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

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

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

Cellular 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.

Original languageEnglish
Pages (from-to)2524-2535
Number of pages12
JournalCell Reports
Volume15
Issue number11
DOIs
Publication statusPublished - 14-06-2016
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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