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NF-{\kappa}B is a pleiotropic protein whose nucleo-cytoplasmic trafficking istightly regulated by multiple negative feedback loops embedded in theNF-{\kappa}B signaling network and contributes to diverse gene expressionprofiles important in immune cell differentiation, cell apoptosis, and innateimmunity. The intracellular signaling processes and their control mechanisms,however, are susceptible to both extrinsic and intrinsic noise. In thisarticle, we present numerical evidence for a universal dynamic behavior ofNF-{\kappa}B, namely oscillatory nucleo-cytoplasmic shuttling, due to thefundamentally stochastic nature of the NF-{\kappa}B signaling network. Wesimulated the effect of extrinsic noise with a deterministic ODE model, using astatistical ensemble approach, generating many copies of the signaling networkwith different kinetic rates sampled from a biologically feasible parameterspace. We modeled the effect of intrinsic noise by simulating the same networksstochastically using the Gillespie algorithm. The results demonstrate thatextrinsic noise diversifies the shuttling patterns of NF-{\kappa}B response,whereas intrinsic noise induces oscillatory behavior in many of the otherwisenon-oscillatory patterns. We identify two key model parameters whichsignificantly affect the NF-{\kappa}B dynamic response and deduce atwo-dimensional phase-diagram of the NF-{\kappa}B response as a function ofthese parameters. We conclude that if single-cell experiments are performed, arich variety of NF-{\kappa}B response will be observed, even ifpopulation-level experiments, which average response over large numbers ofcells, do not evidence oscillatory behavior.

Noise-induced oscillatory shuttling of NF-{\kappa}B in a two compartment IKK-NF-{\kappa}B-I{\kappa}B-A20 signaling model