Document Type
Article
Publication Date
2016
College/Unit
Eberly College of Arts and Sciences
Department/Program/Center
Mathematics
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.
Digital Commons Citation
Kerketta, Romica; Halasz, Adam M.; Steinkamp, Mara P.; Wilson, Bridget S.; and Edwards, Jeremy S., "Effect of Spatial Inhomogeneities on the Membrane Surface on Receptor Dimerization and Signal Initiation" (2016). Faculty & Staff Scholarship. 2458.
https://researchrepository.wvu.edu/faculty_publications/2458
Source Citation
Kerketta, R., Halász, Á. M., Steinkamp, M. P., Wilson, B. S., & Edwards, J. S. (2016). Effect of Spatial Inhomogeneities on the Membrane Surface on Receptor Dimerization and Signal Initiation. Frontiers in Cell and Developmental Biology, 4. https://doi.org/10.3389/fcell.2016.00081
Comments
Copyright © 2016 Kerketta, Halász, Steinkamp, Wilson and Edwards. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.