Robustness of MEK-ERK Dynamics and Origins of Cell-to-Cell Variability in MAPK Signaling.

Sarah Filippi,Siobhan S Mcmahon,Shinya Kuroda,Takamasa Kudo,Michael P.H Stumpf,Katsuyuki Kunida,Paul D.W Kirk,Takumi Wada,Chris P Barnes,Takaho Tsuchiya

doi:10.1016/j.celrep.2016.05.024

Abstract

SummaryCellular signaling processes can exhibit pronounced cell-to-cell variability in genetically identical cells. This affects how individual cells respond differentially to the same environmental stimulus. However, the origins of cell-to-cell variability in cellular signaling systems remain poorly understood. Here, we measure the dynamics of phosphorylated MEK and ERK across cell populations and quantify the levels of population heterogeneity over time using high-throughput image cytometry. We use a statistical modeling framework to show that extrinsic noise, particularly that from upstream MEK, is the dominant factor causing cell-to-cell variability in ERK phosphorylation, rather than stochasticity in the phosphorylation/dephosphorylation of ERK. We furthermore show that without extrinsic noise in the core module, variable (including noisy) signals would be faithfully reproduced downstream, but the within-module extrinsic variability distorts these signals and leads to a drastic reduction in the mutual information between incoming signal and ERK activity.

Highlights

The behavior of eukaryotic cells is determined by an intricate interplay between signaling, gene regulation, and epigenetic processes
We develop a statistical framework for just this purpose, and we apply it to measurements obtained by quantitative image cytometry (Ozaki et al, 2010): data are obtained at discrete time points but encompass thousands of cells, which allows one to investigate the causes of cell-to-cell variability (Johnston, 2014)
Quantifying Temporal Evolution of Cell-to-Cell Variability We investigate the causes of cellular heterogeneity in vivo during ERK activation by phosphorylated MEK in PC12 cells

Summary

Introduction

The behavior of eukaryotic cells is determined by an intricate interplay between signaling, gene regulation, and epigenetic processes. Each single molecular reaction occurs stochastically, and the expression levels of molecules can vary considerably in individual cells (Bowsher and Swain, 2012) These non-genetic differences frequently add up to macroscopically observable phenotypic variation (Spencer et al, 2009; Balazsi et al, 2011; Spiller et al, 2010). Two notions have come to dominate the literature: intrinsic and extrinsic causes of cell-to-cell variability (Swain et al, 2002; Komorowski et al, 2010; Hilfinger and Paulsson, 2011; Toni and Tidor, 2013; Bowsher and Swain, 2012) The former refers to the chance events governing the molecular collisions in biochemical reactions. This includes the impact of stochastic dynamics in any components upstream and/or downstream of the biological system of interest, which may be caused, for example, by the stage of the cell cycle and the multitude of factors deriving from it

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