Emergence of bimodal cell population responses from the interplay between analog single-cell signaling and protein expression noise.

Authors

Marc R Birtwistle, Mount Sinai School of Medicine, New York
Jens Rauch, University College Dublin
Anatoly Kiyatkin, Thomas Jefferson UniversityFollow
Edita Aksamitiene, Thomas Jefferson UniversityFollow
Maciej Dobrzyński, University College Dublin
Jan B. Hoek, Thomas Jefferson UniversityFollow
Walter Kolch, University College DublinFollow
Babatunde A Ogunnaike, University of DelawareFollow
Boris N Kholodenko, University College DublinFollow

Document Type

Article

Publication Date

1-1-2012

Comments

This article has been peer reviewed. It was published in: BMC systems biology

2012 Aug 24;6:109.

The published version is available at DOI:10.1186/1752-0509-6-109.. Copyright © BioMed Central.

Abstract

BACKGROUND: Cell-to-cell variability in protein expression can be large, and its propagation through signaling networks affects biological outcomes. Here, we apply deterministic and probabilistic models and biochemical measurements to study how network topologies and cell-to-cell protein abundance variations interact to shape signaling responses.

RESULTS: We observe bimodal distributions of extracellular signal-regulated kinase (ERK) responses to epidermal growth factor (EGF) stimulation, which are generally thought to indicate bistable or ultrasensitive signaling behavior in single cells. Surprisingly, we find that a simple MAPK/ERK-cascade model with negative feedback that displays graded, analog ERK responses at a single cell level can explain the experimentally observed bimodality at the cell population level. Model analysis suggests that a conversion of graded input-output responses in single cells to digital responses at the population level is caused by a broad distribution of ERK pathway activation thresholds brought about by cell-to-cell variability in protein expression.

CONCLUSIONS: Our results show that bimodal signaling response distributions do not necessarily imply digital (ultrasensitive or bistable) single cell signaling, and the interplay between protein expression noise and network topologies can bring about digital population responses from analog single cell dose responses. Thus, cells can retain the benefits of robustness arising from negative feedback, while simultaneously generating population-level on/off responses that are thought to be critical for regulating cell fate decisions.

Recommended Citation

Birtwistle, Marc R; Rauch, Jens; Kiyatkin, Anatoly; Aksamitiene, Edita; Dobrzyński, Maciej; Hoek, Jan B.; Kolch, Walter; Ogunnaike, Babatunde A; and Kholodenko, Boris N, "Emergence of bimodal cell population responses from the interplay between analog single-cell signaling and protein expression noise." (2012). Department of Pathology, Anatomy, and Cell Biology Faculty Papers. Paper 123.
https://jdc.jefferson.edu/pacbfp/123

PubMed ID

22920937