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. We study models of two topologically different signaling pathways that exhibit bistability, examining the effects of reduced protein mobility and increased concentration at the membrane, as well as effects due to differences in spatiotemporal correlations between the membrane environment and three-dimensional cytoplasm. The two model networks represent the distributive enzymatic modification of a protein at multiple sites and the positive feedback-mediated activation of a protein. In both cases, we find that confining proteins to a membrane-like environment can markedly alter the emergent dynamics. For the distributive protein modification network, increased concentration promotes bistability through enhanced protein protein binding, 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, which can induce bistability or stabilize a monostable, active state. Importantly, the influence of the membrane environment on signaling dynamics can be qualitatively different for signaling modules with different network topologies.