INHIBITORY EFFECTS OF ALPHA-INTERFERON ON EPIDERMAL GROWTH FACTOR-MEDIATED RECEPTOR-DEPENDENT EVENTS

To examine the mechanisms by which alpha-interferon (IFN-alpha) inhibi ts growth factor-mediated proliferative responses, we examined specifi c ligand-activated, receptor-dependent events. In direct ligand bindin g studies, we showed that IFN-alpha treatment of cells leads to a redu ction in epidermal growth factor (EGF) receptor recognition at the cel l surface, coupled with an alteration in the binding characteristics o f EGF for its specific receptors. Specifically, the heterogeneity of b inding exhibited by EGF was affected, and there was loss of the high a ffinity binding component. EGF-induced autophosphorylation of the EGF receptor was unaffected by IFN treatment. The trafficking of EGF-recep tor complexes was followed using three-dimensional confocal microscopy . Confocal imaging revealed that the rapid internalization of EGF-rece ptor complexes was significantly reduced when cells were exposed to IF N. Accompanying the IFN-induced changes in receptor binding characteri stics, we identified an alteration in EGF receptor gene expression; wh en cells were treated with IFN-alpha, elevated RNA levels specific for the EGF receptor were detected. Overall, IFN-alpha treatment inhibite d EGF-induced cell proliferation. Our results imply that EGF-bound rec eptors that are unable to internalize are not fully competent with res pect to signal regulation of both gene expression and growth. The data suggest that the signaling potential of the bound growth factor-recep tor complex is apparently increased by an unspecified, species-specifi c, high affinity binding component. We propose that IFN treatment of r esponsive cells prevents the interaction of EGF-bound receptor with th is component.