ARF promotes the degradation of the Epidermal Growth Factor Receptor by the lysosome

Epidermal Growth Factor Receptor (EGFR) signaling regulates multiple cellular processes including proliferation, survival and apoptosis, and is attenuated by lysosomal receptor degradation. EGFR is a potent oncogene and activating mutations of EGFR are critical determinants of oncogenic transformation as well as therapeutic targets in non-small cell lung cancer. We previously demonstrated that wild type and mutant EGFRs repress the expression of the ARF tumor suppressor to promote the survival of lung tumor cells. In this study, using transient transfection systems in CHO EGFR-null cells as well as in various lung tumor cell lines carrying wild type or activated mutant EGFR, we show that ARF downregulates the expression of EGFR protein by reducing its half life. In wild type EGFR cells, ARF promotes canonical lysosomal degradation of the receptor through enhanced phosphorylation of EGFR-Y1045 and Cbl-Y731. In contrast, in mutant EGFR cells, ARF induces EGFR degradation by activating a non-canonical AKT-dependent lysosomal pathway. Taken together, these results uncover a feedback loop by which ARF may control EGFR turnover to restrain oncogenic signaling. They also highlight distinct degradation promoting pathways between wild type and mutant EGFRs in response to ARF.