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 (HRGbeta1) on cultured rat hepatocytes and an inhibitory influence of insulin on HRGbeta1 binding. HRGbeta1 (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 HRGbeta1 bound to a single population of 19,600 +/- 1,800 binding sites/cell with a Kd of 360 +/- 22 pM. Cross-linking experiments showed binding of HRGbeta1 to ErbB3 but not ErbB2 or ErbB4. HRGbeta1 induced phosphorylation of ErbB3 and decreased ErbB3 protein levels, suggesting that HRGbeta1 activates signaling through the ErbB3 receptor and influences receptor trafficking. Following plating, [125I]HRGbeta1 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 Kd 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.