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

Document Type

Journal Article

Publication Date

1-1-2002

Journal

Biochemical and Biophysical Research Communications

Volume

290

Issue

1

DOI

10.1006/bbrc.2001.6157

Keywords

c-met; ErbB; Hepatocyte; Hepatocyte growth factor; Liver; Liver regeneration; PI-3 kinase; PKI166; Transforming growth factor-α

Abstract

Hepatocyte growth factor (HGF), insulin, and TGF-α 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-α production while TGF-α 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 (IC50 = 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-α. © 2002 Elsevier Science.

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