Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades
By N. Markevich, Jan B. Hoek, Boris N. Kholodenko. Journal of Cell Biology, 2004
729 citations recorded by the source corpus.
Mitogen-activated protein kinase (MAPK) cascades can operate as bistable switches residing in either of two different stable states. MAPK cascades are often embedded in positive feedback loops, which are considered to be a prerequisite for bistable behavior. Here we demonstrate that in the absence of any imposed feedback regulation, bistability and hysteresis can arise solely from a distributive kinetic mechanism of the two-site MAPK phosphorylation and dephosphorylation. Importantly, the reported kinetic properties of the kinase (MEK) and phosphatase (MKP3) of extracellular signal–regulated kinase (ERK) fulfill the essential requirements for generating a bistable switch at a single MAPK cascade level. Likewise, a cycle where multisite phosphorylations are performed by different kinases, but dephosphorylation reactions are catalyzed by the same phosphatase, can also exhibit bistability and hysteresis. Hence, bistability induced by multisite covalent modification may be a widespread mechanism of the control of protein activity.
Subfields: Molecular Biology
View Paper: https://www.semanticscholar.org/paper/9d1e185348dca2c036fe189abba3ab6cd1fb5a7a
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Citations in the corpus
- How can memories last for days, years, or a lifetime? Proposed mechanisms for maintaining synaptic potentiation and memory (2019, background): “ERK has also been hypothesized to persistently upregulate its own activity, via phosphorylation and activation of its upstream activator, MEK kinase (Markevich et al. 2004; Smolen et al. 2008).”
- Cell-signalling dynamics in time and space (2006, background): “) was shown to increase output–input sensitivity dramatically, resisting the sequestration effect and leading to switch-like response”
- Network resilience (2020, background): “For example, in protein kinase cascades, bistability and hysteresis can arise solely from a distributive kinetic mechanism of the two-site Mitogen-activated protein kinase (MAPK) phosphorylation and dephosphorylation, with no apparent feedback [296].”