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- Title
Cell Surface Receptors for Signal Transduction and Ligand Transport: A Design Principles Study.
- Authors
Shankaran, Harish; Resat, Haluk; Wiley, H. Steven
- 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.
- Subjects
CELL receptors; CELLULAR signal transduction; LIGANDS (Biochemistry); CELLULAR control mechanisms; TRANSFERRIN; LOW density lipoproteins; EPIDERMAL growth factor; ENDOCYTOSIS
- Publication
PLoS Computational Biology, 2007, Vol 3, Issue 6, pe101
- ISSN
1553-734X
- Publication type
Article
- DOI
10.1371/journal.pcbi.0030101