Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades

Abstract

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.

Formal Cell Biology in Biocham

“…The same property of independence from the kinetic expressions holds for the influence graph inferred from the MAPK signalling model of Levchenko et al [17]. This influence graph exhibits positive as well as negative feedbacks that are hidden in the purely directional cascade of the reaction graph [18] and were the subject of a misinterpretation in [19].…”

“…These are a necessary condition for multistationarity [3,6] that has been observed in the MAPK model, and experimentally in Xenopus oocytes [19]. Note that the absence of circuit in the (directional) reaction graph of MAPK was misinterpreted as a counterexample to Thomas' rule in [19] because of a confusion between both kinds of graphs. Furthermore in this large example no molecule is both an activator and an inhibitor of the same target molecule.…”

“…Such influence graphs are in fact an abstraction of complex reaction networks, and can be applied as such to protein interaction networks. However the distinction between the influence graph and the reaction (hyper)graph is crucial to the application of Thomas's conditions of multistationarity and oscillations [3,6] to protein interaction network, and there has been some confusion between the two kinds of graphs [19].…”

Biological switches and clocks

“…In the late 1990s, Ferrell and colleagues published a series of papers on the MAP kinase pathway in Xenopus eggs, in which they experimentally demonstrated bistability of its response to progesterone signals, and used modelling to suggest that this bistability is due to positive feedback in the signalling pathway (Ferrell & Machelder 1998;Ferrell & Xiong 2001). Recently, Kholodenko and others have shown theoretically that positive feedback in the MAP kinase pathway is not necessary for bistability but can arise subtly from the multisite phosphorylation reactions that are ubiquitous features of these kinase cascades (Markevich et al 2004;Gunawardena 2005;Chickarmane et al 2007). A major emphasis of the workshop was modelling of signalling networks, for example, pheromone signalling in yeast (Behar et al 2007), bacterial chemotaxis (Keymer et al 2006), regulatory circuits in the AIDS virus (Weinberger & Shenk 2007;Weinberger et al 2008) and osmo-adaptation in yeast .…”

Stochastic transitions in a bistable reaction system on the membrane

“…The system encompasses the simplest case of the ubiquitous multi-site phosphorylation and exhibits bistability [44,45]. Since it consists of eight reactions, it may be viewed as far from minimal [46]; however, in contrast to other small bistable systems [47,48], all its reactions are bimolecular and elementary (i.e.…”