Dataset Information

Becker2010_EpoR_AuxiliaryModel

ABSTRACT: This is the auxiliary model described in the article: Covering a Broad Dynamic Range: Information Processing at the Erythropoietin Receptor Verena Becker, Marcel Schilling, Julie Bachmann, Ute Baumann, Andreas Raue, Thomas Maiwald, Jens Timmer and Ursula Klingmüller; Science Published Online May 20, 2010; DOI: 10.1126/science.1184913 PMID: 20488988 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 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, covering a broad range of ligand concentrations. This relation solely depends on EpoR turnover independent of ligand binding, suggesting 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. SBML model exported from PottersWheel. % PottersWheel model definition file function m = BeckerSchilling2010_EpoR_AuxiliaryMode() m = pwGetEmptyModel(); %% Meta information m.ID = 'BeckerSchilling2010_EpoR_AuxiliaryMode'; m.name = 'BeckerSchilling2010_EpoR_AuxiliaryModel'; m.description = 'BeckerSchilling2010_EpoR_AuxiliaryModel'; m.authors = {'Verena Becker',' Marcel Schilling'}; m.dates = {'2010'}; m.type = 'PW-2-0-42'; %% X: Dynamic variables % m = pwAddX(m, ID, startValue, type, minValue, maxValue, unit, compartment, name, description, typeOfStartValue) m = pwAddX(m, 'EpoR' , 76, 'fix' , 0, 10000, [], 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'SAv' , 999.293, 'global', 900, 1100, [], 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'SAv_EpoR' , 0, 'fix' , 0, 10000, [], 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'SAv_EpoRi', 0, 'fix' , 0, 10000, [], 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'dSAvi' , 0, 'fix' , 0, 10000, [], 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'dSAve' , 0, 'fix' , 0, 10000, [], 'cell', [] , [] , [] , [] , 'protein.generic'); %% R: Reactions % m = pwAddR(m, reactants, products, modifiers, type, options, rateSignature, parameters, description, ID, name, fast, compartments, parameterTrunks, designerPropsR, stoichiometry, reversible) m = pwAddR(m, { }, {'EpoR' }, { }, 'C' , [] , 'k1*k2', {'kt','Bmax_SAv'}, [], 'reaction0001'); m = pwAddR(m, {'EpoR' }, { }, { }, 'MA', [] , [] , {'kt' }, [], 'reaction0002'); m = pwAddR(m, {'SAv','EpoR'}, {'SAv_EpoR' }, { }, 'MA', [] , [] , {'kon_SAv' }, [], 'reaction0003'); m = pwAddR(m, {'SAv_EpoR' }, {'SAv','EpoR'}, { }, 'MA', [] , [] , {'koff_SAv' }, [], 'reaction0004'); m = pwAddR(m, {'SAv_EpoR' }, {'SAv_EpoRi' }, { }, 'MA', [] , [] , {'kt' }, [], 'reaction0005'); m = pwAddR(m, {'SAv_EpoRi' }, {'SAv' }, { }, 'MA', [] , [] , {'kex_SAv' }, [], 'reaction0006'); m = pwAddR(m, {'SAv_EpoRi' }, {'dSAvi' }, { }, 'MA', [] , [] , {'kdi' }, [], 'reaction0007'); m = pwAddR(m, {'SAv_EpoRi' }, {'dSAve' }, { }, 'MA', [] , [] , {'kde' }, [], 'reaction0008'); %% C: Compartments % m = pwAddC(m, ID, size, outside, spatialDimensions, name, unit, constant) m = pwAddC(m, 'cell', 1); %% K: Dynamical parameters % m = pwAddK(m, ID, value, type, minValue, maxValue, unit, name, description) m = pwAddK(m, 'kt' , 0.0329366 , 'global', 1e-007, 1000); m = pwAddK(m, 'Bmax_SAv', 76 , 'fix' , 61 , 91 ); m = pwAddK(m, 'kon_SAv' , 2.29402e-006, 'global', 1e-007, 1000); m = pwAddK(m, 'koff_SAv', 0.00679946 , 'global', 1e-007, 1000); m = pwAddK(m, 'kex_SAv' , 0.01101 , 'global', 1e-007, 1000); m = pwAddK(m, 'kdi' , 0.00317871 , 'global', 1e-007, 1000); m = pwAddK(m, 'kde' , 0.0164042 , 'global', 1e-007, 1000); %% Default sampling time points m.t = 0:3:99; %% Y: Observables % m = pwAddY(m, rhs, ID, scalingParameter, errorModel, noiseType, unit, name, description, alternativeIDs, designerProps) m = pwAddY(m, 'SAv + dSAve' , 'SAv_extracellular_obs'); m = pwAddY(m, 'SAv_EpoR' , 'SAv_cellsurface_obs' ); m = pwAddY(m, 'SAv_EpoRi + dSAvi', 'SAv_intracellular_obs'); %% S: Scaling parameters % m = pwAddS(m, ID, value, type, minValue, maxValue, unit, name, description) m = pwAddS(m, 'scale_SAv_extracellular_obs', 1, 'fix', 0, 100); m = pwAddS(m, 'scale_SAv_cellsurface_obs' , 1, 'fix', 0, 100); m = pwAddS(m, 'scale_SAv_intracellular_obs', 1, 'fix', 0, 100); %% Designer properties (do not modify) m.designerPropsM = [1 1 1 0 0 0 400 250 600 400 1 1 1 0 0 0 0]; This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2010 The BioModels.net Team. For more information see the terms of use . To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

SUBMITTER: Verena Becker

PROVIDER: BIOMD0000000272 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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Dataset's files

Source:

			Action	DRS
	BIOMD0000000272?filename=BIOMD0000000272-biopax2.owl	Owl
	BIOMD0000000272?filename=BIOMD0000000272-biopax3.owl	Owl
	BIOMD0000000272?filename=BIOMD0000000272-matlab.m	Other
	BIOMD0000000272?filename=BIOMD0000000272-octave.m	Other
	BIOMD0000000272?filename=BIOMD0000000272.m	Other

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Publications

Covering a broad dynamic range: information processing at the erythropoietin receptor.

Becker Verena V Schilling Marcel M Bachmann Julie J Baumann Ute U Raue Andreas A Maiwald Thomas T Timmer Jens J Klingmüller Ursula U

Science (New York, N.Y.) 20100520 5984

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 erythr ...[more]

PMID: 20488988

Similar Datasets

Project description:This is the core model described in the article: Covering a Broad Dynamic Range: Information Processing at the Erythropoietin Receptor Verena Becker, Marcel Schilling, Julie Bachmann, Ute Baumann, Andreas Raue, Thomas Maiwald, Jens Timmer and Ursula Klingmüller; Science Published Online May 20, 2010; DOI: 10.1126/science.1184913 PMID: 20488988 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 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, covering a broad range of ligand concentrations. This relation solely depends on EpoR turnover independent of ligand binding, suggesting 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. SBML model exported from PottersWheel. % PottersWheel model definition file function m = BeckerSchilling2010_EpoR_CoreModel() m = pwGetEmptyModel(); %% Meta information m.ID = 'BeckerSchilling2010_EpoR_CoreModel'; m.name = 'BeckerSchilling2010_EpoR_CoreModel'; m.description = 'BeckerSchilling2010_EpoR_CoreModel'; m.authors = {'Verena Becker',' Marcel Schilling'}; m.dates = {'2010'}; m.type = 'PW-2-0-42'; %% X: Dynamic variables % m = pwAddX(m, ID, startValue, type, minValue, maxValue, unit, compartment, name, description, typeOfStartValue) m = pwAddX(m, 'EpoR' , 516, 'fix' , 0, 10000, [], 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'Epo' , 2030.19, 'global', 1890, 2310, [], 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'Epo_EpoR' , 0, 'fix' , 0, 10000, [], 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'Epo_EpoRi', 0, 'fix' , 0, 10000, [], 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'dEpoi' , 0, 'fix' , 0, 10000, [], 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'dEpoe' , 0, 'fix' , 0, 10000, [], 'cell', [] , [] , [] , [] , 'protein.generic'); %% R: Reactions % m = pwAddR(m, reactants, products, modifiers, type, options, rateSignature, parameters, description, ID, name, fast, compartments, parameterTrunks, designerPropsR, stoichiometry, reversible) m = pwAddR(m, { }, {'EpoR' }, { }, 'C' , [] , 'k1*k2', {'kt','Bmax'}, [], 'reaction0001'); m = pwAddR(m, {'EpoR' }, { }, { }, 'MA', [] , [] , {'kt' }, [], 'reaction0002'); m = pwAddR(m, {'Epo','EpoR'}, {'Epo_EpoR' }, { }, 'MA', [] , [] , {'kon' }, [], 'reaction0003'); m = pwAddR(m, {'Epo_EpoR' }, {'Epo','EpoR'}, { }, 'MA', [] , [] , {'koff' }, [], 'reaction0004'); m = pwAddR(m, {'Epo_EpoR' }, {'Epo_EpoRi' }, { }, 'MA', [] , [] , {'ke' }, [], 'reaction0005'); m = pwAddR(m, {'Epo_EpoRi' }, {'Epo','EpoR'}, { }, 'MA', [] , [] , {'kex' }, [], 'reaction0006'); m = pwAddR(m, {'Epo_EpoRi' }, {'dEpoi' }, { }, 'MA', [] , [] , {'kdi' }, [], 'reaction0007'); m = pwAddR(m, {'Epo_EpoRi' }, {'dEpoe' }, { }, 'MA', [] , [] , {'kde' }, [], 'reaction0008'); %% C: Compartments % m = pwAddC(m, ID, size, outside, spatialDimensions, name, unit, constant) m = pwAddC(m, 'cell', 1); %% K: Dynamical parameters % m = pwAddK(m, ID, value, type, minValue, maxValue, unit, name, description) m = pwAddK(m, 'kt' , 0.0329366 , 'global', 1e-007, 1000); m = pwAddK(m, 'Bmax', 516 , 'fix' , 492 , 540 ); m = pwAddK(m, 'kon' , 0.00010496, 'global', 1e-007, 1000); m = pwAddK(m, 'koff', 0.0172135 , 'global', 1e-007, 1000); m = pwAddK(m, 'ke' , 0.0748267 , 'global', 1e-007, 1000); m = pwAddK(m, 'kex' , 0.00993805, 'global', 1e-007, 1000); m = pwAddK(m, 'kdi' , 0.00317871, 'global', 1e-007, 1000); m = pwAddK(m, 'kde' , 0.0164042 , 'global', 1e-007, 1000); %% Default sampling time points m.t = 0:3:99; %% Y: Observables % m = pwAddY(m, rhs, ID, scalingParameter, errorModel, noiseType, unit, name, description, alternativeIDs, designerProps) m = pwAddY(m, 'Epo + dEpoe' , 'Epo_extracellular_obs'); m = pwAddY(m, 'Epo_EpoR' , 'Epo_cellsurface_obs' ); m = pwAddY(m, 'Epo_EpoRi + dEpoi', 'Epo_intracellular_obs'); %% S: Scaling parameters % m = pwAddS(m, ID, value, type, minValue, maxValue, unit, name, description) m = pwAddS(m, 'scale_Epo_extracellular_obs', 1, 'fix', 0, 100); m = pwAddS(m, 'scale_Epo_cellsurface_obs' , 1, 'fix', 0, 100); m = pwAddS(m, 'scale_Epo_intracellular_obs', 1, 'fix', 0, 100); %% Designer properties (do not modify) m.designerPropsM = [1 1 1 0 0 0 400 250 600 400 1 1 1 0 0 0 0]; This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2010 The BioModels.net Team. For more information see the terms of use . To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Project description:This is the model of IL13 induced signalling in L1236 cells described in the article: Dynamic Mathematical Modeling of IL13-Induced Signaling in Hodgkin and Primary Mediastinal B-Cell Lymphoma Allows Prediction of Therapeutic Targets. Raia V, Schilling M, Böhm M, Hahn B, Kowarsch A, Raue A, Sticht C, Bohl S, Saile M, Möller P, Gretz N, Timmer J, Theis F, Lehmann WD, Lichter P and Klingmüller U. Cancer Res. 2011 Feb 1;71(3):693-704. PubmedID: 21127196 ; DOI: 10.1158/0008-5472.CAN-10-2987 Abstract: Primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL) share a frequent constitutive activation of JAK (Janus kinase)/STAT signaling pathway. Because of complex, nonlinear relations within the pathway, key dynamic properties remained to be identified to predict possible strategies for intervention. We report the development of dynamic pathway models based on quantitative data collected on signaling components of JAK/STAT pathway in two lymphoma-derived cell lines, MedB-1 and L1236, representative of PMBL and cHL, respectively. We show that the amounts of STAT5 and STAT6 are higher whereas those of SHP1 are lower in the two lymphoma cell lines than in normal B cells. Distinctively, L1236 cells harbor more JAK2 and less SHP1 molecules per cell than MedB-1 or control cells. In both lymphoma cell lines, we observe interleukin-13 (IL13)-induced activation of IL4 receptor α, JAK2, and STAT5, but not of STAT6. Genome-wide, 11 early and 16 sustained genes are upregulated by IL13 in both lymphoma cell lines. Specifically, the known STAT-inducible negative regulators CISH and SOCS3 are upregulated within 2 hours in MedB-1 but not in L1236 cells. On the basis of this detailed quantitative information, we established two mathematical models, MedB-1 and L1236 model, able to describe the respective experimental data. Most of the model parameters are identifiable and therefore the models are predictive. Sensitivity analysis of the model identifies six possible therapeutic targets able to reduce gene expression levels in L1236 cells and three in MedB-1. We experimentally confirm reduction in target gene expression in response to inhibition of STAT5 phosphorylation, thereby validating one of the predicted targets. All concentrations in the model, apart from IL13, are in molecules/cell. IL13 is given in ng/ml. As the cell volume is not explicitely given in the article, it is just approximately derived from the MW of IL13 (15.8 kDa) and the conversion factor 3.776 molecules IL13/cell = 1 ng/ml to be around 100 fl. SBML model exported from PottersWheel on 2010-08-10 12:14:57. Inline follows the original matlab code: % PottersWheel model definition file function m = Raia2010_IL13_L1236() m = pwGetEmptyModel(); %% Meta information m.ID = 'Raia2010_IL13_L1236'; m.name = 'Raia2010_IL13_L1236'; m.description = ''; m.authors = {'Raia et al'}; m.dates = {'2010'}; m.type = 'PW-2-0-47'; %% X: Dynamic variables % m = pwAddX(m, ID, startValue, type, minValue, maxValue, unit, compartment, name, description, typeOfStartValue) m = pwAddX(m, 'Rec' , 1.8, 'fix' , 1e-006, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'Rec_i' , 118.598421286338, 'global', 0.001, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'IL13_Rec' , 0, 'fix' , 1e-006, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'p_IL13_Rec' , 0, 'fix' , 1e-006, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'p_IL13_Rec_i', 0, 'fix' , 1e-006, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'JAK2' , 24, 'fix' , 1e-006, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'pJAK2' , 0, 'fix' , 1e-006, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'SHP1' , 9.4, 'fix' , 1e-006, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'STAT5' , 209, 'fix' , 1e-006, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'pSTAT5' , 0, 'fix' , 1e-006, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'CD274mRNA' , 0, 'fix' , 1e-006, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); %% R: Reactions % m = pwAddR(m, reactants, products, modifiers, type, options, rateSignature, parameters, description, ID, name, fast, compartments, parameterTrunks, designerPropsR, stoichiometry, reversible) m = pwAddR(m, {'Rec' }, {'IL13_Rec' }, {'IL13stimulation'}, 'C' , [] , 'k1 * m1 * r1 * 3.776', {'Kon_IL13Rec' }); m = pwAddR(m, {'Rec' }, {'Rec_i' }, { }, 'MA', [] , [] , {'Rec_intern' }); m = pwAddR(m, {'Rec_i' }, {'Rec' }, { }, 'MA', [] , [] , {'Rec_recycle' }); m = pwAddR(m, {'IL13_Rec' }, {'p_IL13_Rec' }, {'pJAK2' }, 'E' , [] , [] , {'Rec_phosphorylation' }); m = pwAddR(m, {'JAK2' }, {'pJAK2' }, {'IL13_Rec' }, 'E' , [] , [] , {'JAK2_phosphorylation' }); m = pwAddR(m, {'JAK2' }, {'pJAK2' }, {'p_IL13_Rec' }, 'E' , [] , [] , {'JAK2_phosphorylation' }); m = pwAddR(m, {'p_IL13_Rec' }, {'p_IL13_Rec_i'}, { }, 'MA', [] , [] , {'pRec_intern' }); m = pwAddR(m, {'p_IL13_Rec_i'}, { }, { }, 'MA', [] , [] , {'pRec_degradation' }); m = pwAddR(m, {'pJAK2' }, {'JAK2' }, {'SHP1' }, 'E' , [] , [] , {'pJAK2_dephosphorylation' }); m = pwAddR(m, {'STAT5' }, {'pSTAT5' }, {'pJAK2' }, 'E' , [] , [] , {'STAT5_phosphorylation' }); m = pwAddR(m, {'pSTAT5' }, {'STAT5' }, {'SHP1' }, 'E' , [] , [] , {'pSTAT5_dephosphorylation'}); m = pwAddR(m, { }, {'CD274mRNA' }, {'pSTAT5' }, 'C' , [] , 'm1*k1' , {'CD274mRNA_production' }); %% C: Compartments % m = pwAddC(m, ID, size, outside, spatialDimensions, name, unit, constant) m = pwAddC(m, 'cell', 1); %% K: Dynamical parameters % m = pwAddK(m, ID, value, type, minValue, maxValue, unit, name, description) m = pwAddK(m, 'Kon_IL13Rec' , 0.00174086832237195, 'global', 1e-009, 1000); m = pwAddK(m, 'Rec_phosphorylation' , 9.07540737285078 , 'global', 1e-009, 1000); m = pwAddK(m, 'pRec_intern' , 0.324132341358502 , 'global', 1e-009, 1000); m = pwAddK(m, 'pRec_degradation' , 0.417538218767296 , 'global', 1e-009, 1000); m = pwAddK(m, 'Rec_intern' , 0.259685756311325 , 'global', 1e-009, 1000); m = pwAddK(m, 'Rec_recycle' , 0.00392430355501153, 'global', 1e-009, 1000); m = pwAddK(m, 'JAK2_phosphorylation' , 0.300019047540849 , 'global', 1e-009, 1000); m = pwAddK(m, 'pJAK2_dephosphorylation' , 0.0981610557569751 , 'global', 1e-009, 1000); m = pwAddK(m, 'STAT5_phosphorylation' , 0.00426766529531612, 'global', 1e-009, 1000); m = pwAddK(m, 'pSTAT5_dephosphorylation', 0.0116388587580445 , 'global', 1e-009, 1000); m = pwAddK(m, 'CD274mRNA_production' , 0.0115927572109515 , 'global', 1e-009, 1000); %% U: Driving input % m = pwAddU(m, ID, uType, uTimes, uValues, compartment, name, description, u2Values, alternativeIDs, designerProps) m = pwAddU(m, 'IL13stimulation', 'steps', [-100 0] , [0 1] , [], [], [], [], {}, [], 'protein.generic'); %% Default sampling time points m.t = 0:1:120; %% Y: Observables % m = pwAddY(m, rhs, ID, scalingParameter, errorModel, noiseType, unit, name, description, alternativeIDs, designerProps) m = pwAddY(m, 'Rec + IL13_Rec + p_IL13_Rec' , 'RecSurf_obs' , 'scale_RecSurf' , '0.1 * y + 0.1 * max(y)'); m = pwAddY(m, 'IL13_Rec + p_IL13_Rec + p_IL13_Rec_i', 'IL13-cell_obs', 'scale_IL13-cell', '0.15 * y + 0.05 * max(y)'); m = pwAddY(m, 'p_IL13_Rec + p_IL13_Rec_i' , 'pIL4Ra_obs' , 'scale_pIL4Ra' , '0.10 * y + 0.15 * max(y)'); m = pwAddY(m, 'pJAK2' , 'pJAK2_obs' , 'scale_pJAK2' , '0.1 * y + 0.1 * max(y)'); m = pwAddY(m, 'CD274mRNA' , 'CD274mRNA_obs', 'scale_CD274mRNA', '0.1 * y + 0.1 * max(y)'); m = pwAddY(m, 'pSTAT5' , 'pSTAT5_obs' , 'scale_pSTAT5' , '0.1 * y + 0.1 * max(y)'); %% S: Scaling parameters % m = pwAddS(m, ID, value, type, minValue, maxValue, unit, name, description) m = pwAddS(m, 'scale_pJAK2' , 0.469836894150194, 'global', 0.001, 10000); m = pwAddS(m, 'scale_pIL4Ra' , 1.80002942264669, 'global', 0.001, 10000); m = pwAddS(m, 'scale_RecSurf' , 1, 'fix', 0.0001, 10000); m = pwAddS(m, 'scale_IL13-cell', 174.726805005048, 'global', 0.001, 10000); m = pwAddS(m, 'scale_CD274mRNA', 0.110568221201943, 'global', 0.001, 10000); m = pwAddS(m, 'scale_pSTAT5' , 1, 'fix', 0.001, 10000); %% Designer properties (do not modify) m.designerPropsM = [1 1 1 0 0 0 400 250 600 400 1 1 1 0 0 0 0];

Project description:This is the model of IL13 induced signalling in MedB-1 cell described in the article: Dynamic Mathematical Modeling of IL13-Induced Signaling in Hodgkin and Primary Mediastinal B-Cell Lymphoma Allows Prediction of Therapeutic Targets. Raia V, Schilling M, Böhm M, Hahn B, Kowarsch A, Raue A, Sticht C, Bohl S, Saile M, Möller P, Gretz N, Timmer J, Theis F, Lehmann WD, Lichter P and Klingmüller U. Cancer Res. 2011 Feb 1;71(3):693-704. PubmedID:21127196; DOI:10.1158/0008-5472.CAN-10-2987 Abstract: Primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL) share a frequent constitutive activation of JAK (Janus kinase)/STAT signaling pathway. Because of complex, nonlinear relations within the pathway, key dynamic properties remained to be identified to predict possible strategies for intervention. We report the development of dynamic pathway models based on quantitative data collected on signaling components of JAK/STAT pathway in two lymphoma-derived cell lines, MedB-1 and L1236, representative of PMBL and cHL, respectively. We show that the amounts of STAT5 and STAT6 are higher whereas those of SHP1 are lower in the two lymphoma cell lines than in normal B cells. Distinctively, L1236 cells harbor more JAK2 and less SHP1 molecules per cell than MedB-1 or control cells. In both lymphoma cell lines, we observe interleukin-13 (IL13)-induced activation of IL4 receptor α, JAK2, and STAT5, but not of STAT6. Genome-wide, 11 early and 16 sustained genes are upregulated by IL13 in both lymphoma cell lines. Specifically, the known STAT-inducible negative regulators CISH and SOCS3 are upregulated within 2 hours in MedB-1 but not in L1236 cells. On the basis of this detailed quantitative information, we established two mathematical models, MedB-1 and L1236 model, able to describe the respective experimental data. Most of the model parameters are identifiable and therefore the models are predictive. Sensitivity analysis of the model identifies six possible therapeutic targets able to reduce gene expression levels in L1236 cells and three in MedB-1. We experimentally confirm reduction in target gene expression in response to inhibition of STAT5 phosphorylation, thereby validating one of the predicted targets. All concentrations in the model, apart from IL13, are in molecules/cell. IL13 is given in ng/ml. As the cell volume is not explicitely given in the article, it is just approximately derived from the MW of IL13 () and the conversion factor 2.265 molecules IL13/cell = 1 ng/ml to be around 60 fl. SBML model exported from PottersWheel on 2010-08-10 12:14:57. Inline follows the original matlab code: % PottersWheel model definition file function m = Raia2010_IL13_MedB1() m = pwGetEmptyModel(); %% Meta information m.ID = 'Raia2010_IL13_MedB1'; m.name = 'Raia2010_IL13_MedB1'; m.description = ''; m.authors = {'Raia et al'}; m.dates = {'2010'}; m.type = 'PW-2-0-47'; %% X: Dynamic variables % m = pwAddX(m, ID, startValue, type, minValue, maxValue, unit, compartment, name, description, typeOfStartValue) m = pwAddX(m, 'Rec' , 1.3, 'fix' , 1e-006, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'Rec_i' , 113.193916718733, 'global', 0.001, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'IL13_Rec' , 0, 'fix' , 1e-006, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'p_IL13_Rec' , 0, 'fix' , 1e-006, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'p_IL13_Rec_i', 0, 'fix' , 1e-006, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'JAK2' , 2.8, 'fix' , 1e-006, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'pJAK2' , 0, 'fix' , 1e-006, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'SHP1' , 91, 'fix' , 1e-006, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'STAT5' , 165, 'fix' , 1e-006, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'pSTAT5' , 0, 'fix' , 1e-006, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'SOCS3mRNA' , 0, 'fix' , 1e-006, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'DecoyR' , 0.34, 'fix' , 1e-006, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'IL13_DecoyR' , 0, 'fix' , 1e-006, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'SOCS3' , 0, 'fix' , 1e-006, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); m = pwAddX(m, 'CD274mRNA' , 0, 'fix' , 1e-006, 10000, 'molecules/cell (x 1000)', 'cell', [] , [] , [] , [] , 'protein.generic'); %% R: Reactions % m = pwAddR(m, reactants, products, modifiers, type, options, rateSignature, parameters, description, ID, name, fast, compartments, parameterTrunks, designerPropsR, stoichiometry, reversible) m = pwAddR(m, {'Rec' }, {'IL13_Rec' }, {'IL13stimulation' }, 'C' , [] , 'k1 * m1 * r1 * 2.265' , {'Kon_IL13Rec' }); m = pwAddR(m, {'Rec' }, {'Rec_i' }, { }, 'MA', [] , [] , {'Rec_intern' }); m = pwAddR(m, {'Rec_i' }, {'Rec' }, { }, 'MA', [] , [] , {'Rec_recycle' }); m = pwAddR(m, {'IL13_Rec' }, {'p_IL13_Rec' }, {'pJAK2' }, 'E' , [] , [] , {'Rec_phosphorylation' }); m = pwAddR(m, {'JAK2' }, {'pJAK2' }, {'IL13_Rec','SOCS3' }, 'C' , [] , 'k1 * m1 * r1 / (1 + k2 * m2)', {'JAK2_phosphorylation','JAK2_p_inhibition'}); m = pwAddR(m, {'JAK2' }, {'pJAK2' }, {'p_IL13_Rec','SOCS3'}, 'C' , [] , 'k1 * m1 * r1 / (1 + k2 * m2)', {'JAK2_phosphorylation','JAK2_p_inhibition'}); m = pwAddR(m, {'p_IL13_Rec' }, {'p_IL13_Rec_i'}, { }, 'MA', [] , [] , {'pRec_intern' }); m = pwAddR(m, {'p_IL13_Rec_i'}, { }, { }, 'MA', [] , [] , {'pRec_degradation' }); m = pwAddR(m, {'pJAK2' }, {'JAK2' }, {'SHP1' }, 'E' , [] , [] , {'pJAK2_dephosphorylation' }); m = pwAddR(m, {'STAT5' }, {'pSTAT5' }, {'pJAK2' }, 'E' , [] , [] , {'STAT5_phosphorylation' }); m = pwAddR(m, {'pSTAT5' }, {'STAT5' }, {'SHP1' }, 'E' , [] , [] , {'pSTAT5_dephosphorylation' }); m = pwAddR(m, {'DecoyR' }, {'IL13_DecoyR' }, {'IL13stimulation' }, 'C' , [] , 'k1 * m1 * r1 * 2.265' , {'DecoyR_binding' }); m = pwAddR(m, { }, {'SOCS3mRNA' }, {'pSTAT5' }, 'C' , [] , 'm1*k1' , {'SOCS3mRNA_production' }); m = pwAddR(m, { }, {'SOCS3' }, {'SOCS3mRNA' }, 'C' , [] , 'm1*k1/(k2+m1)' , {'SOCS3_translation','SOCS3_accumulation' }); m = pwAddR(m, {'SOCS3' }, { }, { }, 'MA', [] , [] , {'SOCS3_degradation' }); m = pwAddR(m, { }, {'CD274mRNA' }, {'pSTAT5' }, 'C' , [] , 'm1*k1' , {'CD274mRNA_production' }); %% C: Compartments % m = pwAddC(m, ID, size, outside, spatialDimensions, name, unit, constant) m = pwAddC(m, 'cell', 1); %% K: Dynamical parameters % m = pwAddK(m, ID, value, type, minValue, maxValue, unit, name, description) m = pwAddK(m, 'Kon_IL13Rec' , 0.00341992477561527 , 'global', 1e-009, 1000); m = pwAddK(m, 'Rec_phosphorylation' , 999.630699390459 , 'global', 1e-009, 1000); m = pwAddK(m, 'pRec_intern' , 0.152540135862128 , 'global', 1e-009, 1000); m = pwAddK(m, 'pRec_degradation' , 0.17292753960894 , 'global', 1e-009, 1000); m = pwAddK(m, 'Rec_intern' , 0.103345784175639 , 'global', 1e-009, 1000); m = pwAddK(m, 'Rec_recycle' , 0.00135598001330518 , 'global', 1e-009, 1000); m = pwAddK(m, 'JAK2_phosphorylation' , 0.157057142470047 , 'global', 1e-009, 1000); m = pwAddK(m, 'pJAK2_dephosphorylation' , 0.000621906059346898 , 'global', 1e-009, 1000); m = pwAddK(m, 'STAT5_phosphorylation' , 0.0382596267705733 , 'global', 1e-009, 1000); m = pwAddK(m, 'pSTAT5_dephosphorylation', 0.000343391620492938 , 'global', 1e-009, 1000); m = pwAddK(m, 'SOCS3mRNA_production' , 0.00215826062955433 , 'global', 1e-009, 1000); m = pwAddK(m, 'DecoyR_binding' , 0.000124391087466499 , 'global', 1e-009, 1000); m = pwAddK(m, 'JAK2_p_inhibition' , 0.0168267797836881 , 'global', 1e-009, 1000); m = pwAddK(m, 'SOCS3_translation' , 11.9086462945188 , 'global', 1e-009, 1000); m = pwAddK(m, 'SOCS3_accumulation' , 3.70803336415341 , 'global', 1 , 1000); m = pwAddK(m, 'SOCS3_degradation' , 0.0429185935645562 , 'global', 1e-009, 1000); m = pwAddK(m, 'CD274mRNA_production' , 8.21752278733562e-005, 'global', 1e-009, 1000); %% U: Driving input % m = pwAddU(m, ID, uType, uTimes, uValues, compartment, name, description, u2Values, alternativeIDs, designerProps) m = pwAddU(m, 'IL13stimulation', 'steps', [-100 0] , [0 1] , [], [], [], [], {}, [], 'protein.generic'); %% Default sampling time points m.t = 0:1:120; %% Y: Observables % m = pwAddY(m, rhs, ID, scalingParameter, errorModel, noiseType, unit, name, description, alternativeIDs, designerProps) m = pwAddY(m, 'Rec + IL13_Rec + p_IL13_Rec' , 'RecSurf_obs' , 'scale_RecSurf' , '0.10 * y + 0.1 * max(y)'); m = pwAddY(m, 'IL13_Rec + p_IL13_Rec + p_IL13_Rec_i + IL13_DecoyR', 'IL13-cell_obs', 'scale_IL13-cell', '0.15 * y + 0.05 * max(y)'); m = pwAddY(m, 'p_IL13_Rec + p_IL13_Rec_i' , 'pIL4Ra_obs' , 'scale_pIL4Ra' , '0.1 * y + 0.15 * max(y)'); m = pwAddY(m, 'pJAK2' , 'pJAK2_obs' , 'scale_pJAK2' , '0.15 * y + 0.1 * max(y)'); m = pwAddY(m, 'SOCS3mRNA' , 'SOCS3mRNA_obs', 'scale_SOCS3mRNA', '0.1 * y + 0.1 * max(y)'); m = pwAddY(m, 'CD274mRNA' , 'CD274mRNA_obs', 'scale_CD274mRNA', '0.1 * y + 0.1 * max(y)'); m = pwAddY(m, 'SOCS3' , 'SOCS3_obs' , 'scale_SOCS3' , '0.1 * y + 0.15 * max(y)'); m = pwAddY(m, 'pSTAT5' , 'pSTAT5_obs' , 'scale_pSTAT5' , '0.15 * y + 0.1 * max(y)'); %% S: Scaling parameters % m = pwAddS(m, ID, value, type, minValue, maxValue, unit, name, description) m = pwAddS(m, 'scale_pJAK2' , 1.39039557075997, 'global', 0.001, 10000); m = pwAddS(m, 'scale_pIL4Ra' , 1.88700484471494, 'global', 0.001, 10000); m = pwAddS(m, 'scale_RecSurf' , 1, 'fix', 0.001, 10000); m = pwAddS(m, 'scale_IL13-cell', 5.56750251420935, 'global', 0.001, 10000); m = pwAddS(m, 'scale_SOCS3mRNA', 17.6699101927908, 'global', 0.001, 10000); m = pwAddS(m, 'scale_CD274mRNA', 2.48547378765387, 'global', 0.001, 10000); m = pwAddS(m, 'scale_pSTAT5' , 1, 'fix', 0.001, 10000); m = pwAddS(m, 'scale_SOCS3' , 1, 'fix', 0.001, 10000); %% Designer properties (do not modify) m.designerPropsM = [1 1 1 0 0 0 400 250 600 400 1 1 1 0 0 0 0]; This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. For more information see the terms of use. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Nov��re N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.