Incubation of fetal rat hepatocytes (FRH) with transforming growth factor β1 (TGF-β1) resulted in growth arrest and a biphasic effect on epidermal growth factor (EGF) receptor. After 2 h of exposure, EGF receptor (EGFR) was reduced by 43%. From 6 to 24 h, TGF-β1 exposure resulted in progressive increase in EGFR up to 74% over control. The increased binding was due to increase in high affinity EGF binding sites. FRH grown in medium containing EGF exhibited down-regulated EGFR with loss of high affinity EGF binding sites. With TGF-β1 exposure, high affinity EGFR was not down-regulated by EGF. Since downregulation of EGFR involves internalization, the kinetics of EGF receptor-mediated endocytosis were examined. In TGF-β1 exposed FRH, EGF endocytosis was inhibited, with a reduction in the first order rate constant for the process from 0.078 to 0.043 min−1. Despite inhibition of growth, receptor downregulation, and EGF endocytosis after TGF-β1 exposure, EGF-induced receptor autophosphorylation was preserved as demonstrated by [32P]phosphatelabeling of immunoprecipitated EGFR. These observations provide direct evidence that TGF-β1 regulates growth of fetal cells. Further, they suggest that TGF-β1 regulates endocytosis of EGF and possibly of other ligands.
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