Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 328 (5984): 1404-1408

Copyright © 2010 by the American Association for the Advancement of Science

Covering a Broad Dynamic Range: Information Processing at the Erythropoietin Receptor

Verena Becker,1,2,* Marcel Schilling,1,* Julie Bachmann,1 Ute Baumann,1 Andreas Raue,3 Thomas Maiwald,3,{dagger} Jens Timmer,3,4,5 Ursula Klingmüller1,2,{ddagger}

Abstract: Cell surface receptors convert extracellular cues into receptor activation, thereby triggering intracellular signaling networks and controlling cellular decisions. A major unresolved issue is the identification of receptor properties that critically determine processing of ligand-encoded information. We show by mathematical modeling of quantitative data and experimental validation that rapid ligand depletion and replenishment of the cell surface receptor are characteristic features of the erythropoietin (Epo) receptor (EpoR). The amount of Epo-EpoR complexes and EpoR activation integrated over time corresponds linearly to ligand input; this process is carried out over a broad range of ligand concentrations. This relation depends solely on EpoR turnover independent of ligand binding, which suggests an essential role of large intracellular receptor pools. These receptor properties enable the system to cope with basal and acute demand in the hematopoietic system.

1 Division Systems Biology of Signal Transduction, DKFZ-ZMBH Alliance, German Cancer Research Center, 69120 Heidelberg, Germany.
2 Bioquant, Heidelberg University, 69120 Heidelberg, Germany.
3 Institute of Physics, University of Freiburg, 79104 Freiburg, Germany.
4 Freiburg Institute for Advanced Studies, University of Freiburg, 79104 Freiburg, Germany.
5 Centre for Biological Signalling Studies (BIOSS), University of Freiburg, 79104 Freiburg, Germany.

* These authors contributed equally to this work.

{dagger} Present address: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.

{ddagger} To whom correspondence should be addressed. E-mail: u.klingmueller{at}

Division of labor by dual feedback regulators controls JAK2/STAT5 signaling over broad ligand range.
J. Bachmann, A. Raue, M. Schilling, M. E. Bohm, C. Kreutz, D. Kaschek, H. Busch, N. Gretz, W. D. Lehmann, J. Timmer, et al. (2014)
Mol Syst Biol 7, 516
   Abstract »    Full Text »    PDF »
Structural and functional protein network analyses predict novel signaling functions for rhodopsin.
C. Kiel, A. Vogt, A. Campagna, A. Chatr-aryamontri, M. Swiatek-de Lange, M. Beer, S. Bolz, A. F. Mack, N. Kinkl, G. Cesareni, et al. (2014)
Mol Syst Biol 7, 551
   Abstract »    Full Text »    PDF »
Cracking the NF-{kappa}B Code.
K. E. Tkach, J. E. Oyler, and G. Altan-Bonnet (2014)
Science Signaling 7, pe5
   Abstract »    Full Text »    PDF »
Comparison of approaches for parameter identifiability analysis of biological systems.
A. Raue, J. Karlsson, M. P. Saccomani, M. Jirstrand, and J. Timmer (2014)
   Abstract »    Full Text »    PDF »
T cells translate individual, quantal activation into collective, analog cytokine responses via time-integrated feedbacks.
K. E. Tkach, D. Barik, G. Voisinne, N. Malandro, M. M. Hathorn, J. W. Cotari, R. Vogel, T. Merghoub, J. Wolchok, O. Krichevsky, et al. (2014)
eLife Sci 3, e01944
   Abstract »    Full Text »    PDF »
Controlling Long-Term Signaling: Receptor Dynamics Determine Attenuation and Refractory Behavior of the TGF-{beta} Pathway.
P. Vizan, D. S. J. Miller, I. Gori, D. Das, B. Schmierer, and C. S. Hill (2013)
Science Signaling 6, ra106
   Abstract »    Full Text »    PDF »
Darbepoietin-alfa has comparable erythropoietic stimulatory effects to recombinant erythropoietin whilst preserving the bone marrow microenvironment.
S. R. Dewamitta, M. R. Russell, H. Nandurkar, and C. R. Walkley (2013)
Haematologica 98, 686-690
   Abstract »    Full Text »    PDF »
Joining forces of Bayesian and frequentist methodology: a study for inference in the presence of non-identifiability.
A. Raue, C. Kreutz, F. J. Theis, and J. Timmer (2012)
Phil Trans R Soc A 371, 20110544
   Abstract »    Full Text »    PDF »
Targeted Near-Infrared Imaging of the Erythropoietin Receptor in Human Lung Cancer Xenografts.
D. Doleschel, O. Mundigl, A. Wessner, F. Gremse, J. Bachmann, A. Rodriguez, U. Klingmuller, M. Jarsch, F. Kiessling, and W. Lederle (2012)
J. Nucl. Med. 53, 304-311
   Abstract »    Full Text »    PDF »
Statistical analysis of nonlinear dynamical systems using differential geometric sampling methods.
B. Calderhead and M. Girolami (2011)
Interface Focus 1, 821-835
   Abstract »    Full Text »    PDF »
Receptor-Based Dosing Optimization of Erythropoietin in Juvenile Sheep after Phlebotomy.
M. Rosebraugh, J. A. Widness, and P. Veng-Pedersen (2011)
Drug Metab. Dispos. 39, 1214-1220
   Abstract »    Full Text »    PDF »
SBML-PET-MPI: a parallel parameter estimation tool for Systems Biology Markup Language based models.
Z. Zi (2011)
Bioinformatics 27, 1028-1029
   Abstract »    Full Text »    PDF »
Transferrin receptor 2 is a component of the erythropoietin receptor complex and is required for efficient erythropoiesis.
H. Forejtnikova, M. Vieillevoye, Y. Zermati, M. Lambert, R. M. Pellegrino, S. Guihard, M. Gaudry, C. Camaschella, C. Lacombe, A. Roetto, et al. (2010)
Blood 116, 5357-5367
   Abstract »    Full Text »    PDF »
Non-erythroid effects of erythropoietin.
M. O. Arcasoy (2010)
Haematologica 95, 1803-1805
   Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882