Exploring in vivo cholesterol-mediated interactions between activated EGF receptors in plasma membrane with single-molecule optical tracking.

Jung Y. Huang,Chien Y. Lin,Leu-Wei Lo

doi:10.1186/s13628-016-0030-5

Abstract

BackgroundThe first step in many cellular signaling processes occurs at various types of receptors in the plasma membrane. Membrane cholesterol can alter these signaling pathways of living cells. However, the process in which the interaction of activated receptors is modulated by cholesterol remains unclear.MethodsIn this study, we measured single-molecule optical trajectories of epidermal growth factor receptors moving in the plasma membranes of two cancerous cell lines and one normal endothelial cell line. A stochastic model was developed and applied to identify critical information from single-molecule trajectories.ResultsWe discovered that unliganded epidermal growth factor receptors may reside nearby cholesterol-riched regions of the plasma membrane and can move into these lipid domains when subjected to ligand binding. The amount of membrane cholesterol considerably affects the stability of correlated motion of activated epidermal growth factor receptors.ConclusionsOur results provide single-molecule evidence of membrane cholesterol in regulating signaling receptors. Because the three cell lines used for this study are quite diverse, our results may be useful to shed light on the mechanism of cholesterol-mediated interaction between activated receptors in live cells.

Highlights

The first step in many cellular signaling processes occurs at various types of receptors in the plasma membrane
We found that unliganded epidermal growth factor receptor (EGFR) may reside outside cholesterol-rich lipid domains of the plasma membranes and can move into lipid raft domains when subjected to ligand binding
In summary, we studied single-molecule optical trajectories of EGFRs moving in the plasma membranes of two cancerous cell lines (A431 and HeLa) and one normal epithelial cell line (MCF-12A)

Summary

Introduction

The first step in many cellular signaling processes occurs at various types of receptors in the plasma membrane. Membrane cholesterol can alter these signaling pathways of living cells. The process in which the interaction of activated receptors is modulated by cholesterol remains unclear. Receptor proteins are ubiquitous in the plasma membrane of mammalian cells, which transduce information about cellular environment to intracellular signaling networks [1,2,3]. There are approximately 1352 receptor proteins coded by human genome [4]. The diverse cellular processes regulated by such receptor proteins include cell growth and division, differentiation, migration, and apoptosis [5]. Receptor signaling dysregulation is attributed to the pathogenesis of several diseases [6, 7].

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