Mathematical model to uncover the role of receptor ubiquitination in dose dependent EGFR trafficking

Abstract

Precise regulation of epidermal growth factor (EGF) receptor (EGFR) activated sig- naling pathways is essential in cell fate decisions. Recent experiments observe change in EGFR internalization route from clathrin mediated (CME) to clathrin independent endocytosis (CIE) with rising EGF concentration, which alters the re- ceptor localization and modulates associated signaling. The regulatory mechanism controlling the shift in endocytosis remains unknown. In this study, we present a novel mathematical model that describes the dose dependent regulation of EGFR trafficking through receptor ubiquitination. We assume that the receptor-ubiquitin binding reaction follows a sigmoidal behavior as function of EGF dose, which is responsible for a switch-like activation of CIE. Using the model we illustrate the change in the EGFR localization as function of EGF dose and route of endocytosis. The model is further utilized to explore the effect of defective ubiquitination on the EGFR trafficking. At high EGF concentrations, model results quantitatively cap- ture experimentally observed changes in receptor localization caused by selective inhibition of CME or CIE. These results elucidate the ubiquitin guided sorting of EGFR during internalization. In agreement with experiments for low EGF dose, our model predicts that CIE remains largely inactive causing prolonged EGFR transport and decreased ligand degradation and strengthens our assumption of ultrasensitive receptor-ubiquitin binding. Our model accurately captures the experimentally ob- served deregulation in EGFR trafficking resulting from mutation induced defective ubiquitination and demonstrates the importance of receptor ubiquitination. The predictions obtained clearly indicate that our model successfully captures the un- derlying dynamics of ubiquitin regulated EGFR sorting and trafficking and provides valuable insights into the experimental observations. The model may thus provide a framework to study the dose-dependent attenuation of EGFR activated signaling pathways.