RESPONSE TO TRANSFORMING-GROWTH-FACTOR OR (TGF-ALPHA) AND EPIDERMAL GROWTH-FACTOR (EGF) IN HEPATOCYTES - LOWER EGF RECEPTOR AFFINITY OF TGF-ALPHA IS ASSOCIATED WITH MORE SUSTAINED ACTIVATION OF P42 P44 MITOGEN-ACTIVATED PROTEIN-KINASE AND GREATER EFFICACY IN STIMULATION OF DNA-SYNTHESIS/

The epidermal growth factor (EGF) receptor mediates the effects of bot h EGF and transforming growth factor alpha (TGF alpha). Recent data su ggested that EGF acts as a partial agonist/antagonist in hepatocytes, TGF alpha exerting a larger maximal stimulation of DNA synthesis than EGF. To further study the mechanisms involved in mediating the differe nt effects of EGF and TGF alpha, we have examined receptor binding of the two growth factors and their action on the p42/p44 mitogen-activat ed protein (MAP) kinase activity in hepatocytes. Single-ligand concent ration curves and competition experiments showed that the binding affi nity to a common population of surface binding sites was about 20-fold lower for TGF alpha than for EGF. MAP kinase activity responded to EG F and TGF alpha with different kinetics. While the two agents produced almost identical acute (5 min) stimulation (peak about fivefold), TGF alpha produced a more sustained MAP kinase activity than EGF. The dif ference between EGF and TGF alpha was still detectable 24 h after grow th Factor addition. The results show that in hepatocytes a lower recep tor affinity of TGF alpha, as compared to EGF, is associated with a mo re sustained activation of the MAP kinase and a greater efficacy in th e stimulation of DNA synthesis. This suggests that differential intera ction of these two agents with the EGF receptor results in differences in the downstream events elicited at a given level of receptor occupa ncy. The data also are compatible with a role of a prolonged MAP kinas e activity in the mitogenic effects of EGF and TGF alpha. (C) 1998 Wil ey-Liss, Inc.