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

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

Trading the micro-world of combinatorial complexity for the macro-world of protein interaction domains

Membrane receptors and proteins involved in signal transduction display numerous binding domains and operate as molecular scaffolds generating a variety of parallel reactions and protein complexes. The resulting combinatorial explosion of the number of feasible chemical species and, hence, different states of a network greatly impedes mechanistic modeling of signaling systems. Here we present novel general principles and identify kinetic requirements that allow us to replace a mechanistic picture of all possible micro-states and transitions by a macro-description of states of separate binding sites of network proteins. This domain-oriented approach dramatically reduces computational models of cellular signaling networks by dissecting mechanistic trajectories into the dynamics of macro- and meso-variables. We specify the conditions when the temporal dynamics of micro-states can be exactly or approximately expressed in terms of the product of the relative concentrations of separate domains. We prove that our macro-modeling approach equally applies to signaling systems with low population levels, analyzed by stochastic rather than deterministic equations. Thus, our results greatly facilitate quantitative analysis and computational modeling of multi-protein signaling networks

Generating functional analysis of complex formation and dissociation in large protein interaction networks

We analyze large systems of interacting proteins, using techniques from the non-equilibrium statistical mechanics of disordered many-particle systems. Apart from protein production and removal, the most relevant microscopic processes in the proteome are complex formation and dissociation, and the microscopic degrees of freedom are the evolving concentrations of unbound proteins (in multiple post-translational states) and of protein complexes. Here we only include dimer-complexes, for mathematical simplicity, and we draw the network that describes which proteins are reaction partners from an ensemble of random graphs with an arbitrary degree distribution. We show how generating functional analysis methods can be used successfully to derive closed equations for dynamical order parameters, representing an exact macroscopic description of the complex formation and dissociation dynamics in the infinite system limit. We end this paper with a discussion of the possible routes towards solving the nontrivial order parameter equations, either exactly (in specific limits) or approximately.Comment: 14 pages, to be published in Proc of IW-SMI-2009 in Kyoto (Journal of Phys Conference Series

Analysis of signalling pathways using continuous time Markov chains

We describe a quantitative modelling and analysis approach for signal transduction networks. We illustrate the approach with an example, the RKIP inhibited ERK pathway [CSK+03]. Our models are high level descriptions of continuous time Markov chains: proteins are modelled by synchronous processes and reactions by transitions. Concentrations are modelled by discrete, abstract quantities. The main advantage of our approach is that using a (continuous time) stochastic logic and the PRISM model checker, we can perform quantitative analysis such as what is the probability that if a concentration reaches a certain level, it will remain at that level thereafter? or how does varying a given reaction rate affect that probability? We also perform standard simulations and compare our results with a traditional ordinary differential equation model. An interesting result is that for the example pathway, only a small number of discrete data values is required to render the simulations practically indistinguishable

Elementary derivation of Spitzer's asymptotic law for Brownian windings and some of its physical applications

A simple derivation of Spitzer'z asymptotic law for Brownian windings [Trans.Am.Math.Soc.87,187 (1958)]is presented along with its generalizations >.These include the cases of planar Brownian walks interacting with a single puncture and Brownian walks on a single truncated cone with variable conical angle interacting with the truncated conical tip.Such situations are typical in the theories of quantum Hall effect and 2+1 quantum gravity, respectively .They also have some applications in polymer physic

Long-range signaling by phosphoprotein waves arising from bistability in protein kinase cascades

A hallmark of protein kinase/phosphatase cascades, including mitogen-activated protein kinase (MAPK) pathways, is the spatial separation of their components within cells. The top-level kinase, MAP3K, is phosphorylated at the cell membrane, and cytoplasmic kinases at sequential downstream levels (MAP2K and MAPK) spread the signal to distant targets. Given measured protein diffusivity and phosphatase activities, signal propagation by diffusion would result in a steep decline of MAP2K activity and low bisphosphorylated MAPK (ppMAPK) levels near the nucleus, especially in large cells, such as oocytes. Here, we show that bistability in a two-site MAPK (de)phosphorylation cycle generates a novel type of phosphoprotein wave that propagates from the surface deep into the cell interior. Positive feedback from ppMAPK to cytoplasmic MAP2K enhances the propagation span of the ppMAPK wave, making it possible to convey phosphorylation signals over exceedingly long distances. The finding of phosphorylation waves traveling with constant amplitude and high velocity may solve a long-standing enigma of survival signaling in developing neurons

Adaptive response and enlargement of dynamic range

Many membrane channels and receptors exhibit adaptive, or desensitized, response to a strong sustained input stimulus, often supported by protein activity-dependent inactivation. Adaptive response is thought to be related to various cellular functions such as homeostasis and enlargement of dynamic range by background compensation. Here we study the quantitative relation between adaptive response and background compensation within a modeling framework. We show that any particular type of adaptive response is neither sufficient nor necessary for adaptive enlargement of dynamic range. In particular a precise adaptive response, where system activity is maintained at a constant level at steady state, does not ensure a large dynamic range neither in input signal nor in system output. A general mechanism for input dynamic range enlargement can come about from the activity-dependent modulation of protein responsiveness by multiple biochemical modification, regardless of the type of adaptive response it induces. Therefore hierarchical biochemical processes such as methylation and phosphorylation are natural candidates to induce this property in signaling systems.Comment: Corrected typos, minor text revision

A transfer matrix approach to the enumeration of plane meanders

A closed plane meander of order $n$ is a closed self-avoiding curve intersecting an infinite line $2n$ times. Meanders are considered distinct up to any smooth deformation leaving the line fixed. We have developed an improved algorithm, based on transfer matrix methods, for the enumeration of plane meanders. While the algorithm has exponential complexity, its rate of growth is much smaller than that of previous algorithms. The algorithm is easily modified to enumerate various systems of closed meanders, semi-meanders, open meanders and many other geometries.Comment: 13 pages, 9 eps figures, to appear in J. Phys.

Pathwise Sensitivity Analysis in Transient Regimes

The instantaneous relative entropy (IRE) and the corresponding instanta- neous Fisher information matrix (IFIM) for transient stochastic processes are pre- sented in this paper. These novel tools for sensitivity analysis of stochastic models serve as an extension of the well known relative entropy rate (RER) and the corre- sponding Fisher information matrix (FIM) that apply to stationary processes. Three cases are studied here, discrete-time Markov chains, continuous-time Markov chains and stochastic differential equations. A biological reaction network is presented as a demonstration numerical example

Field theoretical representation of the Hohenberg-Kohn free energy for fluids

To go beyond Gaussian approximation to the Hohenberg-Kohn free energy playing the key role in the density functional theory (DFT), the density functional \textit{integral} representation would be relevant, because field theoretical approach to perturbative calculations becomes available. Then the present letter first derives the associated Hamiltonian of density functional, explicitly including logarithmic entropy term, from the grand partition function expressed by configurational integrals. Moreover, two things are done so that the efficiency of the obtained form may be revealed: to demonstrate that this representation facilitates the field theoretical treatment of the perturbative calculation, and further to compare our perturbative formulation with that of the DFT.Comment: 5 pages, revtex, modified on 13 April 2000 [see eqs. (3), (6), and (13)