Signaling outcomes driven by critical fluctuations

Many signaling cascades take place in the dynamic yet structured plasma membrane. Recent evidence suggests that proximity to thermodynamic phase separation through a critical point may underlie some of these membrane domains. These liquid domains, sometimes termed rafts, have been implicated in the functioning of various signaling cascades, influencing function by sorting the interactions between components. Here we present a model and Monte-Carlo simulation framework for proteins coupled to their surrounding lipid membrane using a modified 2D Ising model. In addition to simulations, we introduce schematic diagrams that predict the effects of reduced temperature on the outcomes of signaling cascades in which components have domain preference. Our model naturally explains how changes in the domain size, arising from perturbations to membrane criticality can lead to changes in the rates of interactions among signaling components, eventually leading to altered signaling outcomes. We predict that near the critical point many different cascades will have their outcomes depend sensitively on perturbations that influence the critical behavior.