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

## TL;DR

The study reveals that wild-type and mutant EGFR use different mechanisms to leave the endoplasmic reticulum, which is crucial for their activation.

## Contribution

The research identifies a conserved polyR motif in EGFR that interacts with SAR1A for ER export, and shows that the oncogenic L858R mutant uses a different mechanism.

## Key findings

- The polyR motif in EGFR interacts with SAR1A's D198 residue to facilitate ER export.
- EGFR activation is impaired when the polyR motif is depleted.
- The L858R mutant EGFR's ER export does not rely on the polyR motif or SAR1A's D198 residue.

## Abstract

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 EGFRL858R mutant and WT EGFR are mediated by distinct molecular machineries, essential for their activation.