Spatial Regulation and the Rate of Signal Transduction Activation

Open Access
Publisher Website
Google Scholar
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. Cells coordinate activities with their neighboring cells by releasing and responding to chemical signals, such as hormones and growth factors. These extracellular signals often are transmitted to the intracellular regulatory machinery through associations of freely diffusing cell surface receptors whose random movement (Brownian motion) results from collisions with thermally agitated lipid molecules. Receptors on the cell surface signaling proteins are co-localized transiently on membrane patches, but how such spatial restriction contributes to signal transduction is unclear. Batada and colleagues set out to determine which is more likely to be the biophysical function of co-localization: increasing coupling efficiency of slowly diffusing membrane proteins or reducing cross talk along pathways with common intermediates. Using a mathematical model to describe Brownian motion–based association of receptors on a 2-D spherical surface, the authors show that the rate of signal transduction initiation is extremely fast compared with the cytoplasmic signal relay events, even when the number of receptors is low. Because enhancement of a process that is already fast is not beneficial to the cell, minimization of detrimental cross talk among pathways is the most likely reason why cells need to co-localize plasma membrane signaling proteins.