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.
Highlights
The plasma membrane is the initiation site for signaling pathways that govern cell differentiation, proliferation and survival (Groves and Kuriyan, 2010; Radhakrishnan et al, 2012)
ErbB2 and ErbB3 are members of the ErbB family of receptor tyrosine kinases that are often co-expressed in cells
In the absence of ligand, dimerization is limited by the constant fluxing of the ErbB3 extracellular domain from a tethered, inactive conformation to an upright, active conformation with the active conformation stabilized by ligand binding (Dawson et al, 2007)
Summary
The plasma membrane is the initiation site for signaling pathways that govern cell differentiation, proliferation and survival (Groves and Kuriyan, 2010; Radhakrishnan et al, 2012). The authors showed electron microscopy images of major histocompatibility antigen “patches,” providing early evidence for membrane organization. Considerable evidence has accumulated showing that membrane proteins and lipids can be transiently confined in specific domains (Kaizuka et al, 2007; Chung et al, 2010; Treanor et al, 2010; Radhakrishnan et al, 2012; Goñi, 2014). The exchange of proteins between domains is highly variable, ranging from very low exchange rates observed in yeast membranes (Spira et al, 2012) to very rapid exchanges described for the EGFR in mammalian cell membranes (Low-Nam et al, 2011)
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