title: Emergence of bimodal cell population responses from the interplay between analog single-cell signaling and protein expression noise.
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.
authors.affiliation: Dept. of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Birtwistle
authors.forename: Jens
authors.initials: J
authors.lastname: Rauch
authors.forename: Anatoly
authors.initials: A
authors.lastname: Kiyatkin
authors.forename: Edita
authors.initials: E
authors.lastname: Aksamitiene
authors.forename: Maciej
authors.initials: M
authors.lastname: Dobrzyński
authors.forename: Jan B
authors.initials: JB
authors.lastname: Hoek
authors.forename: Walter
authors.initials: W
authors.lastname: Kolch
authors.forename: Babatunde A
authors.initials: BA
authors.lastname: Ogunnaike
authors.forename: Boris N
authors.initials: BN
authors.lastname: Kholodenko
mesh_terms: D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D025461:Feedback, Physiological / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008954:Models, Biological; D015398:Signal Transduction / Q000187:drug effects; D013269:Stochastic Processes; D018631:ras Proteins / Q000378:metabolism
chemical_list: D004815:Epidermal Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins