Abstract
Cells interact with the extracellular environment by means of receptor molecules on their surface. Receptors can bind different ligands, leading to the formation of receptor–ligand complexes. For a subset of receptors, called receptor tyrosine kinases, binding to ligand enables sequential phosphorylation of intra-cellular residues, which initiates a signalling cascade that regulates cellular function and fate. Most mathematical modelling approaches employed to analyse receptor signalling are deterministic, especially when studying scenarios of high ligand concentration or large receptor numbers. There exist, however, biological scenarios where low copy numbers of ligands and/or receptors need to be considered, or where signalling by a few bound receptor–ligand complexes is enough to initiate a cellular response. Under these conditions stochastic approaches are appropriate, and in fact, different attempts have been made in the literature to measure the timescales of receptor signalling initiation in receptor–ligand systems. However, these approaches have made use of numerical simulations or approximations, such as moment-closure techniques. In this paper, we study, from an analytical perspective, the stochastic times to reach a given signalling threshold for two receptor–ligand models. We identify this time as an extinction time for a conveniently defined auxiliary absorbing continuous time Markov process, since receptor–ligand association/dissociation events can be analysed in terms of quasi-birth-and-death processes. We implement algorithmic techniques to compute the different order moments of this time, as well as the steady-state probability distribution of the system. A novel feature of the approach introduced here is that it allows one to quantify the role played by each kinetic rate in the timescales of signal initiation, and in the steady-state probability distribution of the system. Finally, we illustrate our approach by carrying out numerical studies for the vascular endothelial growth factor and one of its receptors, the vascular endothelial growth factor receptor of human endothelial cells.
Highlights
Cells interact with the extracellular environment by means of molecules located on their surface, referred to as receptors
We aim to develop a new quantitative study of receptor–ligand interaction and phosphorylation kinetics to aid our understanding of processes such as angiogenesis and vasculogenesis
An homogeneous spatial distribution of VEGFR2 on the cell surface [30,31], neglecting receptor clustering, which might be initiated upon ligand stimulation [32]
Summary
Cells interact with the extracellular environment by means of molecules located on their surface, referred to as receptors. We analyse receptor–ligand interactions and phosphorylation dynamics on the cell surface, to compute the time to reach a given signalling threshold [7], and the late time probability distribution of the system To this end, we first introduce a mathematical model (instantaneous phosphorylation (IP) model), in which receptor monomers can bind a bivalent ligand, which allows a second receptor monomer to cross-link. In the IP model, ligandbound receptor dimers are assumed to be instantaneously phosphorylated, so that the time to initiate the signalling cascade is identified with the time to reach a given threshold number of ligand-bound phosphorylated receptor dimers This results in the analysis of a first-passage time or an absorption time in the theory of continuous time Markov processes. The notation used in the paper is introduced in appendix A
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