Four-dimensional dynamics of MAPK information-processing systems

Boris N. Kholodenko, Marc R. Birtwistle

Research output: Contribution to journalReview articlepeer-review

64 Scopus citations


Mitogen-activated protein kinase (MAPK) cascades process a myriad of stimuli received by cell-surface receptors and generate precise spatiotemporal guidance for multiple target proteins, dictating receptor-specific cellular outcomes. Computational modeling 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 signaltransducers if they spread solely by diffusion. Endocytotic trafficking of active kinases driven bymolecular motors and travelingwaves of protein phosphorylation can propagate phosphorylation signals from the plasmamembrane to the nucleus, especially in large cells, such as Xenopus eggs.

Original languageEnglish
Pages (from-to)28-44
Number of pages17
JournalWiley Interdisciplinary Reviews: Systems Biology and Medicine
Issue number1
StatePublished - Jul 2009
Externally publishedYes


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