Epidermal Growth Factor Behaves as a Partial Agonist in Hepatocytes: Effects on DNA Synthesis in Primary Culture and Competition with Transforming Growth Factor α

The structurally related mitogens epidermal growth factor (EGF) and transforming growth factor (alpha (TGFalpha) are believed to exert all their effects via the same receptor. We have compared the effects of EGF and TGFalpha, and examined their interaction, on DNA synthesis in cultured rat hepatocytes. The potency of the two agents was similar, or slightly higher for EGF, but TGFalpha stimulated the DNA synthesis more efficiently, producing at high levels a rate of S phase entry that clearly exceeded (two to threefold) that obtained with maximally effective concentrations of EGF. While the hepatocytes became more sensitive both to TGFalpha and EGF when addition of the agents was postponed until late in the prereplicative period, TGFalpha exhibited higher efficacy than EGF both at early and late exposure. When EGF and TGFalpha were added together at 24 h, TGFalpha further enhanced the DNA synthesis in the presence of a saturating concentration (5 nM) of EGF, while EGF dose-dependently reduced the DNA synthesis in the presence of a high concentration (10 nM) of TGFalpha. The results show a lower efficacy of EGF than of TGFalpha, and, therefore, EGF displays the characteristics of a partial agonist in its EGF receptor-mediated growth stimulation in hepatocytes.