Bachmann2011 - Division of labor by dual feedback regulators controls JAK2/STAT5 signaling over broad ligand range
Model Identifier
BIOMD0000000861
Short description
This is a dynamic pathway model examining the roles of of the two transcriptional negative feedback regulators of the suppressor of cytokine signaling (SOCS) family, CIS and SOCS3, in JAK/STAT5 signaling, within the context of primary erythroid progenitor cells.
Format
SBML
(L2V1)
Related Publication
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Division of labor by dual feedback regulators controls JAK2/STAT5 signaling over broad ligand range.
- Bachmann J, Raue A, Schilling M, Böhm ME, Kreutz C, Kaschek D, Busch H, Gretz N, Lehmann WD, Timmer J, Klingmüller U
- Molecular Systems Biology , 7/ 2011 , Volume 7 , pages: 516 , PubMed ID: 21772264
- Division of Systems Biology of Signal Transduction, DKFZ-ZMBH Alliance, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, Germany.
- 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.
Contributors
Submitter of the first revision: Johannes Meyer
Submitter of this revision: Johannes Meyer
Modellers: Johannes Meyer
Submitter of this revision: Johannes Meyer
Modellers: Johannes Meyer
Metadata information
isDescribedBy (1 statement)
hasTaxon (1 statement)
hasProperty (3 statements)
hasTaxon (1 statement)
hasProperty (3 statements)
Gene Ontology
erythropoietin-mediated signaling pathway
Mathematical Modelling Ontology Ordinary differential equation model
NCIt Apoptosis
Mathematical Modelling Ontology Ordinary differential equation model
NCIt Apoptosis
Curation status
Curated
Modelling approach(es)
Tags
Connected external resources
SBGN view in Newt Editor
| Name | Description | Size | Actions |
|---|---|---|---|
Model files |
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| Bachmann2011.xml | SBML L2V4 Representation of Bachmann2011 - Division of labor by dual feedback regulators controls JAK2/STAT5 signaling over broad ligand range | 152.70 KB | Preview | Download |
Additional files |
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| Bachmann2011.cps | COPASI file of Bachmann2011 - Division of labor by dual feedback regulators controls JAK2/STAT5 signaling over broad ligand range | 226.81 KB | Preview | Download |
| Bachmann2011.sedml | SED-ML file of Bachmann2011 - Division of labor by dual feedback regulators controls JAK2/STAT5 signaling over broad ligand range | 1.74 KB | Preview | Download |
- Model originally submitted by : Johannes Meyer
- Submitted: Nov 14, 2019 11:06:36 AM
- Last Modified: Nov 14, 2019 11:06:36 AM
Revisions
-
Version: 2
- Submitted on: Nov 14, 2019 11:06:36 AM
- Submitted by: Johannes Meyer
- With comment: Automatically added model identifier BIOMD0000000861
Legends
: Variable used inside SBML models
: Variable used inside SBML models
Species
| Species | Initial Concentration/Amount |
|---|---|
| EpoRpJAK2 PR:000009197 ; PR:000007142 ; phosphorylated |
0.0 nmol |
| p1EpoRpJAK2 PR:000007142 ; PR:000009197 ; phosphorylated |
0.0 nmol |
| SHP1 PR:000013461 |
26.7251 nmol |
| pSTAT5 C28668 ; phosphorylated |
0.0 nmol |
| STAT5 C28668 |
79.7535 nmol |
| CISnRNA4 Q9NSE2 ; ribonucleic acid |
0.0 nmol |
| SOCS3nRNA4 C97975 ; ribonucleic acid |
0.0 nmol |
| SOCS3 C97975 |
0.0 nmol |
| SOCS3nRNA2 C97975 ; ribonucleic acid |
0.0 nmol |
Reactions
| Reactions | Rate | Parameters |
|---|---|---|
| EpoRJAK2 => EpoRpJAK2; Epo, SOCS3 | cyt*JAK2ActEpo*Epo*EpoRJAK2/(SOCS3Inh*SOCS3/SOCS3Eqc+1) | SOCS3Eqc = 173.653; SOCS3Inh = 10.408; JAK2ActEpo = 633253.0 |
| p1EpoRpJAK2 => EpoRJAK2; SHP1Act | cyt*JAK2EpoRDeaSHP1*SHP1Act*p1EpoRpJAK2/init_SHP1 | JAK2EpoRDeaSHP1 = 142.722; init_SHP1 = 26.7251 |
| SHP1 => SHP1Act; EpoRpJAK2, p12EpoRpJAK2, p1EpoRpJAK2, p2EpoRpJAK2 | cyt*SHP1ActEpoR*SHP1*(EpoRpJAK2+p12EpoRpJAK2+p1EpoRpJAK2+p2EpoRpJAK2)/init_EpoRJAK2 | SHP1ActEpoR = 0.001; init_EpoRJAK2 = 3.97622 |
| STAT5 => pSTAT5; CIS, SOCS3, p12EpoRpJAK2, p1EpoRpJAK2 | cyt*STAT5ActEpoR*STAT5*(p12EpoRpJAK2+p1EpoRpJAK2)^2/(init_EpoRJAK2^2*(CISInh*CIS/CISEqc+1)*(SOCS3Inh*SOCS3/SOCS3Eqc+1)) | init_EpoRJAK2 = 3.97622; SOCS3Eqc = 173.653; CISEqc = 432.871; SOCS3Inh = 10.408; STAT5ActEpoR = 38.9757; CISInh = 7.84653E8 |
| EpoRpJAK2 => p2EpoRpJAK2; EpoRJAK2_CIS, SOCS3 | cyt*3*EpoRActJAK2*EpoRpJAK2/((SOCS3Inh*SOCS3/SOCS3Eqc+1)*(EpoRCISInh*EpoRJAK2_CIS+1)) | SOCS3Eqc = 173.653; SOCS3Inh = 10.408; EpoRActJAK2 = 0.267308; EpoRCISInh = 1000000.0 |
| CISnRNA3 => CISnRNA4 | nuc*CISRNADelay*CISnRNA3 | CISRNADelay = 0.144775 |
| SOCS3nRNA3 => SOCS3nRNA4 | nuc*SOCS3RNADelay*SOCS3nRNA3 | SOCS3RNADelay = 1.06465 |
| => SOCS3 | cyt*SOCS3oe*SOCS3Eqc*SOCS3Turn*SOCS3EqcOE/cyt | SOCS3EqcOE = 0.679157; SOCS3Eqc = 173.653; SOCS3oe = 0.0; SOCS3Turn = 10000.0 |
| SOCS3nRNA2 => SOCS3nRNA3 | nuc*SOCS3RNADelay*SOCS3nRNA2 | SOCS3RNADelay = 1.06465 |
Curator's comment:
(added: 14 Nov 2019, 11:06:25, updated: 14 Nov 2019, 11:06:25)
(added: 14 Nov 2019, 11:06:25, updated: 14 Nov 2019, 11:06:25)
Reproduced plot of Figure 5(A, wt) in the original publication.
Model simulated and plot produced using COPASI 4.24 (Build 197).