Controlling receptor/ligand trafficking: effects of cellular and molecular properties on endosomal sorting.

Receptor-mediated endocytosis is the process by which cells internalize ligands that have specifically interacted with cell surface receptors. Within intracellular endosomal compartments, receptor/ligand complexes can be targeted to lysosomes for degradation, recycled back to the plasma membrane, or sorted separately to these destinations. We have developed a mechanistic mathematical model that can account for the spectrum of experimentally observed endosomal sorting outcomes. The central hypothesis of this model is that receptors may be selectively retained by putative endosomal retention components and that this process may be modulated by receptor occupancy. This hypothesis is supported by the recent discovery of an endosomal retention component involved in targeting epidermal growth factor receptors to lysosomes. In this paper, we use the model to predict how changes in key cellular and molecular parameters alter sorting outcomes. This analysis provides guidance for rationally modulating the sorting process in a variety of biomedical applications, either by the manipulation of cellular parameters or the design of ligand properties.