Quantitative modeling of EGF receptor ligand discrimination via internalization proofreading

Abstract

The epidermal growth factor receptor (EGFR) is a central regulator of cell physiology that is stimulated by multiple distinct ligands. Although ligands bind to EGFR while the receptor is exposed on the plasma membrane, EGFR incorporation into endosomes following receptor internalization is an important aspect of EGFR signaling, with EGFR internalization behavior dependent upon the type of ligand bound. We develop quantitative modeling for EGFR recruitment to and internalization from clathrin domains, focusing on how internalization competes with ligand unbinding from EGFR. We develop two model versions: a kinetic model with EGFR behavior described as transitions between discrete states and a spatial model with EGFR diffusion to circular clathrin domains. We find that a combination of spatial and kinetic proofreading leads to enhanced EGFR internalization ratios in comparison to unbinding differences between ligand types. Various stages of the EGFR internalization process, including recruitment to and internalization from clathrin domains, modulate the internalization differences between receptors bound to different ligands. Our results indicate that following ligand binding, EGFR may encounter multiple clathrin domains before successful recruitment and internalization. The quantitative modeling we have developed describes competition between EGFR internalization and ligand unbinding and the resulting proofreading.

Targeted Inhibitors of EGFR: Structure, Biology, Biomarkers, and Clinical Applications

“…HB-EGF and BTC also behave the same way. On the other hand, when subjected to the low pH of endosomes, TGF-α, EPR, and AR quickly separate from the receptor, which leads to de-ubiquitination of the receptor and its subsequent recycling to the plasma membrane ( Figure 2 b) [ 22 ].…”