Division of labor by dual feedback regulators controls JAK2/STAT5 signaling over broad ligand range


Cellular signal transduction is governed by multiple feedback mechanisms to elicit robust cellular decisions. The specific contributions of individual feedback regulators, however, remain unclear. Based on extensive time-resolved data sets in primary erythroid progenitor cells, we established a dynamic pathway model to dissect the roles of the two transcriptional negative feedback regulators of the suppressor of cytokine signaling (SOCS) family, CIS and SOCS3, in JAK2/STAT5 signaling. Facilitated by the model, we calculated the STAT5 response for experimentally unobservable Epo concentrations and provide a quantitative link between cell survival and the integrated response of STAT5 in the nucleus. Model predictions show that the two feedbacks CIS and SOCS3 are most effective at different ligand concentration ranges due to their distinct inhibitory mechanisms. This divided function of dual feedback regulation enables control of STAT5 responses for Epo concentrations that can vary 1000-fold in vivo. Our modeling approach reveals dose-dependent feedback control as key property to regulate STAT5-mediated survival decisions over a broad range of ligand concentrations.

FAIRDOMHub ID: https://seek.sysmo-db.org/publications/248

DOI: 10.1038/msb.2011.50

Projects: Molecular Systems Biology

Journal: Molecular Systems Biology

Citation: Molecular Systems Biology 7(1) : 516

Date Published: 2011

Authors: J. Bachmann, A. Raue, Marcel Schilling, Martin Böhm, C. Kreutz, D. Kaschek, H. Busch, N. Gretz, W. D. Lehmann, Jens Timmer, Ursula Klingmüller

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Bachmann, J., Raue, A., Schilling, M., Bohm, M. E., Kreutz, C., Kaschek, D., … Klingmuller, U. (2014). Division of labor by dual feedback regulators controls JAK2/STAT5 signaling over broad ligand range. Molecular Systems Biology, 7(1), 516–516. http://doi.org/10.1038/msb.2011.50

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Created: 3rd Mar 2016 at 10:48

Last updated: 10th Mar 2017 at 13:56

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