Cell Surface Receptors for Signal Transduction and Ligand Transport: A Design Principles Study

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Abstract
Receptors constitute the interface of cells to their external environment. These molecules bind specific ligands involved in multiple processes, such as signal transduction and nutrient transport. Although a variety of cell surface receptors undergo endocytosis, the systems-level design principles that govern the evolution of receptor trafficking dynamics are far from fully understood. We have constructed a generalized mathematical model of receptor–ligand binding and internalization to understand how receptor internalization dynamics encodes receptor function and regulation. A given signaling or transport receptor system represents a particular implementation of this module with a specific set of kinetic parameters. Parametric analysis of the response of receptor systems to ligand inputs reveals that receptor systems can be characterized as being: i) avidity-controlled where the response control depends primarily on the extracellular ligand capture efficiency, ii) consumption-controlled where the ability to internalize surface-bound ligand is the primary control parameter, and iii) dual-sensitivity where both the avidity and consumption parameters are important. We show that the transferrin and low-density lipoprotein receptors are avidity-controlled, the vitellogenin receptor is consumption-controlled, and the epidermal growth factor receptor is a dual-sensitivity receptor. Significantly, we show that ligand-induced endocytosis is a mechanism to enhance the accuracy of signaling receptors rather than merely serving to attenuate signaling. Our analysis reveals that the location of a receptor system in the avidity-consumption parameter space can be used to understand both its function and its regulation. Cells interact with their environment using molecules on their surface known as receptors. Receptors bind specific companion molecules known as ligands, which either carry information about the outside environment or are critical cell nutrients. Signaling receptors bind the former ligand type and convert information about the outside environment to a cell response such as migration or growth. Transport receptors bind the latter class of ligand and deliver them to the cell interior. A variety of receptors are internalized into the cell through a process known as endocytosis. Receptors display a wide range of endocytosis patterns, but the functional motivation behind the observed differences is not well understood. We have constructed a generalized model to understand how receptor endocytosis and other receptor–ligand properties affect the function of receptor systems. We find that the efficiency and robustness of receptor systems are encoded by two fundamental parameters: i) the avidity which quantifies the ability of a receptor system to capture ligand, and ii) the consumption which quantifies the ability to internalize bound ligand. By examining a number of receptor systems, we demonstrate that the internalization dynamics of receptor systems can be explained by examining its effect on the avidity and consumption parameters.