EGF receptor trafficking: consequences for signaling and cancer

Abstract

The ligand-stimulated epidermal growth factor receptor (EGFR) has been extensively studied in the analysis of molecular mechanisms regulating endocytic traffic and the role of that traffic in signal transduction. Although such studies have largely focused on mitogenic signaling and dysregulated traffic in tumorigenesis, there is growing interest in the potential role of EGFR traffic in cell survival and the consequent response to cancer therapy. Here we review recent advances in our understanding of molecular mechanisms regulating ligand-stimulated EGFR activation, internalization, and post-endocytic sorting. The role of EGFR overexpression/mutation and new modulators of EGFR traffic in cancer and the response to cancer therapeutics are also discussed. Finally, we speculate on the relationship between EGFR traffic and cell survival.

Keywords: antineoplastic therapy; endocytosis; epidermal growth factor receptor (EGFR); oncogenes; trafficking; ubiquitination.

Figure 1

EGF receptor (EGFR) trafficking pathways and associated outcomes. Activated cell-surface EGFRs are internalized and sorted at the early endosome. The fate of the receptor has important consequences for biological cell outputs, with the recycling pathway favoring cell proliferation (depicted green), although the degradative pathway via ESCRT (endosomal sorting complex required for transport)-mediated sorting within multivesicular bodies (MVBs)/lysosomes correlates with normal cellular homeostasis (depicted in blue). Atypical trafficking pathways to the nucleus and mitochondria have also been described and are proposed to favor survival, but the transport mechanisms are not well established. Exposure to stress leads to the removal of the receptor from the cell surface, and this has been proposed to potentiate cell death (depicted in red). Conversely, stress-activated receptor might also be recycled, thereby promoting cell survival and/or proliferation.

Figure 2

Effectors of ligand-stimulated EGF receptor (EGFR) trafficking pathways. Ligand binding mediates dimerization of EGFRs at the cell-surface, resulting in autophosphorylation, activation, and internalization. Under normal physiological conditions clathrin-mediated endocytosis (CME) is believed to be the major route of internalization, but clathrin-independent mechanisms have also been reported under conditions of potent activation [high concentrations of EGF or heparin-binding EGF-like growth factor (HB-EGF)/betacellulin (BTC)]. Internalized receptors are sorted at the endosome onto the recycling or degradative pathways, with ubiquitination targeting receptors for lysosomal degradation. Alternative fates reported for endocytosed EGFR, to the nucleus and the mitochondria, are also depicted.