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Inhibitory Effects of -Interferon on Epidermal Growth Factor-mediated Receptor-dependent Events¹

Department of Microbiology, University of Toronto, Ontario M5S 1A8, Canada [E. N. F., J. G.], and Eye Research Institute of Canada, Toronto Hospital, Toronto, Ontario M5T 2S8, Canada [J. T., J. K. S.]

To examine the mechanisms by which -interferon (IFN-) inhibits growth factor-mediated proliferative responses, we examined specific ligand-activated, receptor-dependent events. In direct ligand binding studies, we showed that IFN- treatment of cells leads to a reduction in epidermal growth factor (EGF) receptor recognition at the cell surface, coupled with an alteration in the binding characteristics of EGF for its specific receptors. Specifically, the heterogeneity of binding exhibited by EGF was affected, and there was loss of the high affinity binding component. EGF-induced autophosphorylation of the EGF receptor was unaffected by IFN treatment. The trafficking of EGF-receptor complexes was followed using three-dimensional confocal microscopy. Confocal imaging revealed that the rapid internalization of EGF-receptor complexes was significantly reduced when cells were exposed to IFN. Accompanying the IFN-induced changes in receptor binding characteristics, we identified an alteration in EGF receptor gene expression; when cells were treated with IFN-, elevated RNA levels specific for the EGF receptor were detected. Overall, IFN- treatment inhibited EGF-induced cell proliferation. Our results imply that EGF-bound receptors that are unable to internalize are not fully competent with respect to signal regulation of both gene expression and growth. The data suggest that the signaling potential of the bound growth factor-receptor complex is apparently increased by an unspecified, species-specific, high affinity binding component. We propose that IFN treatment of responsive cells prevents the interaction of EGF-bound receptor with this component.

¹ These studies were supported by grants from the Medical Research Council of Canada and the Leukemia Research Fund, Canada to E. N. F., who is a recipient of an Ontario Ministry of Health Career Scientist Award. J. G. is a recipient of a Medical Research Council of Canada Studentship Award.

² To whom requests for reprints should be addressed, at Department of Microbiology, University of Toronto, FitzGerald Building, Room 73, 150 College Street, Toronto, Ontario M5S 1A8, Canada.

Received 3/31/93. Accepted 8/24/93.

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