGFR signalling does not depend on c-Met tyrosine kinase activity. ► c-Met signalling does not require EGFR activation to mediate proliferation and survival.