Cell surface receptors for signal transduction and ligand transport: a design principles study.
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.
Shankaran
Harish
H
Systems Biology Program, Pacific Northwest National Laboratory, Richland, Washington, United States of America.
Resat
Haluk
H
Wiley
H Steven
HS
D000595:Amino Acid Sequence; D001693:Biological Transport, Active / Q000502:physiology*; D003198:Computer Simulation; D005786:Gene Expression Regulation / Q000502:physiology; D008024:Ligands; D008954:Models, Biological; D008969:Molecular Sequence Data; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D008024:Ligands; D011956:Receptors, Cell Surface