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.
- Adlung, L.
- Stapor, P.
- Tönsing, C.
- Schmiester, L.
- Schwarzmüller, L. E.
- Postawa, L.
- Wang, D.
- Timmer, J.
- Klingmüller, U.
- Hasenauer, J.
- Schilling, M.
Keywords
- CFU-E cells
- Epo
- Jak/stat
- apoptosis
- cell fate decision
- heterogeneity
- mathematical modeling
- signal transduction
- single-cell modeling
- transcription factor
