Effect of Spatial Inhomogeneities on the Membrane Surface on Receptor Dimerization and Signal Initiation

Abstract

Important signal transduction pathways originate on the plasma membrane, where microdomains may transiently entrap diffusing receptors. This results in a non-random distribution of receptors even in the resting state, which can be visualized as “clusters” by high resolution imaging methods. Here, we explore how spatial in-homogeneities in the plasma membrane might influence the dimerization and phosphorylation status of ErbB2 and ErbB3, two receptor tyrosine kinases that preferentially heterodimerize and are often co-expressed in cancer. This theoretical study is based upon spatial stochastic simulations of the two-dimensional membrane landscape, where variables include differential distributions and overlap of transient confinement zones (“domains”) for the two receptor species. The in silico model is parameterized and validated using data from single particle tracking experiments. We report key differences in signaling output based on the degree of overlap between domains and the relative retention of receptors in such domains, expressed as escape probability. Results predict that a high overlap of domains, which favors transient co-confinement of both receptor species, will enhance the rate of hetero-interactions. Where domains do not overlap, simulations confirm expectations that homo-interactions are favored. Since ErbB3 is uniquely dependent on ErbB2 interactions for activation of its catalytic activity, variations in domain overlap or escape probability markedly alter the predicted patterns and time course of ErbB3 and ErbB2 phosphorylation. Taken together, these results implicate membrane domain organization as an important modulator of signal initiation, motivating the design of novel experimental approaches to measure these important parameters across a wider range of receptor systems.

Parameter estimation and uncertainty quantification for systems biology models

“…** [77] The authors use single-particle tracking data to parameterize a spatial model of receptor tyrosine kinase signaling.…”

Reducing Spatial Stochastic Models of Membrane Receptors to Approximately Equivalent Chemical Reaction Networks through Coarse Graining

“…This makes both receptor-ligand systems important for medical science. The starkest contrast between the two systems comes from VEGF ligand being bivalent [21] while EGF ligand is monovalent [39]. Because of this difference, VEGF receptors can experience high dose inhibition while EGF cannot.…”

“…In the discussion below, we refer to a spatial simulation algorithm, as implemented in [39] and references therein. The motion simulator and triggering of reactions is essentially identical to Smoldyn [3].…”

“…The goal of this paper is to investigate the relation between a popular type of spatial simulation (based on Smoldyn [3][2] and implemented by this group [39] [45]), ODE models, and non-spatial stochastic simulations. We will not discuss numerical simulation of ODE systems, which is a mature discipline with well-established methods [23].…”

“…This work was motivated by our investigation [39] [50] of the EGF ligand / receptor family, in particular ErbB2 and ErbB3, which are important for their role in cancer [15]. The membrane bound receptors are capable of both homodimerization and heterodimerization [50].…”