Parameter Region for Multistationarity in n-Site Phosphorylation Networks

DOI10.1137/22M1504548zbMATH Open1520.92032arXiv2206.08908OpenAlexW4385576874MaRDI QIDQ6132790FDOQ6132790

Authors: Elisenda Feliu, Nidhi Kaihnsa, Timo de Wolff, Oğuzhan Yürük 

Publication date: 17 August 2023

Published in: SIAM Journal on Applied Dynamical Systems (Search for Journal in Brave)

Abstract: Multisite phosphorylation is a signaling mechanism well known to give rise to multiple steady states, a property termed multistationarity. When phosphorylation occurs in a sequential and distributive manner, we obtain a family of networks indexed by the number of phosphorylation sites $n$. This work addresses the problem of understanding the parameter region where this family of networks displays multistationarity, by focusing on the projection of this region onto the set of kinetic parameters. The problem is phrased in the context of real algebraic geometry and reduced to studying whether a polynomial, defined as the determinant of a parametric matrix of size three, attains negative values over the positive orthant. The coefficients of the polynomial are functions of the kinetic parameters. For any $n$, we provide sufficient conditions for the polynomial to be positive and hence, preclude multistationarity, and also sufficient conditions for it to attain negative values and hence, enable multistationarity. These conditions are derived by exploiting the structure of the polynomial, its Newton polytope, and employing circuit polynomials. A relevant consequence of our results is that the set of kinetic parameters that enable or preclude multistationarity are both connected for all $n$.

Full work available at URL: https://arxiv.org/abs/2206.08908

Recommendations

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• Multistationarity in the space of total concentrations for systems that admit a monomial parametrization

zbMATH Keywords

parameter estimationreal algebraic geometrychemical reaction networkconnectednessmultistationaritycircuit polynomialphosphorylation network

Mathematics Subject Classification ID

Biochemistry, molecular biology (92C40) Systems biology, networks (92C42) Real algebraic and real-analytic geometry (14P99)

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Cited In (15)

• A global convergence result for processive multisite phosphorylation systems
• Regions of multistationarity in cascades of Goldbeter-Koshland loops
• Multistationarity in the space of total concentrations for systems that admit a monomial parametrization
• Parameter regions that give rise to \(2\lfloor \frac{n}{2} \rfloor +1\) positive steady states in the \(n\)-site phosphorylation system
• The kinetic space of multistationarity in dual phosphorylation
• Multistationarity in Biochemical Networks: Results, Analysis, and Examples
• \(n\)-site phosphorylation systems with \(2n-1\) steady states
• The rational parameterisation theorem for multisite post-translational modification systems
• Connectivity of parameter regions of multistationarity for multisite phosphorylation networks
• Geometry of the signed support of a multivariate polynomial and Descartes' rule of signs
• Oscillatory dynamics arising from competitive inhibition and multisite phosphorylation
• On the connectedness of multistationarity regions of small reaction networks
• How quantitative measures unravel design principles in multi-stage phosphorylation cascades
• A proof of unlimited multistability for phosphorylation cycles
• Multistationarity in sequential distributed multisite phosphorylation networks

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