Clathrin-Mediated Internalization Is Essential for Sustained EGFR Signaling but Dispensable for Degradation

Abstract

Clathrin-mediated endocytosis (CME) is the major pathway of epidermal growth factor receptor (EGFR) internalization. It is commonly believed that CME mediates long-term attenuation of EGFR signaling by targeting the receptor for degradation. However, the EGFR can also be internalized through (a) clathrin-independent pathway(s), and it remains unclear why distinct mechanisms of internalization have evolved. Here, we report that EGFRs internalized via CME are not targeted for degradation, but instead are recycled to the cell surface. By contrast, clathrin-independent internalization preferentially commits the receptor to degradation. This finding has profound implications for signaling, as by skewing EGFR fate toward recycling rather than degradation, CME prolongs the duration of signaling. Our data show that CME determines the longevity of some EGFR-activated signaling pathways and that EGF-dependent biological responses, such as DNA synthesis, absolutely require CME. Thus, CME of the EGFR unexpectedly has a greater impact on receptor signaling than on receptor degradation.

β1 integrin controls EGFR signaling and tumorigenic properties of lung cancer cells

“…It is commonly believed that EGFR internalization through canonical pathways is essential for EGFR signaling (Sigismund et al, 2008;Sorkin and von Zastrow, 2009). Our data suggest that b1 integrin has a dual role in EGFR internalization and signaling.…”

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

“…dissociation of EGFR signal elements from caveolar domains), internalisation of raft-localised EGFR may thus be fundamental to signal transduction (Balbis and Posner, 2010). Data collectively support activity-dependent EGFR internalisation, with low-level agonism triggering clathrin-dependent/cholesterolindependent recycling to the cell membrane (Sigismund et al, 2005;Sigismund et al, 2008), whereas higher level agonism results in clathrin-independent/cholesteroldependent EGFR internalisation and trafficking to late endosomes (Lai et al, 1989).…”

MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701

“…On the cell surface, ligand/receptor complexes can be further recruited into clathrin‐coated pits (CCP) and can invaginate inward and pinch off vesicles into the cytoplasm. Clathrin‐mediated endocytosis (CME) mainly mediates the internalization of EGFR and HER2 and sustains the duration of EGFR/HER2 signaling by skewing the fate of internalized RTK toward recycling rather than degradation (Garay et al ., 2015; Sigismund et al ., 2008). After stimulation with EGF for 1 or 5 h, the interaction of clathrin with HER2 (Fig.…”

“…Concomitant to the activation of signaling pathway, ligand‐bound EGFR complex undergoes internalization through CME at low dose of EGF stimulation or clathrin‐independent endocytosis at high ligand concentrations (Sigismund et al ., 2008). As a scaffold protein, clathrin recruits the cargo protein EGFR and many additional cytosolic proteins, and assembles them into CCP.…”