Survival or apoptosis is a binary decision in individual cells. However, at the cell-population level, a graded increase in survival of colony-forming unit-erythroid (CFU-E) cells is observed upon stimulation with erythropoietin (Epo). To identify components of Janus kinase 2/signal transducer and activator of transcription 5 (JAK2/STAT5) signal transduction that contribute to the graded population response, we extended a cell-population-level model calibrated with experimental data to study the behavior in single cells. The single-cell model shows that the high cell-to-cell variability in nuclear phosphorylated STAT5 is caused by variability in the amount of Epo receptor (EpoR):JAK2 complexes and of SHP1, as well as the extent of nuclear import because of the large variance in the cytoplasmic volume of CFU-E cells. 24–118 pSTAT5 molecules in the nucleus for 120 min are sufficient to ensure cell survival. Thus, variability in membrane-associated processes is sufficient to convert a switch-like behavior at the single-cell level to a graded population-level response.
FörderungenDeutsche Forschungsgemeinschaft (DFG) European Union's Horizon 2020 research and innovation program (CanPathPro) German Ministry of Education and Research (BMBF) within the e:Bio collaborative research projects ''Systems Biology of Erythropoietin'' (SBEpo) German Federal Ministry of Education and Research (BMBF) Systems Medicine network LiSyM Deutsche Forschungsgemeinschaft (DFG) under Germany's Excellence Strategy state of Baden-Wurttemberg, Germany, through bwHPC