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BIOMD0000000478 - Besozzi2012 - Oscillatory regimes in the Ras/cAMP/PKA pathway in S.cerevisiae

 

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Reference Publication
Publication ID: 22818197
Besozzi D, Cazzaniga P, Pescini D, Mauri G, Colombo S, Martegani E.
The role of feedback control mechanisms on the establishment of oscillatory regimes in the Ras/cAMP/PKA pathway in S. cerevisiae.
EURASIP J Bioinform Syst Biol 2012; 2012(1): 10
Universit√† degli Studi di Milano, Dipartimento di Informatica, Via Comelico 39, 20135 Milano, Italy. besozzi@di.unimi.it.  [more]
Model
Original Model: BIOMD0000000478.origin
Submitter: Paolo Cazzaniga
Submission ID: MODEL1309060000
Submission Date: 06 Sep 2013 14:52:15 UTC
Last Modification Date: 10 Mar 2014 15:38:27 UTC
Creation Date: 11 Sep 2013 11:38:48 UTC
Encoders:  Vijayalakshmi Chelliah
   Daniela Besozzi
set #1
bqbiol:hasPart Gene Ontology protein kinase A signaling
Gene Ontology cAMP-mediated signaling
Pathway Ontology protein kinase A (PKA) signaling pathway
bqbiol:hasTaxon Taxonomy Saccharomyces cerevisiae
bqbiol:hasProperty Mathematical Modelling Ontology MAMO_0000046
set #2
bqmodel:isDerivedFrom PubMed 21741466
PubMed 18023904
Notes
Besozzi2012 - Oscillatory regimes in the Ras/cAMP/PKA pathway in S.cerevisiae

Mechanistic model of the Ras/cAMP/PKA in yeast S.cerevisiae. The Ras/cAMP/PKA pathway plays a major role in the regulation of metabolism, stress resistance and cell cycle progress and is tightly regulated by multiple feedback loops, exerted by the protein kinase A (PKA). This model investigates the dynamics of the second messenger cAMP on Ras/cAMP/PKA pathway, to determine the effects of the feedback mechanisms on establising stable oscillatory regimes.

The model has been defined according to the stochastic formulation of chemical kinetics [Gillespie DT, 1977] , which requires to specify the set of molecular species occurring in the pathway and their respective interactions, formally described as a set of biochemical reactions.

The volume considered for this system is 30fL; this value can be used to convert the model into the deterministic formulation.

This model is described in the article:

Besozzi D, Cazzaniga P, Pescini D, Mauri G, Colombo S, Martegani E.
EURASIP J Bioinform Syst Biol. 2012 Jul 20;2012(1):10.

Abstract:

In the yeast Saccharomyces cerevisiae, the Ras/cAMP/PKA pathway is involved in the regulation of cell growth and proliferation in response to nutritional sensing and stress conditions. The pathway is tightly regulated by multiple feedback loops, exerted by the protein kinase A (PKA) on a few pivotal components of the pathway. In this article, we investigate the dynamics of the second messenger cAMP by performing stochastic simulations and parameter sweep analysis of a mechanistic model of the Ras/cAMP/PKA pathway, to determine the effects that the modulation of these feedback mechanisms has on the establishment of stable oscillatory regimes. In particular, we start by studying the role of phosphodiesterases, the enzymes that catalyze the degradation of cAMP, which represent the major negative feedback in this pathway. Then, we show the results on cAMP oscillations when perturbing the amount of protein Cdc25 coupled with the alteration of the intracellular ratio of the guanine nucleotides (GTP/GDP), which are known to regulate the switch of the GTPase Ras protein. This multi-level regulation of the amplitude and frequency of oscillations in the Ras/cAMP/PKA pathway might act as a fine tuning mechanism for the downstream targets of PKA, as also recently evidenced by some experimental investigations on the nucleocytoplasmic shuttling of the transcription factor Msn2 in yeast cells.

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: 22818197 Submission Date: 06 Sep 2013 14:52:15 UTC Last Modification Date: 10 Mar 2014 15:38:27 UTC Creation Date: 11 Sep 2013 11:38:48 UTC
Mathematical expressions
Reactions
R0 R1 R2 R3
R4 R5 R6 R7
R8 R9 R10 R11
R12 R13 R14 R15
R16 R17 R18 R19
R20 R21 R22 R23
R24 R25 R26 R27
R28 R29 R30 R31
R32 R33 R34 R35
R36 R37 R38  
Physical entities
Compartments Species
compartment01 Ras2_GDP Cdc25 Ras2_GDP_Cdc25
Ras2_Cdc25 GDP GTP
Ras2_GTP_Cdc25 Ras2_GTP Ira2
Ras2_GTP_Ira2 CYR1 Ras2_GTP_CYR1
ATP cAMP PKA
cAMP_PKA IIcAMP_PKA IIIcAMP_PKA
IVcAMP_PKA C R_2cAMP
R R_C Pde1
Pde1f cAMP_Pde1f AMP
PPA2 Pde2 cAMP_Pde2
Cdc25f Ira2P Ras2_GTP_Ira2P
Global parameters
K0 K1 K2 K3
K4 K5 K6 K7
K8 K9 K10 K11
K12 K13 K14 K15
K16 K17 K18 K19
K20 K21 K22 K23
K24 K25 K26 K27
K28 K29 K30 K31
K32 K33 K34 K35
K36 K37 K38  
Reactions (39)
 
 R0 [Ras2_GDP] + [Cdc25] → [Ras2_GDP_Cdc25];   {Ras2_GDP} , {Cdc25}
 
 R1 [Ras2_GDP_Cdc25] → [Ras2_GDP] + [Cdc25];   {Ras2_GDP_Cdc25}
 
 R2 [Ras2_GDP_Cdc25] → [Ras2_Cdc25] + [GDP];   {Ras2_GDP_Cdc25}
 
 R3 [Ras2_Cdc25] + [GDP] → [Ras2_GDP_Cdc25];   {Ras2_Cdc25} , {GDP}
 
 R4 [Ras2_Cdc25] + [GTP] → [Ras2_GTP_Cdc25];   {Ras2_Cdc25} , {GTP}
 
 R5 [Ras2_GTP_Cdc25] → [Ras2_Cdc25] + [GTP];   {Ras2_GTP_Cdc25}
 
 R6 [Ras2_GTP_Cdc25] → [Cdc25] + [Ras2_GTP];   {Ras2_GTP_Cdc25}
 
 R7 [Cdc25] + [Ras2_GTP] → [Ras2_GTP_Cdc25];   {Cdc25} , {Ras2_GTP}
 
 R8 [Ras2_GTP] + [Ira2] → [Ras2_GTP_Ira2];   {Ras2_GTP} , {Ira2}
 
 R9 [Ras2_GTP_Ira2] → [Ras2_GDP] + [Ira2];   {Ras2_GTP_Ira2}
 
 R10 [Ras2_GTP] + [CYR1] → [Ras2_GTP_CYR1];   {Ras2_GTP} , {CYR1}
 
 R11 [Ras2_GTP_CYR1] + [ATP] → [Ras2_GTP_CYR1] + [cAMP];   {Ras2_GTP_CYR1} , {ATP}
 
 R12 [Ira2] + [Ras2_GTP_CYR1] → [Ras2_GDP] + [Ira2] + [CYR1];   {Ira2} , {Ras2_GTP_CYR1}
 
 R13 [cAMP] + [PKA] → [cAMP_PKA];   {cAMP} , {PKA}
 
 R14 [cAMP] + [cAMP_PKA] → [IIcAMP_PKA];   {cAMP} , {cAMP_PKA}
 
 R15 [cAMP] + [IIcAMP_PKA] → [IIIcAMP_PKA];   {cAMP} , {IIcAMP_PKA}
 
 R16 [cAMP] + [IIIcAMP_PKA] → [IVcAMP_PKA];   {cAMP} , {IIIcAMP_PKA}
 
 R17 [IVcAMP_PKA] → [cAMP] + [IIIcAMP_PKA];   {IVcAMP_PKA}
 
 R18 [IIIcAMP_PKA] → [cAMP] + [IIcAMP_PKA];   {IIIcAMP_PKA}
 
 R19 [IIcAMP_PKA] → [cAMP] + [cAMP_PKA];   {IIcAMP_PKA}
 
 R20 [cAMP_PKA] → [cAMP] + [PKA];   {cAMP_PKA}
 
 R21 [IVcAMP_PKA] → 2.0 × [C] + 2.0 × [R_2cAMP];   {IVcAMP_PKA}
 
 R22 [R_2cAMP] → 2.0 × [cAMP] + [R];   {R_2cAMP}
 
 R23 [C] + [R] → [R_C];   {C} , {R}
 
 R24 2.0 × [R_C] → [PKA];   {R_C}
 
 R25 [C] + [Pde1] → [C] + [Pde1f];   {C} , {Pde1}
 
 R26 [cAMP] + [Pde1f] → [cAMP_Pde1f];   {cAMP} , {Pde1f}
 
 R27 [cAMP_Pde1f] → [cAMP] + [Pde1f];   {cAMP_Pde1f}
 
 R28 [cAMP_Pde1f] → [Pde1f] + [AMP];   {cAMP_Pde1f}
 
 R29 [Pde1f] + [PPA2] → [Pde1] + [PPA2];   {Pde1f} , {PPA2}
 
 R30 [cAMP] + [Pde2] → [cAMP_Pde2];   {cAMP} , {Pde2}
 
 R31 [cAMP_Pde2] → [cAMP] + [Pde2];   {cAMP_Pde2}
 
 R32 [cAMP_Pde2] → [AMP] + [Pde2];   {cAMP_Pde2}
 
 R33 [Cdc25] + [C] → [C] + [Cdc25f];   {Cdc25} , {C}
 
 R34 [PPA2] + [Cdc25f] → [Cdc25] + [PPA2];   {PPA2} , {Cdc25f}
 
 R35 [Ira2] + [C] → [C] + [Ira2P];   {Ira2} , {C}
 
 R36 [Ras2_GTP] + [Ira2P] → [Ras2_GTP_Ira2P];   {Ras2_GTP} , {Ira2P}
 
 R37 [Ras2_GTP_Ira2P] → [Ras2_GDP] + [Ira2P];   {Ras2_GTP_Ira2P}
 
 R38 [Ira2P] → [Ira2];   {Ira2P}
 
  Spatial dimensions: 3.0  Compartment size: 1.0
 
 Ras2_GDP
Compartment: compartment01
Initial amount: 20000.0
 
 Cdc25
Compartment: compartment01
Initial amount: 300.0
 
 Ras2_GDP_Cdc25
Compartment: compartment01
Initial amount: 0.0
 
 Ras2_Cdc25
Compartment: compartment01
Initial amount: 0.0
 
 GDP
Compartment: compartment01
Initial amount: 1500000.0
Constant
 
 GTP
Compartment: compartment01
Initial amount: 5000000.0
Constant
 
 Ras2_GTP_Cdc25
Compartment: compartment01
Initial amount: 0.0
 
 Ras2_GTP
Compartment: compartment01
Initial amount: 0.0
 
 Ira2
Compartment: compartment01
Initial amount: 200.0
 
 Ras2_GTP_Ira2
Compartment: compartment01
Initial amount: 0.0
 
 CYR1
Compartment: compartment01
Initial amount: 200.0
 
 Ras2_GTP_CYR1
Compartment: compartment01
Initial amount: 0.0
 
 ATP
Compartment: compartment01
Initial amount: 2.4E7
Constant
 
 cAMP
Compartment: compartment01
Initial amount: 0.0
 
 PKA
Compartment: compartment01
Initial amount: 2500.0
 
 cAMP_PKA
Compartment: compartment01
Initial amount: 0.0
 
 IIcAMP_PKA
Compartment: compartment01
Initial amount: 0.0
 
 IIIcAMP_PKA
Compartment: compartment01
Initial amount: 0.0
 
 IVcAMP_PKA
Compartment: compartment01
Initial amount: 0.0
 
 C
Compartment: compartment01
Initial amount: 0.0
 
 R_2cAMP
Compartment: compartment01
Initial amount: 0.0
 
 R
Compartment: compartment01
Initial amount: 0.0
 
 R_C
Compartment: compartment01
Initial amount: 0.0
 
 Pde1
Compartment: compartment01
Initial amount: 1400.0
 
 Pde1f
Compartment: compartment01
Initial amount: 0.0
 
 cAMP_Pde1f
Compartment: compartment01
Initial amount: 0.0
 
 AMP
Compartment: compartment01
Initial amount: 0.0
 
 PPA2
Compartment: compartment01
Initial amount: 4000.0
 
 Pde2
Compartment: compartment01
Initial amount: 6500.0
 
 cAMP_Pde2
Compartment: compartment01
Initial amount: 0.0
 
 Cdc25f
Compartment: compartment01
Initial amount: 0.0
 
 Ira2P
Compartment: compartment01
Initial amount: 0.0
 
 Ras2_GTP_Ira2P
Compartment: compartment01
Initial amount: 0.0
 
Global Parameters (39)
 
   K0
Value: 1.0   (Units: per_second)
Constant
 
   K1
Value: 1.0   (Units: per_second)
Constant
 
   K2
Value: 1.5   (Units: per_second)
Constant
 
   K3
Value: 1.0   (Units: per_second)
Constant
 
   K4
Value: 1.0   (Units: per_second)
Constant
 
   K5
Value: 1.0   (Units: per_second)
Constant
 
   K6
Value: 1.0   (Units: per_second)
Constant
 
   K7
Value: 1.0   (Units: per_second)
Constant
 
   K8
Value: 0.01   (Units: per_second)
Constant
 
   K9
Value: 0.25   (Units: per_second)
Constant
 
   K10
Value: 0.001   (Units: per_second)
Constant
 
   K11
Value: 2.1E-6   (Units: per_second)
Constant
 
   K12
Value: 0.001   (Units: per_second)
Constant
 
   K13
Value: 1.0E-5   (Units: per_second)
Constant
 
   K14
Value: 1.0E-5   (Units: per_second)
Constant
 
   K15
Value: 1.0E-5   (Units: per_second)
Constant
 
   K16
Value: 1.0E-5   (Units: per_second)
Constant
 
   K17
Value: 0.1   (Units: per_second)
Constant
 
   K18
Value: 0.1   (Units: per_second)
Constant
 
   K19
Value: 0.1   (Units: per_second)
Constant
 
   K20
Value: 0.1   (Units: per_second)
Constant
 
   K21
Value: 1.0   (Units: per_second)
Constant
 
   K22
Value: 1.0   (Units: per_second)
Constant
 
   K23
Value: 0.75   (Units: per_second)
Constant
 
   K24
Value: 1.0   (Units: per_second)
Constant
 
   K25
Value: 1.0E-6   (Units: per_second)
Constant
 
   K26
Value: 0.1   (Units: per_second)
Constant
 
   K27
Value: 0.1   (Units: per_second)
Constant
 
   K28
Value: 7.5   (Units: per_second)
Constant
 
   K29
Value: 1.0E-4   (Units: per_second)
Constant
 
   K30
Value: 1.0E-4   (Units: per_second)
Constant
 
   K31
Value: 1.0   (Units: per_second)
Constant
 
   K32
Value: 1.7   (Units: per_second)
Constant
 
   K33
Value: 1.0   (Units: per_second)
Constant
 
   K34
Value: 0.01   (Units: per_second)
Constant
 
   K35
Value: 0.001   (Units: per_second)
Constant
 
   K36
Value: 1.25   (Units: per_second)
Constant
 
   K37
Value: 2.5   (Units: per_second)
Constant
 
   K38
Value: 10.0   (Units: per_second)
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000478

Curator's comment: (updated: 11 Sep 2013 12:38:21 BST)

Figure 6 of the corresponding publication has been reproduced here. The value for Cdc25 in the model is 300. The deterministic and stochastic simulation results for cAMP at different values of Cdc25 has been obtained using Copasi v4.10 (Build 55). For stochastic simulation - Stochastic (Gibson + Bruck) algorithm was used. For deterministc simulation - Determininstic (LSODA) algorithm was used. The simulation data were obtained from Copasi and the plots were generated using Gnuplot.

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