Integral role of the EGF receptor in HGF-mediated hepatocyte proliferation.
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.
Scheving
Lawrence A
LA
Department of Pediatrics, Medical Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Stevenson
Mary C
MC
Taylormoore
Jonathan M
JM
Traxler
Peter
P
Russell
William E
WE
D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000502:physiology*; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007328:Insulin / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration; D014443:Tyrosine / Q000378:metabolism
D007328:Insulin; D008024:Ligands; D014443:Tyrosine; D017228:Hepatocyte Growth Factor; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met