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BIOMD0000000347 - Bachmann2011_JAK2-STAT5_FeedbackControl

 

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Reference Publication
Publication ID: 21772264
Bachmann J, Raue A, Schilling M, Böhm ME, Kreutz C, Kaschek D, Busch H, Gretz N, Lehmann WD, Timmer J, Klingmüller U.
Division of labor by dual feedback regulators controls JAK2/STAT5 signaling over broad ligand range.
Mol. Syst. Biol. 2011; 7: 516
Division of Systems Biology of Signal Transduction, DKFZ-ZMBH Alliance, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, Germany.  [more]
Model
Original Model: BIOMD0000000347.xml.origin
Submitter: Marcel Schilling
Submission ID: MODEL1107220000
Submission Date: 22 Jul 2011 09:26:10 UTC
Last Modification Date: 31 Jan 2012 13:56:40 UTC
Creation Date: 09 Aug 2011 16:20:30 UTC
Encoders:  Vijayalakshmi Chelliah
   Andreas Raue
set #1
bqbiol:occursIn Taxonomy Mus musculus
Brenda Tissue Ontology BTO:0004911
set #2
bqbiol:isVersionOf Gene Ontology regulation of JAK-STAT cascade
Notes

This model is from the article:
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. Mol Syst Biol. 2011 Jul 19;7:516. 21772264 ,
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.

Model
Publication ID: 21772264 Submission Date: 22 Jul 2011 09:26:10 UTC Last Modification Date: 31 Jan 2012 13:56:40 UTC Creation Date: 09 Aug 2011 16:20:30 UTC
Mathematical expressions
Reactions
reaction_1 reaction_2 reaction_3 reaction_4
reaction_5 reaction_6 reaction_7 reaction_8
reaction_9 reaction_10 reaction_11 reaction_12
reaction_13 reaction_14 reaction_15 reaction_16
reaction_17 reaction_18 reaction_19 reaction_20
reaction_21 reaction_22 reaction_23 reaction_24
reaction_25 reaction_26 reaction_27 reaction_28
reaction_29 reaction_30 reaction_31 reaction_32
reaction_33 reaction_34 reaction_35 reaction_36
Physical entities
Compartments Species
cyt EpoRJAK2 EpoRpJAK2 p1EpoRpJAK2
p2EpoRpJAK2 p12EpoRpJAK2 EpoRJAK2_CIS
SHP1 SHP1Act STAT5
pSTAT5 CISRNA CIS
SOCS3RNA SOCS3 Epo
nuc npSTAT5 CISnRNA1 CISnRNA2
CISnRNA3 CISnRNA4 CISnRNA5
SOCS3nRNA1 SOCS3nRNA2 SOCS3nRNA3
SOCS3nRNA4 SOCS3nRNA5  
Global parameters
ActD CISEqc CISEqcOE CISInh
CISRNADelay CISRNAEqc CISRNATurn CISTurn
CISoe EpoRActJAK2 EpoRCISInh EpoRCISRemove
JAK2ActEpo JAK2EpoRDeaSHP1 SHP1ActEpoR SHP1Dea
SOCS3Eqc SOCS3EqcOE SOCS3Inh SOCS3RNADelay
SOCS3RNAEqc SOCS3RNATurn SOCS3Turn SOCS3oe
STAT5ActEpoR STAT5ActJAK2 STAT5Exp STAT5Imp
epo_level init_EpoRJAK2 init_SHP1 init_STAT5
Reactions (36)
 
 reaction_1 [EpoRJAK2] → [EpoRpJAK2];   {Epo} , {SOCS3}
 
 reaction_2 [EpoRpJAK2] → [EpoRJAK2];   {SHP1Act}
 
 reaction_3 [EpoRpJAK2] → [p1EpoRpJAK2];   {SOCS3}
 
 reaction_4 [EpoRpJAK2] → [p2EpoRpJAK2];   {EpoRJAK2_CIS} , {SOCS3}
 
 reaction_5 [p1EpoRpJAK2] → [p12EpoRpJAK2];   {EpoRJAK2_CIS} , {SOCS3}
 
 reaction_6 [p2EpoRpJAK2] → [p12EpoRpJAK2];   {SOCS3}
 
 reaction_7 [p1EpoRpJAK2] → [EpoRJAK2];   {SHP1Act}
 
 reaction_8 [p2EpoRpJAK2] → [EpoRJAK2];   {SHP1Act}
 
 reaction_9 [p12EpoRpJAK2] → [EpoRJAK2];   {SHP1Act}
 
 reaction_10 [EpoRJAK2_CIS] → ;   {p12EpoRpJAK2} , {p1EpoRpJAK2}
 
 reaction_11 [SHP1] → [SHP1Act];   {EpoRpJAK2} , {p12EpoRpJAK2} , {p1EpoRpJAK2} , {p2EpoRpJAK2}
 
 reaction_12 [SHP1Act] → [SHP1];  
 
 reaction_13 [STAT5] → [pSTAT5];   {EpoRpJAK2} , {SOCS3} , {p12EpoRpJAK2} , {p1EpoRpJAK2} , {p2EpoRpJAK2}
 
 reaction_14 [STAT5] → [pSTAT5];   {CIS} , {SOCS3} , {p12EpoRpJAK2} , {p1EpoRpJAK2}
 
 reaction_15 [pSTAT5] → [npSTAT5];  
 
 reaction_16 [npSTAT5] → [STAT5];  
 
 reaction_17  ↔ [CISnRNA1];   {npSTAT5}
 
 reaction_18 [CISnRNA1] → [CISnRNA2];  
 
 reaction_19 [CISnRNA2] → [CISnRNA3];  
 
 reaction_20 [CISnRNA3] → [CISnRNA4];  
 
 reaction_21 [CISnRNA4] → [CISnRNA5];  
 
 reaction_22 [CISnRNA5] → [CISRNA];  
 
 reaction_23 [CISRNA] → ;  
 
 reaction_24  → [CIS];   {CISRNA}
 
 reaction_25 [CIS] → ;  
 
 reaction_26  → [CIS];  
 
 reaction_27  ↔ [SOCS3nRNA1];   {npSTAT5}
 
 reaction_28 [SOCS3nRNA1] → [SOCS3nRNA2];  
 
 reaction_29 [SOCS3nRNA2] → [SOCS3nRNA3];  
 
 reaction_30 [SOCS3nRNA3] → [SOCS3nRNA4];  
 
 reaction_31 [SOCS3nRNA4] → [SOCS3nRNA5];  
 
 reaction_32 [SOCS3nRNA5] → [SOCS3RNA];  
 
 reaction_33 [SOCS3RNA] → ;  
 
 reaction_34  → [SOCS3];   {SOCS3RNA}
 
 reaction_35 [SOCS3] → ;  
 
 reaction_36  → [SOCS3];  
 
 cyt Spatial dimensions: 3.0  Compartment size: 0.4
 
 EpoRJAK2
Compartment: cyt
Initial concentration: 3.97622
 
 EpoRpJAK2
Compartment: cyt
Initial concentration: 0.0
 
 p1EpoRpJAK2
Compartment: cyt
Initial concentration: 0.0
 
 p2EpoRpJAK2
Compartment: cyt
Initial concentration: 0.0
 
 p12EpoRpJAK2
Compartment: cyt
Initial concentration: 0.0
 
 EpoRJAK2_CIS
Compartment: cyt
Initial concentration: 0.0
 
 SHP1
Compartment: cyt
Initial concentration: 26.7251
 
 SHP1Act
Compartment: cyt
Initial concentration: 0.0
 
 STAT5
Compartment: cyt
Initial concentration: 79.7535
 
 pSTAT5
Compartment: cyt
Initial concentration: 0.0
 
 CISRNA
Compartment: cyt
Initial concentration: 0.0
 
 CIS
Compartment: cyt
Initial concentration: 0.0
 
 SOCS3RNA
Compartment: cyt
Initial concentration: 0.0
 
 SOCS3
Compartment: cyt
Initial concentration: 0.0
 
 Epo
Compartment: cyt
Initial concentration: 1.24997E-7
 
 nuc Spatial dimensions: 3.0  Compartment size: 0.275
 
 npSTAT5
Compartment: nuc
Initial concentration: 0.0
 
 CISnRNA1
Compartment: nuc
Initial concentration: 0.0
 
 CISnRNA2
Compartment: nuc
Initial concentration: 0.0
 
 CISnRNA3
Compartment: nuc
Initial concentration: 0.0
 
 CISnRNA4
Compartment: nuc
Initial concentration: 0.0
 
 CISnRNA5
Compartment: nuc
Initial concentration: 0.0
 
 SOCS3nRNA1
Compartment: nuc
Initial concentration: 0.0
 
 SOCS3nRNA2
Compartment: nuc
Initial concentration: 0.0
 
 SOCS3nRNA3
Compartment: nuc
Initial concentration: 0.0
 
 SOCS3nRNA4
Compartment: nuc
Initial concentration: 0.0
 
 SOCS3nRNA5
Compartment: nuc
Initial concentration: 0.0
 
Global Parameters (32)
 
 ActD
Constant
 
 CISEqc
Value: 432.871
Constant
 
 CISEqcOE
Value: 0.530261
Constant
 
 CISInh
Value: 7.84653E8
Constant
 
 CISRNADelay
Value: 0.144775
Constant
 
 CISRNAEqc
Value: 1.0
Constant
 
 CISRNATurn
Value: 1000.0
Constant
 
 CISTurn
Value: 0.00839842
Constant
 
 CISoe
Constant
 
 EpoRActJAK2
Value: 0.267308
Constant
 
 EpoRCISInh
Value: 1000000.0
Constant
 
 EpoRCISRemove
Value: 5.42932
Constant
 
 JAK2ActEpo
Value: 633253.0
Constant
 
 JAK2EpoRDeaSHP1
Value: 142.722
Constant
 
 SHP1ActEpoR
Value: 0.0010
Constant
 
 SHP1Dea
Value: 0.00816391
Constant
 
 SOCS3Eqc
Value: 173.653
Constant
 
 SOCS3EqcOE
Value: 0.679157
Constant
 
 SOCS3Inh
Value: 10.408
Constant
 
 SOCS3RNADelay
Value: 1.06465
Constant
 
 SOCS3RNAEqc
Value: 1.0
Constant
 
 SOCS3RNATurn
Value: 0.00830844
Constant
 
 SOCS3Turn
Value: 10000.0
Constant
 
 SOCS3oe
Constant
 
   STAT5ActEpoR
Value: 38.9757
Constant
 
 STAT5ActJAK2
Value: 0.0780965
Constant
 
 STAT5Exp
Value: 0.0745155
Constant
 
 STAT5Imp
Value: 0.0268889
Constant
 
 epo_level
Value: 1.24997E-7
Constant
 
 init_EpoRJAK2
Value: 3.97622
Constant
 
 init_SHP1
Value: 26.7251
Constant
 
 init_STAT5
Value: 79.7535
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000347

Curator's comment: (updated: 09 Aug 2011 17:19:49 BST)

Figure S9 of the supplementary material has been reproduced here. The model was integrated and simulated using Copasi v4.7 (Build 34). Plots were made using Gnuplot.

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