Options
Emergence of bimodal cell population responses from the interplay between analog single-cell signaling and protein expression noise
Date Issued
2012
Date Available
2013-11-29T10:09:06Z
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 thesholds 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.
Other Sponsorship
SFI
Type of Material
Journal Article
Publisher
Springer (Biomed Central Ltd.)
Journal
BMC Systems Biology
Volume
6
Issue
1
Start Page
Not Listed
End Page
Not Listed
Copyright (Published Version)
2012 Springer (Biomed Central Ltd.)
Language
English
Status of Item
Peer reviewed
This item is made available under a Creative Commons License
File(s)
Owning collection
Scopus© citations
63
Acquisition Date
Mar 28, 2024
Mar 28, 2024
Views
1504
Acquisition Date
Mar 28, 2024
Mar 28, 2024
Downloads
466
Last Week
2
2
Last Month
8
8
Acquisition Date
Mar 28, 2024
Mar 28, 2024