WT EGFR and the oncogenic mutant EGFR (L858R) employ distinct mechanisms for export from the endoplasmic reticulum, a process critical for their activation.

The epidermal growth factor receptor (EGFR) is critical for cell differentiation, growth, proliferation, and migration. To function, newly synthesized EGFR must be transported from the endoplasmic reticulum (ER) to the cell surface, yet the specific molecular mechanisms mediating this trafficking are not fully understood. We found that the ER export of EGFR is facilitated by a conserved polyarginine (polyR) motif located in the juxtamembrane region of the EGFR cytosolic domain. Mechanistic studies show that this motif interacts directly with the D198 residue on SAR1A, regulating the incorporation of EGFR into COPII vesicles for delivery to the Golgi. A depletion of the polyR motif impairs epidermal growth factor-induced EGFR activation. Interestingly, we found that the ER export of the oncogenic mutant EGFR (L858R) is critical for its activation but does not depend on the D198 residue of SAR1A or the polyR motif of EGFR. Our study elucidates a mechanism regulating ER export of WT EGFR and indicates that the ER exports of the EGFR mutant and WT EGFR are mediated by distinct molecular machineries, essential for their activation.