(497a) The Membrane Environment Can Promote or Suppress Bistability in Cell Signaling Networks

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. In an effort to gain insight into the role of the membrane in signal transduction, we use computational methods that explicitly account for stochastic fluctuations to study two topologically different signaling pathways that exhibit bistability: the distributive enzymatic modification of a protein at multiple sites and the positive feedback-mediated activation of a protein. The choice of these networks is motivated by membrane-proximal signaling events in T cells, which act as cellular detectors of pathogens and orchestrate adaptive immunity. In both networks we find that confining proteins to a membrane-like environment can markedly alter the emergent dynamics. The signaling motifs are influenced by membrane features including reduced protein mobility, increased protein concentration, and altered spatiotemporal correlations between pairs of enzyme and substrate molecules. For the distributive protein modification network, increased protein concentration promotes bistability, while lower mobility and membrane-enhanced spatiotemporal correlations suppress bistability. For the positive feedback-mediated activation network, confinement to a membrane environment enhances protein activation, and spatially localized concentration fluctuations can result in the formation and growth of regions with high concentrations of active proteins. By comparing the behavior of the two networks, it is seen that the influence of the membrane on signaling can be qualitatively different for signaling motifs with different network topologies.