Integral role of the EGF receptor in HGF-mediated hepatocyte proliferation.

Scheving LA, Stevenson MC, Taylormoore JM, Traxler P, Russell WE
Biochem Biophys Res Commun. 2002 290 (1): 197-203

PMID: 11779153 · DOI:10.1006/bbrc.2001.6157

Hepatocyte growth factor (HGF), insulin, and TGF-alpha stimulate DNA synthesis in cultured hepatocytes. Each ligand activates a distinct tyrosine kinase receptor, although receptor cross-talk modulates signaling. In rat hepatocytes, HGF can stimulate TGF-alpha production while TGF-alpha antibodies or antisense oligonucleotides suppress HGF-stimulated DNA synthesis. We report that the epidermal growth factor receptor (EGFR) kinase inhibitor PKI166 blocked both basal and ligand-induced tyrosine phosphorylation of the EGFR (IC(50) = 60 nM), but not of the insulin receptor or c-met. Pharmacologic inhibition of the EGFR kinase abolished the proliferative actions of HGF and EGF, but not insulin, whereas PI-3 kinase inhibition blocked both EGF and insulin actions. We conclude that in cultured hepatocytes (i) PI-3 kinase is required for EGF- and insulin-induced proliferation and (ii) EGFR mediates both the basal rate of DNA synthesis and that induced by EGF and HGF, but not insulin. The mitogenic effect of HGF may be secondary to increased synthesis or processing of EGFR ligands such as TGF-alpha.

(c)2002 Elsevier Science.

MeSH Terms (24)

Animals Blotting, Western Cells, Cultured Cell Survival DNA Dose-Response Relationship, Drug ErbB Receptors Hepatocyte Growth Factor Hepatocytes Inhibitory Concentration 50 Insulin Ligands Liver Male Mice Phosphatidylinositol 3-Kinases Phosphorylation Precipitin Tests Protein-Tyrosine Kinases Proto-Oncogene Proteins c-met Rats Rats, Sprague-Dawley Regeneration Tyrosine

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