Insulin regulates heregulin binding and ErbB3 expression in rat hepatocytes

The heregulin-ErbB system of ligands and receptors are newly described epidermal growth factor (EGF) and EGF receptor-related proteins that regulate growth, differentiation, and gene expression in numerous cell types, This study describes a receptor for heregulin beta-1 (HRG beta 1) on cultured rat hepatocytes and an inhibitory influence of insulin on HRG beta 1 binding. HRG beta 1 (30 nM) stimulated DNA synthesis 2-fold and was not augmented by insulin as is the case with EGF receptor ligands, A labeled peptide corresponding to the EGF domain of HRG beta 1 bound to a single population of 19,600 +/- 1,800 binding sites/cell with a K-d of 360 +/- 22 PM. Cross-linking experiments showed binding of HRG beta 1 to ErbB3 but not ErbB2 or ErbB4. HRG beta 1 induced phosphorylation of ErbB3 and decreased ErbB3 protein levels, suggesting that HRG beta 1 activates signaling through the ErbB3 receptor and influences receptor trafficking, Following plating, [I-125]HRG beta 1 binding and ErbB3 protein levels increased 8- and 3-fold, respectively, over the first 12 h in culture, These increases required de novo protein synthesis and were inhibited with 50 nM insulin resulting in 3500 binding sites with a K-d of 265 PM. These data suggest that the heregulin-ErbB system can regulate liver functions and may be linked to the metabolic and nutritional status of the animal.