Abstract
Of the many important signaling events that take place on the surface of a mammalian cell, activation of signal transduction pathways via interactions of cell surface receptors is one of the most important. Evidence suggests that cell surface proteins are not as freely diffusible as implied by the classic fluid mosaic model and that their confinement to membrane domains is regulated. It is unknown whether these dynamic localization mechanisms function to enhance signal transduction activation rate or to minimize cross talk among pathways that share common intermediates. To determine which of these two possibilities is more likely, we derive an explicit equation for the rate at which cell surface membrane proteins interact based on a Brownian motion model in the presence of endocytosis and exocytosis. We find that in the absence of any diffusion constraints, cell surface protein interaction rate is extremely high relative to cytoplasmic protein interaction rate even in a large mammalian cell with a receptor abundance of a mere two hundred molecules. Since a larger number of downstream signaling events needs to take place, each occurring at a much slower rate than the initial activation via association of cell surface proteins, we conclude that the role of co-localization is most likely that of cross-talk reduction rather than coupling efficiency enhancement.
Highlights
The surface of a eukaryotic cell is embedded with a diversity of receptors that serve as the primary conduits for transmission of environmental information into the cell’s signaling network
Inspired by the recent experimental findings that maintenance of dynamic spatial inhomogeneity of membrane proteins is achieved by transient confinement in high viscosity membrane patches such as lipid rafts [13] and caveolae [14,42], we set out to determine which of the two possible alternatives, increasing response speed or achieving pathway insulation, is the more likely biophysical role of these diffusion restricting structures
Given that diffusion coefficients of membrane receptors are hundreds of times smaller than the diffusion coefficient of sized proteins in the cytoplasm, we initially hypothesized that membrane domains function to increase response rate by enhancing the coupling efficiency of slowly diffusing membrane proteins
Summary
The surface of a eukaryotic cell is embedded with a diversity of receptors that serve as the primary conduits for transmission of environmental information into the cell’s signaling network. In mammalian cells, a common mode of activation of intracellular pathways in response to extracellular peptide hormones is through dimerization of ligandoccupied receptor monomers such as transforming growth factor receptors receptors, epidermal growth factor receptors, and members of the receptor tyrosine kinase family [4]. Dimerization may aid signaling via presentation of more exposed intracellular signaling domains, creating larger and more diverse interfaces for recognition of cytosolic transducer and linker molecules [5]. Another advantage may include the ability to generate diverse combinatorial responses to different inputs [6]. Reuse of membrane proteins in different pathways can result in nonspecific activation or cross talk
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