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BIOMD0000000429 - Schaber2012 - Hog pathway in yeast

 

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Reference Publication
Publication ID: 23149687
Schaber J, Baltanas R, Bush A, Klipp E, Colman-Lerner A.
Modelling reveals novel roles of two parallel signalling pathways and homeostatic feedbacks in yeast.
Mol. Syst. Biol. 2012; 8: 622
Institute for Experimental Internal Medicine, Medical Faculty, Otto von Guericke University, Magdeburg, Germany. schaber@med.ovgu.de  [more]
Model
Original Model: Schaber2012HOGmodel2branches
Submitter: Joerg Schaber
Submission ID: MODEL1209110001
Submission Date: 11 Sep 2012 11:47:29 UTC
Last Modification Date: 14 Dec 2012 14:24:40 UTC
Creation Date: 22 Nov 2012 18:31:29 UTC
Encoders:  Vijayalakshmi Chelliah
   Joerg Schaber
set #1
bqbiol:isVersionOf Gene Ontology MAPK cascade involved in osmosensory signaling pathway
bqbiol:occursIn Taxonomy Saccharomyces cerevisiae
Notes
Schaber2012 - Hog pathway in yeast

The high osmolarity glycerol (HOG) pathway in the yeast Saccharomyces cerevisiae is one of the best-studied mitogen-activated protein kinase (MAPK) pathways and serves as a prototype signalling system for eukaryotes. This pathway is necessary and sufficient to adapt to high external osmolarity. A key component of this pathway is the stress-activated protein kinase (SAPK) Hog1, which is rapidly phosphorylated by the SAPK kinase Pbs2 upon hyper-osmotic shock, and which is the terminal kinase of two parallel signalling pathways, subsequently called the Sho1 branch and the Sln1 branch, respectively. Ensemble modelling (192 models) is used to study the yeast HOG pathway, a prototype for eukaryotic mitogen-activated kinase signalling systems. The best fit model (Model Nr.22: described here) provides new insights into the function of this system, some of which are then experimentally validated.

This model is described in the article:

Schaber J, Baltanas R, Bush A, Klipp E, Colman-Lerner A.
Mol Syst Biol. 2012 Nov 13;8:622.

Abstract:

The high osmolarity glycerol (HOG) pathway in yeast serves as a prototype signalling system for eukaryotes. We used an unprecedented amount of data to parameterise 192 models capturing different hypotheses about molecular mechanisms underlying osmo-adaptation and selected a best approximating model. This model implied novel mechanisms regulating osmo-adaptation in yeast. The model suggested that (i) the main mechanism for osmo-adaptation is a fast and transient non-transcriptional Hog1-mediated activation of glycerol production, (ii) the transcriptional response serves to maintain an increased steady-state glycerol production with low steady-state Hog1 activity, and (iii) fast negative feedbacks of activated Hog1 on upstream signalling branches serves to stabilise adaptation response. The best approximating model also indicated that homoeostatic adaptive systems with two parallel redundant signalling branches show a more robust and faster response than single-branch systems. We corroborated this notion to a large extent by dedicated measurements of volume recovery in single cells. Our study also demonstrates that systematically testing a model ensemble against data has the potential to achieve a better and unbiased understanding of molecular mechanisms.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Model
Publication ID: 23149687 Submission Date: 11 Sep 2012 11:47:29 UTC Last Modification Date: 14 Dec 2012 14:24:40 UTC Creation Date: 22 Nov 2012 18:31:29 UTC
Mathematical expressions
Reactions
v1_fb v2 v5 v6
v11 v12 v13 v14
v9 v10 v7 v8
v4 v3_fb v15_5 v16_6
Rules
Assignment Rule (variable: V) Assignment Rule (variable: Area) Assignment Rule (variable: Turgor) Assignment Rule (variable: ActivationSln1_nlfb)
Assignment Rule (variable: ks) Assignment Rule (variable: Fps1TransportCapacitty) Assignment Rule (variable: FitVrel) Assignment Rule (variable: FitHog1PPrel)
Assignment Rule (variable: FitProteinrel) Assignment Rule (variable: FitGlyinrel) Assignment Rule (variable: Turgor2Osm) Assignment Rule (variable: FitRNArel)
Assignment Rule (variable: Osmin) Assignment Rule (variable: cen) Assignment Rule (variable: Osmex) Assignment Rule (variable: ActivationSho1_nlfb)
Assignment Rule (variable: Fps1TotalTrans) Assignment Rule (variable: TurgorActivation) Assignment Rule (variable: TurgorDeactivation) Assignment Rule (variable: Hog1Inhibition)
Assignment Rule (variable: Hog1PPActive) Rate Rule (variable: Vos)    
Physical entities
Compartments Species
Vos Glyin Hog1 Hog1PP
Pbs2 Pbs2P Phosphatase
Protein RNA Hog1P
Sho1 Sho1Pbs2P Hog1PPActive
     
Vex Glyex    
V      
M Fps1 Fps1P  
Global parameters
R T mol phi
c2p tm Lp P0
eps minf ce_0 V_0
Vb maxHog1nucf VP_0 Area
Hog1PPrelIniwt N2uM ci_0 cin_0
Turgor ActivationSln1_nlfb NaCl ActivOffsetSln1_nlfb
kHog1phos1 kHog1dephos ks Fps1TransportCapacitty
FitVrel FitHog1PPrel FitProteinrel FitGlyinrel
Turgor2Osm Fps1ClosureRate Protein_deg_k FitRNArel
Hog1Total Pbs2Total RNA_deg_k_MM Sho1Total
kHog1phos2 Hog1PPrelIniSln1 Hog1PPrelIniSho1 Osmex
Osmin Vos_0 A_0 ts
cen Glyex_0 Protein_0 RNA_0
Glyin_0 Hog1PP_0 ActivOffsetSho1_nlfb ActivationSho1_nlfb
Sho1BranchActive Sln1BranchActive Fps1TotalIni Fps1TotalTrans
TurgorActiv_h TurgorActivation TurgorDeactivation v16_5_k
v16_6_k v16_7_k Hog1Activity tinh
Hog1Inhibition Inhibition Fps1Delta v2_k
v1_fb_Ki v1_fb_h v1_fb_k v11_k
v9_k v9_Km v4_k1 v3_fb_Ki
v3_fb_h v3_fb_k v15_5_k v16_6_Ki
v16_6_h v13_k1 v13_k2 v13_Km
Reactions (16)
 
 v1_fb [Pbs2] → [Pbs2P];   {Hog1PPActive} , {Pbs2} , {Hog1PPActive}
 
 v2 [Pbs2P] → [Pbs2];   {Phosphatase} , {Phosphatase} , {Pbs2P}
 
 v5 [Hog1] → [Hog1P];   {Pbs2P} , {Sho1Pbs2P} , {Pbs2P} , {Hog1} , {Sho1Pbs2P}
 
 v6 [Hog1P] → [Hog1];   {Phosphatase} , {Phosphatase} , {Hog1P}
 
 v11  → [Protein];   {RNA} , {RNA}
 
 v12 [Protein] → ;   {Protein}
 
 v13  → [Glyin];   {Protein} , {Hog1PPActive} , {Protein} , {Hog1PPActive}
 
 v14 [Glyin] ↔ [Glyex];   {Glyex} , {Glyin}
 
 v9  → [RNA];   {Hog1PPActive} , {Hog1PPActive}
 
 v10 [RNA] → ;   {RNA}
 
 v7 [Hog1P] → [Hog1PP];   {Pbs2P} , {Sho1Pbs2P} , {Pbs2P} , {Hog1P} , {Sho1Pbs2P}
 
 v8 [Hog1PP] → [Hog1P];   {Phosphatase} , {Phosphatase} , {Hog1PP}
 
 v4 [Sho1Pbs2P] → [Sho1] + [Pbs2];   {Sho1Pbs2P}
 
 v3_fb [Pbs2] + [Sho1] → [Sho1Pbs2P];   {Hog1PPActive} , {Pbs2} , {Sho1} , {Hog1PPActive}
 
 v15_5 [Fps1] → [Fps1P];   {Fps1}
 
 v16_6 [Fps1P] → [Fps1];   {Hog1PPActive} , {Fps1P} , {Hog1PPActive}
 
Rules (22)
 
 Assignment Rule (name: compartment_3) V = parameter_13+compartment_1
 
 Assignment Rule (name: parameter_16) Area = (36*pi)^(1/3)*compartment_3^(2/3)
 
 Assignment Rule (name: parameter_21) Turgor = piecewise(parameter_9*log(compartment_3/parameter_15), compartment_3 > parameter_15, 0)
 
 Assignment Rule (name: parameter_22) ActivationSln1_nlfb = piecewise((parameter_47-parameter_16)/parameter_47-parameter_24, (parameter_47-parameter_16)/parameter_47 > parameter_24, 0)
 
 Assignment Rule (name: parameter_27) ks = parameter_86*parameter_51*(1+parameter_87*parameter_54)/(parameter_88+parameter_51*(1+parameter_87*parameter_54))*parameter_46/(0.5*parameter_47*(parameter_53-parameter_50))
 
 Assignment Rule (name: parameter_28) Fps1TransportCapacitty = species_14/compartment_4/parameter_59
 
 Assignment Rule (name: parameter_29) FitVrel = 100*compartment_3/parameter_12
 
 Assignment Rule (name: parameter_30) FitHog1PPrel = 100*species_3/compartment_1*compartment_1/(parameter_14*parameter_37*parameter_46)
 
 Assignment Rule (name: parameter_31) FitProteinrel = 19.9*species_7/compartment_1*compartment_1/(parameter_51*parameter_46)
 
 Assignment Rule (name: parameter_32) FitGlyinrel = 17*species_1/compartment_1*compartment_1/(parameter_53*parameter_46)
 
 Assignment Rule (name: parameter_33) Turgor2Osm = parameter_21/(parameter_1*parameter_2*parameter_5)
 
 Assignment Rule (name: parameter_36) FitRNArel = 3.4*species_8/compartment_1*compartment_1/(parameter_52*parameter_46)
 
 Assignment Rule (name: parameter_45) Osmin = species_1/compartment_1+parameter_20*parameter_46/compartment_1
 
 Assignment Rule (name: parameter_49) cen = piecewise(parameter_11-parameter_50+(1-exp((parameter_48-time)/parameter_6))*2*parameter_4*parameter_23*10^6, time > parameter_48, parameter_11-parameter_50)
 
 Assignment Rule (name: parameter_44) Osmex = parameter_49+species_13/compartment_2
 
 Assignment Rule (name: parameter_56) ActivationSho1_nlfb = piecewise((parameter_47-parameter_16)/parameter_47-parameter_55, (parameter_47-parameter_16)/parameter_47 > parameter_55, 0)
 
 Assignment Rule (name: parameter_60) Fps1TotalTrans = species_14/compartment_4+species_15/compartment_4
 
 Assignment Rule (name: parameter_62) TurgorActivation = parameter_21^parameter_61/(parameter_8^parameter_61+parameter_21^parameter_61)
 
 Assignment Rule (name: parameter_63) TurgorDeactivation = 1-parameter_21^parameter_61/(parameter_8^parameter_61+parameter_21^parameter_61)
 
 Assignment Rule (name: parameter_69) Hog1Inhibition = piecewise(piecewise(parameter_67, time > parameter_68, 1), parameter_70 == 1, 1)
 
 Assignment Rule (name: species_12) Hog1PPActive = parameter_69*species_3/compartment_1*compartment_1
 
 Rate Rule (name: compartment_1) d [ Vos] / d t= (-parameter_7)*parameter_16*(parameter_21+parameter_5*parameter_1*parameter_2*(parameter_44-parameter_45))
 
Functions (10)
 
 1 para inh Mass action (rrev) lambda(ko, k, S, M, Ki, h, ko*k*S/(1+(M/Ki)^h))
 
 3 param mass action (irrev) lambda(ko, k, M, S, ko*k*M*S)
 
 2 param 2 S MA with inhibition (irrev) lambda(ko, k, M1, S1, S2, M2, Ki, h, ko*k*M1*S1*S2/(1+(M2/Ki)^h))
 
 Modified constant flux (irrev) lambda(k, M, k*M)
 
 transport (rev) lambda(A, P, S, f, ks, f*ks*A*(S-P))
 
 Modified mass action (irrev) lambda(k, M, S, k*M*S)
 
 2 param mod. add. constant flux MM (irrev) lambda(k1, M1, k2, M2, Km, k1*M1*(1+k2*M2)/(Km+M1*(1+k2*M2)))
 
 mod. constat flux (MM) (irrev) lambda(k, M, Km, k*M/(Km+M))
 
 mod. MA OR (irrev) lambda(k1, M1, S, k2, M2, k1*M1*S+k2*M2*S)
 
 3 param activation with inhibition (iirev) lambda(ko, k, M1, S, M2, h, Ki, ko*k*M1*S/(1+(M2/Ki)^h))
 
 Vos Spatial dimensions: 3.0  Compartment size: 29.5
 
 Glyin
Compartment: Vos
Initial amount: 5310000.0
 
 Hog1
Compartment: Vos
Initial amount: 9.6760009944572
 
 Hog1PP
Compartment: Vos
Initial amount: 0.201092527399535
 
 Pbs2
Compartment: Vos
Initial amount: 3.57956846222666
 
 Pbs2P
Compartment: Vos
Initial amount: 0.00385515442085361
 
 Phosphatase
Compartment: Vos
Initial amount: 1.27698439056792
 
 Protein
Compartment: Vos
Initial amount: 1.34008635004982
 
 RNA
Compartment: Vos
Initial amount: 1.003
 
 Hog1P
Compartment: Vos
Initial amount: 1.39490913506788
 
 Sho1
Compartment: Vos
Initial amount: 3.86572185643496
 
 Sho1Pbs2P
Compartment: Vos
Initial amount: 0.00342460653415448
 
  Hog1PPActive
Compartment: Vos
Initial amount: 0.201092527399535
 
 Vex Spatial dimensions: 3.0  Compartment size: 50000.0
 
 Glyex
Compartment: Vex
Initial amount: 9.0E7
 
  V Spatial dimensions: 3.0  Compartment size: 50.0
 M Spatial dimensions: 3.0  Compartment size: 1.0
 
 Fps1
Compartment: M
Initial amount: 0.0255278667484759
 
 Fps1P
Compartment: M
Initial amount: 0.0255278667484759
 
Global Parameters (88)
 
 R
Value: 8.314
Constant
 
 T
Value: 303.15
Constant
 
 mol
Value: 6.022E23
Constant
 
 phi
Value: 0.93
Constant
 
 c2p
Value: 1.0E-9
Constant
 
 tm
Value: 10.0
Constant
 
 Lp
Value: 0.013
Constant
 
 P0
Value: 0.61
Constant
 
 eps
Value: 14.3
Constant
 
 minf
Value: 0.41
Constant
 
 ce_0
Value: 260000.0
Constant
 
 V_0
Value: 50.0
Constant
 
 Vb
Value: 20.5
Constant
 
 maxHog1nucf
Value: 0.8
Constant
 
 VP_0
Value: 47.9119840840503
Constant
 
  Area
Value: 65.6342903668733
 
 Hog1PPrelIniwt
Value: 2.23
Constant
 
 N2uM
Value: 5.62907756305974E-5
Constant
 
 ci_0
Value: 502026.122077738
Constant
 
 cin_0
Value: 322026.122077738
Constant
 
  Turgor
Value: 0.609999999999999
 
  ActivationSln1_nlfb
Value: 7.10539561053171E-4
 
 NaCl
Value: 0.4
Constant
 
 ActivOffsetSln1_nlfb
Value: -7.10539561053171E-4
Constant
 
 kHog1phos1
Value: 42.6396538263077
Constant
 
 kHog1dephos
Value: 1.78587
Constant
 
  ks
Value: 4.28194136809108E-4
 
  Fps1TransportCapacitty
Value: 0.5
 
  FitVrel
Value: 100.0
 
  FitHog1PPrel
Value: 2.23
 
  FitProteinrel
Value: 19.9
 
  FitGlyinrel
Value: 17.0
 
  Turgor2Osm
Value: 242026.122077737
 
 Fps1ClosureRate
Value: 0.128378897200866
Constant
 
 Protein_deg_k
Value: 6.78688610600496E-5
Constant
 
  FitRNArel
Value: 3.4
 
 Hog1Total
Value: 0.382101784980495
Constant
 
 Pbs2Total
Value: 0.12158807536209
Constant
 
 RNA_deg_k_MM
Value: 7.09644965005112
Constant
 
 Sho1Total
Value: 0.131157507219292
Constant
 
 kHog1phos2
Value: 48.0003902091319
Constant
 
 Hog1PPrelIniSln1
Value: 2.23
Constant
 
 Hog1PPrelIniSho1
Value: 2.23
Constant
 
  Osmex
Value: 260000.0
 
  Osmin
Value: 502026.122077738
 
 Vos_0
Value: 29.5
Constant
 
 A_0
Value: 65.6342903668733
Constant
 
 ts
Value: 600.0
Constant
 
  cen
Value: 258200.0
 
 Glyex_0
Value: 1800.0
Constant
 
 Protein_0
Value: 0.0454266559338921
Constant
 
 RNA_0
Value: 0.034
Constant
 
 Glyin_0
Value: 180000.0
Constant
 
 Hog1PP_0
Value: 0.00681669584405203
Constant
 
 ActivOffsetSho1_nlfb
Value: -0.0036065403549782
Constant
 
  ActivationSho1_nlfb
Value: 0.0036065403549782
 
   Sho1BranchActive
Value: 1.0
Constant
 
 Sln1BranchActive
Value: 1.0
Constant
 
 Fps1TotalIni
Value: 0.0510557334969518
Constant
 
  Fps1TotalTrans
Value: 0.0510557334969518
 
 TurgorActiv_h
Value: 2.0
Constant
 
  TurgorActivation
Value: 0.499999999999999
 
   TurgorDeactivation
Value: 0.500000000000001
 
 v16_5_k
Value: 0.00264562
Constant
 
 v16_6_k
Value: 0.00320327093093651
Constant
 
 v16_7_k
Value: 0.00529124000000002
Constant
 
 Hog1Activity
Value: 0.0010
Constant
 
   tinh
Value: 600.0
Constant
 
  Hog1Inhibition
Value: 1.0
 
 Inhibition
Constant
 
 Fps1Delta
Value: 1.0
Constant
 
   v2_k
Value: 0.607124
Constant
 
   v1_fb_Ki
Value: 0.00940584
Constant
 
   v1_fb_h
Value: 0.345701
Constant
 
   v1_fb_k
Value: 0.075474
Constant
 
   v11_k
Value: 9.06781E-5
Constant
 
   v9_k
Value: 18.1824
Constant
 
   v9_Km
Value: 0.506878
Constant
 
   v4_k1
Value: 0.00226722
Constant
 
   v3_fb_Ki
Value: 0.297524
Constant
 
   v3_fb_h
Value: 2.0793
Constant
 
   v3_fb_k
Value: 0.00459138
Constant
 
   v15_5_k
Value: 0.00529124
Constant
 
   v16_6_Ki
Value: 0.0811033
Constant
 
   v16_6_h
Value: 0.628719
Constant
 
   v13_k1
Value: 680.818
Constant
 
   v13_k2
Value: 46.8363
Constant
 
   v13_Km
Value: 0.420741
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000429

Curator's comment: (updated: 22 Nov 2012 15:04:21 GMT)

The model as such reproduces the plot the correspond to 0.04M NaCl in figure 3a. Other plots can be obtained by changing the concentration of NaCl accordingly.
In addition, figure 2a can be obtained by setting Sln1BranchActive=0.

The plot data were obtained from simulating the model using SBML odeSolver. Gnuplot was used to generate the plot.

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