Four-dimensional dynamics of MAPK information processing systems

Mitogen activated protein kinase (MAPK) cascades process a myriad of stimuli received by cell-surface receptors and generate precise spatio-temporal guidance for multiple target proteins, dictating receptor-specific cellular outcomes. Computational modelling reveals that the intrinsic topology of MAPK cascades enables them to amplify signal sensitivity and amplitude, reduce noise and display intricate dynamic properties, which include toggle switches, excitation pulses and oscillations. Specificity of signaling responses can be brought about by signal-induced feedback and feedforward wiring imposed on the MAPK cascade backbone. Intracellular gradients of protein activities arise from the spatial separation of opposing reactions in kinase-phosphatase cycles. The membrane confinement of the initiating kinase in MAPK cascades and cytosolic localization of phosphatases can result in precipitous gradients of phosphorylated signal-transducers if they spread solely by diffusion. Endocytotic trafficking of active kinases driven by molecular motors and traveling waves of protein phosphorylation can propagate phosphorylation signals from the plasma membrane to the nucleus, especially in large cells, such as Xenopus eggs.