(332d) Spatial Confinement and Protein Diffusion Modulate Stochastic Switching in Bistable Signaling Networks with Positive Feedback

Many key biochemical reactions that mediate signal transduction in cells occur at the cell membrane, yet how the two-dimensional membrane environment influences the collective behavior of signaling networks is poorly understood. To gain insight into the role of the membrane in signal transduction, we use computational methods that explicitly account for stochastic fluctuations to study signaling networks in which a protein is activated by means of a positive feedback loop. Positive feedback is a common motif in cell signaling networks that can allow cells to make binary decisions in response to graded stimuli. This study is motivated by activation of the small GTPase Ras, which is central to T cell activation in response to antigen. Focusing on a bistable regime, we investigate the effects of spatial confinement and protein diffusion on stochastic switching between inactive and active states. Independently varying the geometry of the system and protein diffusion coefficients allows tuning of the in silico system from one that mimics the cytoplasmic environment to one that mimics the membrane environment. We find that confining the system to a membrane-like environment markedly alters the emergent behavior and that spatially localized concentration fluctuations can result in the formation and growth of regions with high concentrations of active proteins. The process by which small clusters of active proteins nucleate the growth of active regions is the primary mechanism of stochastic switching from inactive to active states and is promoted by slow diffusion. We use analytical methods to investigate the chemical master equation governing the system dynamics to gain additional insight into the likelihood of stochastic switching in the bistable regime.