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

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dc.contributor.authorBirtwistle, Marc R.en
dc.contributor.authorRauch, Jensen
dc.contributor.authorKiyatkin, Anatoly B.en
dc.contributor.authoret al.en
dc.date.copyright2012 Springer (Biomed Central Ltd.)en
dc.identifier.citationBMC Systems Biologyen
dc.description.abstractBackground: 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.en
dc.publisherSpringer (Biomed Central Ltd.)en
dc.rightsThe final publication is available at www.springerlink.comen
dc.subjectbimodal cell population responsesen
dc.subjectnetwork topologiesen
dc.subjectextracellular signal-regulated kinase (ERK)en
dc.subjectMAPK/ERK-cascade modelen
dc.titleEmergence of bimodal cell population responses from the interplay between analog single-cell signaling and protein expression noiseen
dc.typeJournal Articleen
dc.internal.availabilityFull text availableen
dc.statusPeer revieweden
dc.identifier.startpageNot Listeden
dc.identifier.endpageNot Listeden
dc.neeo.contributorBirtwistle|Marc R.|aut|-
dc.neeo.contributorKiyatkin|Anatoly B.|aut|-
dc.neeo.contributoret al.||aut|-
dc.description.adminDeposited by bulk importen
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