title: Division of labor by dual feedback regulators controls JAK2/STAT5 signaling over broad ligand range.
abstract: 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.
authors.affiliation: Division of Systems Biology of Signal Transduction, DKFZ-ZMBH Alliance, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, Germany.
authors.forename: Julie
authors.initials: J
authors.lastname: Bachmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Raue
authors.forename: Marcel
authors.initials: M
authors.lastname: Schilling
authors.forename: Martin E
authors.initials: ME
authors.lastname: Böhm
authors.forename: Clemens
authors.initials: C
authors.lastname: Kreutz
authors.forename: Daniel
authors.initials: D
authors.lastname: Kaschek
authors.forename: Hauke
authors.initials: H
authors.lastname: Busch
authors.forename: Norbert
authors.initials: N
authors.lastname: Gretz
authors.forename: Wolf D
authors.initials: WD
authors.lastname: Lehmann
authors.forename: Jens
authors.initials: J
authors.lastname: Timmer
authors.forename: Ursula
authors.initials: U
authors.lastname: Klingmüller
mesh_terms: D000818:Animals; D017209:Apoptosis; D003001:Cloning, Molecular; D015672:Erythroid Precursor Cells / Q000378:metabolism; D004921:Erythropoietin / Q000494:pharmacology; D005260:Female; D020287:In Situ Nick-End Labeling; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D046228:Microarray Analysis; D008954:Models, Biological; D010766:Phosphorylation; D012333:RNA, Messenger; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D004921:Erythropoietin; D053614:Janus Kinase 2; D008024:Ligands; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C491411:Socs3 protein, mouse; C507926:Jak2 protein, mouse