A proof of bistability for the dual futile cycle

DOI10.1016/J.NONRWA.2015.02.004MaRDI QIDQ892271zbMATH OpenOpenAlexFDO

Authors Juliette Hell, Alan D. Rendall

Publication date 18 November 2015

Published in Nonlinear Analysis. Real World Applications (Search for Journal in Brave)

Full work available at URL https://arxiv.org/abs/1404.0394

zbMATH Keywords

bistabilitycusp bifurcationgeometric singular perturbation theoryMAPkinase cascademultiple futile cycle

Mathematics Subject Classification ID

Topological structure of integral curves, singular points, limit cycles of ordinary differential equations (34C05) Bifurcation theory for ordinary differential equations (34C23) Qualitative investigation and simulation of ordinary differential equation models (34C60) Singular perturbations for ordinary differential equations (34E15) Cell biology (92C37) Kinetics in biochemical problems (pharmacokinetics, enzyme kinetics, etc.) (92C45)

Abstract: The multiple futile cycle is an important building block in networks of chemical reactions arising in molecular biology. A typical process which it describes is the addition of n phosphate groups to a protein. It can be modelled by a system of ordinary differential equations depending on parameters. The special case n = 2 is called the dual futile cycle. The main result of this paper is a proof that there are parameter values for which the system of ODE describing the dual futile cycle has two distinct stable stationary solutions. The proof is based on bifurcation theory and geometric singular perturbation theory. An important entity built of three coupled multiple futile cycles is the MAPK cascade. It is explained how the ideas used to prove bistability for the dual futile cycle might help to prove the existence of periodic solutions for the MAPK cascade.

Review text

The paper investigates a mathematical model of the dual futile cycle in cell biology that originally consists of a system of nine autonomous ordinary differential equations. By rescaling the time variable, this system adopts the caracter of fast-slow dynamics, thus representing a singularly perturbed system of six differential equations, which in the limit leads to a planar vector field (MM) of Michaelis-Menten type. Under some simplifying assumptions, the authors first apply standard tools of bifurcation theory, such as centre manifold theory, to show the existence of cusp bifurcation for (MM), with two stable equilibria and an unstable one. Then, using results from geometric singular perturbation theory, it is proved that the perturbed system inherits the properties of system (MM) and thus exhibits two asymptotically stable equilibria and one saddle. In final remarks, the authors refer to the MAPK cascade, whose mathematical treatment leads to a three-dimensional unperturbed system of a structure similar to (MM). The question of periodic solutions for (MM) is also raised.

Recommendations

• A proof of unlimited multistability for phosphorylation cycles
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Cites work

• \(n\)-site phosphorylation systems with \(2n-1\) steady states
• Applications of centre manifold theory
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• scientific article; zbMATH DE number 3270885 (Why is no real title available?)
• Nonlinear oscillations, dynamical systems, and bifurcations of vector fields
• On the number of steady states in a multiple futile cycle
• Singular Perturbations on the Infinite Interval
• Singularly perturbed monotone systems and an Application to double phosphorylation cycles
• Translation-invariant monotone systems, and a global convergence result for enzymatic futile cycles

Cited in

(22)

• Stability analysis of the Michaelis-Menten approximation of a mixed mechanism of a phosphorylation system
• Parameter regions that give rise to \(2\lfloor \frac{n}{2} \rfloor +1\) positive steady states in the \(n\)-site phosphorylation system
• On the existence of Hopf bifurcations in the sequential and distributive double phosphorylation cycle
• The kinetic space of multistationarity in dual phosphorylation
• Addition of flow reactions preserving multistationarity and bistability
• A global convergence result for processive multisite phosphorylation systems
• An all-encompassing global convergence result for processive multisite phosphorylation systems
• Emergence of oscillations in a mixed-mechanism phosphorylation system
• Reciprocal enzyme regulation as a source of bistability in covalent modification cycles
• A mathematical model for the admission process in intensive care units
• Algebra and geometry in the study of enzymatic cascades
• Stability of stationary solutions in models of the Calvin cycle
• Sustained oscillations in the MAP kinase cascade
• Global stability of a class of futile cycles
• A proof of unlimited multistability for phosphorylation cycles
• Symbolic Proof of Bistability in Reaction Networks
• Structural Conditions for Saddle-Node Bifurcations in Chemical Reaction Networks
• In distributive phosphorylation catalytic constants enable non-trivial dynamics
• Precluding oscillations in Michaelis-Menten approximations of dual-site phosphorylation systems
• Unstable cores are the source of instability in chemical reaction networks
• Network reduction and absence of Hopf bifurcations in dual phosphorylation networks with three intermediates
• On the number of steady states in a multiple futile cycle

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