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

Hdl Handle:
http://hdl.handle.net/10147/250631
Title:
Emergence of bimodal cell population responses from the interplay between analog single-cell signaling and protein expression noise
Authors:
Birtwistle, Marc R; Rauch, Jens; Kiyatkin, Anatoly; Aksamitiene, Edita; Dobrzyński, Maciej; Hoek, Jan B; Kolch, Walter; Ogunnaike, Babatunde A; Kholodenko, Boris N
Citation:
BMC Systems Biology. 2012 Aug 24;6(1):109
Issue Date:
24-Aug-2012
URI:
http://dx.doi.org/10.1186/1752-0509-6-109; http://hdl.handle.net/10147/250631
Abstract:
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.
Item Type:
Journal Article

Full metadata record

DC FieldValue Language
dc.contributor.authorBirtwistle, Marc R-
dc.contributor.authorRauch, Jens-
dc.contributor.authorKiyatkin, Anatoly-
dc.contributor.authorAksamitiene, Edita-
dc.contributor.authorDobrzyński, Maciej-
dc.contributor.authorHoek, Jan B-
dc.contributor.authorKolch, Walter-
dc.contributor.authorOgunnaike, Babatunde A-
dc.contributor.authorKholodenko, Boris N-
dc.date.accessioned2012-10-31T09:35:01Z-
dc.date.available2012-10-31T09:35:01Z-
dc.date.issued2012-08-24-
dc.identifier.citationBMC Systems Biology. 2012 Aug 24;6(1):109-
dc.identifier.urihttp://dx.doi.org/10.1186/1752-0509-6-109-
dc.identifier.urihttp://hdl.handle.net/10147/250631-
dc.description.abstractAbstract 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.-
dc.titleEmergence of bimodal cell population responses from the interplay between analog single-cell signaling and protein expression noise-
dc.typeJournal Article-
dc.language.rfc3066en-
dc.rights.holderMarc R Birtwistle et al.; licensee BioMed Central Ltd.-
dc.description.statusPeer Reviewed-
dc.date.updated2012-10-30T16:06:55Z-
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