Epidermal growth factor (EGF) is important in the regulation of proliferation in hepatocytes. The receptor for EGF belongs to the receptor tyrosine kinase family, and activates different intracellular signaling proteins by tyrosine phosphorylation. The EGF
receptor can activate several signaling pathways, and their role in growth regulation has been extensively studied. But the molecular mechanisms that modulate the different signaling pathways are not clear. This study focuses on the regulation of STAT signaling
by the EGF receptor, and particularly the involvement of Stat5b in growth control in hepatocytes. We found that the EGF receptor activated Stat5b by phosphorylation on residue Tyr-699 and other sites, but it was the Tyr-699 phosphorylation that correlated
with the DNA binding activity. This activation was dependent of the non-receptor tyrosine kinsase Src, but Stat5b activation by other growth factors was not. Furthermore, the EGF induced Stat5b activation was downregulated in mitogenically responsive hepatocytes, and provides more evidence against Stat5b involvement in mitogenic signaling from the EGF receptor in hepatocytes. In addition we examined the mechanism behind the comitogenic effect of G protein coupled receptor (GPCR) ligands on EGF induced growth. Vasopressin, norephenephrine, angiotensin II, and prostaglandin F2á are such ligands, and they acts as comitogens in hepatocytes. We found that in hepatocytes GPCR ligands did not transactivate the EGF receptor, but rather regulated the transcription of early response genes c-Myc and ATF3.