Oscillations in intracellular signaling cascades.

In this paper, we study the oscillatory dynamics of intracellular signaling cascades. We derive a reaction-diffusion model of the mitogen-activated protein kinase cascade, and use it to show how oscillations of the protein kinase concentrations can occur as a function of the depth of the cascade. We find that only cascades with depths of three or more layers undergo oscillatory instabilities. In addition, the oscillatory instability is spatially uniform. Thus, the oscillations synchronize the protein kinase concentrations and result in them being uniformly distributed in the cytosol, despite the presence of protein kinase diffusion. Finally, we show how the oscillations are perturbed when parallel cascades "crosstalk." We find that the protein kinases in the downstream layers of the cascade are less perturbed than those in the upstream layers. In particular, cascades of three layers are able to maintain the total power of the protein kinase activities at approximately the unperturbed level. Taken together, our results suggest that only cascades of at least three layers can synchronize the oscillations of protein kinases in the cytosol and operate in parallel in the presence of crosstalk without loss of signaling fidelity.