New trend in ligand-induced EGFR trafficking: A dual-mode clathrin-mediated endocytosis model

Accumulated evidence has established that ligand-bound activated epidermal growth factor receptor (EGFR) dimers rapidly undergo endocytosis via clathrin-mediated endocytosis (CME) and clathrin-independent endocytosis (CIE), and are then sorted to recycling and degradation pathways, respectively. On the other hand, cellular stress triggers the non-canonical CME of ligand-free EGFR monomers via the phosphorylation of serine/threonine residues by p38. By integrating these findings on ligand- and stress-induced events, we herein propose a dual-mode CME model in which physiological concentrations of EGF trigger the non-canonical CME of ligand-free monomeric EGFR in parallel with the canonical CME of ligand-bound activated dimeric EGFR. Our established understanding of the EGFR endosomal trafficking pathway needs to be reconsidered with the application of this model. Significance: In this review, we propose a dual-mode clathrin-mediated endocytosis (CME) model, in which physiological concentrations of EGF trigger the p38-mediated non-canonical CME of ligand-free monomeric EGFR in parallel with the canonical CME of ligand-bound activated dimeric EGFR. It has been 60 years since the discovery of EGF this year, and it has become necessary to reconsider the mechanism of EGFR activation and to analyze its new physiological functions. By adapting a new trafficking model, it is expected to be applied to anti-EGFR therapy that has been developed in this century.