Correlated receptor transport processes buffer single-cell heterogeneity

Stefan M Kallenberger; Anne L Unger; Stefan Legewie; Konstantinos Lymperopoulos; Ursula Klingmüller; Roland Eils; Dirk-Peter Herten

doi:10.1371/journal.pcbi.1005779

Correlated receptor transport processes buffer single-cell heterogeneity

PLoS Comput Biol. 2017 Sep 25;13(9):e1005779. doi: 10.1371/journal.pcbi.1005779. eCollection 2017 Sep.

Authors

Stefan M Kallenberger¹, Anne L Unger², Stefan Legewie³, Konstantinos Lymperopoulos², Ursula Klingmüller^{4

5}, Roland Eils¹, Dirk-Peter Herten²

Affiliations

¹ Department for Bioinformatics and Functional Genomics, Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg, Germany.
² Cellnetworks Cluster and Institute of Physical Chemistry, BioQuant, Heidelberg University, Heidelberg, Germany.
³ Institute of Molecular Biology, Mainz, Germany.
⁴ Division Systems Biology of Signal Transduction, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁵ Translational Lung Research Center (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.

Abstract

Cells typically vary in their response to extracellular ligands. Receptor transport processes modulate ligand-receptor induced signal transduction and impact the variability in cellular responses. Here, we quantitatively characterized cellular variability in erythropoietin receptor (EpoR) trafficking at the single-cell level based on live-cell imaging and mathematical modeling. Using ensembles of single-cell mathematical models reduced parameter uncertainties and showed that rapid EpoR turnover, transport of internalized EpoR back to the plasma membrane, and degradation of Epo-EpoR complexes were essential for receptor trafficking. EpoR trafficking dynamics in adherent H838 lung cancer cells closely resembled the dynamics previously characterized by mathematical modeling in suspension cells, indicating that dynamic properties of the EpoR system are widely conserved. Receptor transport processes differed by one order of magnitude between individual cells. However, the concentration of activated Epo-EpoR complexes was less variable due to the correlated kinetics of opposing transport processes acting as a buffering system.

MeSH terms

Biological Transport / physiology*
Cell Line, Tumor
Computational Biology
Fluorescent Dyes / analysis
Fluorescent Dyes / chemistry
Fluorescent Dyes / metabolism
Humans
Image Processing, Computer-Assisted / methods
Kinetics
Microscopy, Confocal
Models, Biological*
Receptors, Cell Surface / analysis
Receptors, Cell Surface / chemistry
Receptors, Cell Surface / metabolism*
Receptors, Erythropoietin
Single-Cell Analysis / methods*

Substances

Fluorescent Dyes
Receptors, Cell Surface
Receptors, Erythropoietin

Grants and funding

This work was supported by the German Federal Ministry of Education and Research (BMBF, www.bmbf.de) via the MedSys-Network LungSys II (http://www.lungsys.de, FKZ 0316042C), SysTec-EpiSys (http://www.episys.org, FKZ 0315502D), the e:Bio RNA-CODE joint research project (FKZ 031A298), and an e:Bio junior group grant, the German Center for Lung Research [Deutsches Zentrum für Lungenforschung (DZL), www.dzl.de], the German Research Foundation (DFG, EXC81), and by the Networking Fund of the Helmholtz Association within the Helmholtz Alliance on Systems Biology / SBCancer (www.helmholtz.de). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.