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PreprintCited by 21Cytokine Signaling Pathways and InteractionsGene Regulatory Network AnalysisErythropoietin and Anemia Treatment

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Cell-to-cell variability in JAK2/STAT5 pathway components and cytoplasmic volumes define survival threshold in erythroid progenitor cells

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Adlung, Lorenz, Stapor, Paul, Tönsing, Christian, Schmiester, Leonard, Schwarzmüller, Luisa E., Wang, Dantong, Timmer, Jens, Klingmüller, Ursula, Hasenauer, Jan, Schilling, Marcel·2019·Cell Reports
DOI 10.1101/866871

Preprint — published as 10.1016/j.celrep.2021.109507

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Abstract

Summary: Survival or apoptosis is a binary decision in individual cells. Yet, at the cell population level, a graded increase in survival of CFU-E cells is observed upon stimulation with Erythropoietin (Epo). To identify components of JAK2/STAT5 signal transduction that contribute to the graded population response, a cell population-level model calibrated with experimental data was extended to study the behavior in single cells. The single-cell model showed that the high cell-to-cell variability in nuclear phosphorylated STAT5 is caused by variability in the amount of EpoR:JAK2 complexes and of SHP1 as well as the extent of nuclear import due to the large variance in the cytoplasmic volume of CFU-E cells. 24 to 118 pSTAT5 molecules in the nucleus for 120 min are sufficient to ensure cell survival. Thus, variability in membrane-associated processes are responsible to convert a switch-like behavior at the single-cell level to a graded population level response. Highlights: Mathematical modeling enables integration of heterogeneous data Single-cell modeling captures binary decision process Multiple sources of cell-to-cell variability in erythroid progenitor cells Minimal amount of active STAT5 sufficient for survival of erythroid progenitor cells

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Metadata

Authors
Adlung, L., Stapor, P., Tönsing, C., Schmiester, L., Schwarzmüller, L. E., Wang, D., Timmer, J., Klingmüller, U., Hasenauer, J., & Schilling, M.
Affiliations
  • German Cancer Research Center (DE)
  • Helmholtz Munich (DE)
  • University of Freiburg (DE)
  • University of Bonn (DE)
Corresponding author
  • Timmer, Jens
  • Klingmüller, Ursula
  • Hasenauer, Jan
  • Schilling, Marcel
ORCID
Venue
Cell Reports
Publisher
openRxiv
Published
2019-12-06
Volume
36
Issue
6
Pages
109507-109507
ISSN
2211-1247 (ISSN-L)
DOI
10.1101/866871
OpenAlex
W3189838849
Cited by
21
References
1
Citations by year
2026: 4 · 2025: 3 · 2024: 6 · 2023: 3 · 2022: 3 · 2021: 2
FWCI
1.28
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Cell Reports (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion, other-oa)
  • Site cant be reached (submittedVersion, cc-by)
Funders
  • Deutsches Krebsforschungszentrum
  • European Commission
  • Deutsche Forschungsgemeinschaft (INST35/1134-1 FUGG)
  • Bundesministerium für Bildung und Forschung (031L0042, 031L0074B, 0316182B, 01KU1902B, EXC-2189, 390939984, 031L0048, 031L0074A, 0316182A, 01KU1902A)
  • Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg
  • Bundesministerium für Forschung und Technologie
  • Horizon 2020 (686282)
  • National Cancer Institute
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
Keywords
JAK2/STAT5 signaling, erythroid progenitor cells, CFU-E, erythropoietin, cell-to-cell variability, single-cell model, graded response, apoptosis, nuclear import, cytoplasmic volume, SHP-1, EPO receptor, switch-like behavior
MeSH terms
Animals, Calibration, Cell Nucleus, Cell Survival, Cells, Cultured, Computer Simulation, Cytoplasm, Erythropoietin, Mice, Inbred BALB C, Models, Biological, Phosphorylation, Signal Transduction, Erythroid Precursor Cells, STAT5 Transcription Factor, Mice, Janus Kinase 2

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