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BIOMD0000000431 - Sarma2012 - Interaction topologies of MAPK cascade (M4_K2_PSEQ)

 

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Reference Publication
Publication ID: 22748295
Sarma U, Ghosh I.
Different designs of kinase-phosphatase interactions and phosphatase sequestration shapes the robustness and signal flow in the MAPK cascade.
BMC Syst Biol 2012; 6: 82
National Centre for Cell Science, Ganeshkhind, Pune-7, India. uddipans@gmail.com  [more]
Model
Original Model: BIOMD0000000431.xml.origin
Submitter: Uddipan Sarma
Submission ID: MODEL1204280024
Submission Date: 28 Apr 2012 05:05:20 UTC
Last Modification Date: 30 May 2014 18:20:24 UTC
Creation Date: 23 Nov 2012 16:11:29 UTC
Encoders:  Vijayalakshmi Chelliah
   Uddipan Sarma
set #1
bqbiol:hasTaxon Taxonomy cellular organisms
bqbiol:isVersionOf Gene Ontology MAPK cascade
set #2
bqmodel:isDerivedFrom PubMed 19897477
Notes
Sarma2012 - Interaction topologies of MAPK cascade (M4_K2_PSEQ)

The paper presents the various interaction topologies between the kinases and phosphatases of MAPK cascade. They are represented as M1, M2, M3 and M4. The kinases of the cascades are MKKK, MKK and MK, and Phos1, Phos2 and Phos3 are phosphatases of the system. All three kinases in a M1 type network have specific phosphatases Phos1, Phos2 and Phos3 for the dephosphorylation process. In a M2 type system, kinases MKKK and MKK are dephosphorylated by Phos1 and MK is dephosphorylated by Phos2. The architecture of system like M3 is such that MKKK gets dephosphorylated by Phos1, whereas Phos2 dephosphorylates both MKK and MK. Finally, the MAPK cascade exhibiting more complex design of interaction such as M4 is such that MKKK and MKK are dephosphorylated by Phos1 whereas MKK and MK are dephosphorylated by Phos2. In addition, as it is plausible that the kinases can sequester their respective phosphatases by binding to them, this is considered in the design of the systems (PSEQ-sequestrated system; USEQ-Unsequestrated system). The robustness of different interaction designs of the systems is checked, considering both MichaelisMenten type kinetics (K1) and elementary mass action kinetics (K2). In the living systems, the MAPK cascade transmit both short and long duration signals where short duration signals trigger proliferation and long duration signals trigger cell differentiation. These signal variants are considered to interpret the systems behaviour. It is also tested how the robustness and signal response behaviour of K2 models are affected when K2 assumes quasi steady state (QSS). The combinations of the above variants resulted in 40 models (MODEL1204280001-MODEL1204280040). All these 40 models are available from BioModels Database .

Models that correspond to type M4 with mass-action kinetics K2, in four condition 1) USEQ [ MODEL1204280020 - M4_K2_USEQ], 2) PSEQ [ MODEL1204280024 - M4_K2_PSEQ], 3) QSS_USEQ [ MODEL1204280036 - M4_K2_QSS_USEQ] and 4) QSS_PSEQ [ MODEL1204280040 - M4_K2_QSS_PSEQ] are available from the curated branch. The remaining 36 models can be accessed from the non-curated branch.

This model [ MODEL1204280024 - M4_K2_PSEQ] correspond to type M4 with mass-action kinetics K2, in PSEQ (sequestrated ) condition. .

This model is described in the article:

Sarma U, Ghosh I.
BMC Syst Biol. 2012 Jul 2;6(1):82.

Abstract:

BACKGROUND: The three layer mitogen activated protein kinase (MAPK) signaling cascade exhibits different designs of interactions between its kinases and phosphatases. While the sequential interactions between the three kinases of the cascade are tightly preserved, the phosphatases of the cascade, such as MKP3 and PP2A, exhibit relatively diverse interactions with their substrate kinases. Additionally, the kinases of the MAPK cascade can also sequester their phosphatases. Thus, each topologically distinct interaction design of kinases and phosphatases could exhibit unique signal processing characteristics, and the presence of phosphatase sequestration may lead to further fine tuning of the propagated signal.

RESULTS: We have built four models of the MAPK cascade, each model with identical kinase-kinase interactions but unique kinases-phosphatases interactions. Our simulations unravelled that MAPK cascade's robustness to external perturbations is a function of nature of interaction between its kinases and phosphatases. The cascade's output robustness was enhanced when phosphatases were sequestrated by their target kinases. We uncovered a novel implicit/hidden negative feedback loop from the phosphatase MKP3 to its upstream kinase Raf-1, in a cascade resembling the B cell MAPK cascade. Notably, strength of the feedback loop was reciprocal to the strength of phosphatases' sequestration and stronger sequestration abolished the feedback loop completely. An experimental method to verify the presence of the feedback loop is also proposed. We further showed, when the models were activated by transient signal, memory (total time taken by the cascade output to reach its unstimulated level after removal of signal) of a cascade was determined by the specific designs of interaction among its kinases and phosphatases.

CONCLUSIONS: Differences in interaction designs among the kinases and phosphatases can differentially shape the robustness and signal response behaviour of the MAPK cascade and phosphatase sequestration dramatically enhances the robustness to perturbations in each of the cascade. An implicit negative feedback loop was uncovered from our analysis and we found that strength of the negative feedback loop is reciprocally related to the strength of phosphatase sequestration. Duration of output phosphorylation in response to a transient signal was also found to be determined by the individual cascade's kinase-phosphatase interaction design.

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: 22748295 Submission Date: 28 Apr 2012 05:05:20 UTC Last Modification Date: 30 May 2014 18:20:24 UTC Creation Date: 23 Nov 2012 16:11:29 UTC
Mathematical expressions
Reactions
15 16 17 18
19 20 21 22
23 6 7 8
9 10_P2 11_P2 12_P2
13_P2 14_P2 1 2
3 4 10_P1 11_P1
12_P1 13_P1 14_P1 5
Physical entities
Compartments Species
compartment MK MKK-PP MK_MKK-PP
MK-P MK-P_MKK-PP MK-PP
MKK MKKK-P MKK_MKKK-P
MKK-P MKK-P_MKKK-P MKK-PP_P2
P2 MKK-P_P2 MKK_P2
MKKK MKKK_Sig Sig
MKKK-P_P1 P1 MK-PP_P2
MK-P_P2 MK_P2 MKK-PP_P1
MKK-P_P1 MKK_P1 MKKK_P1
Global parameters
quantity_1      
Reactions (28)
 
 15 [MK] + [MKK-PP] ↔ [MK_MKK-PP];   {MK} , {MKK-PP} , {MK_MKK-PP}
 
 16 [MK_MKK-PP] → [MK-P] + [MKK-PP];   {MK_MKK-PP}
 
 17 [MK-P] + [MKK-PP] ↔ [MK-P_MKK-PP];   {MK-P} , {MKK-PP} , {MK-P_MKK-PP}
 
 18 [MK-P_MKK-PP] → [MK-PP] + [MKK-PP];   {MK-P_MKK-PP}
 
 19 [MK-PP] + [P2] ↔ [MK-PP_P2];   {MK-PP} , {P2} , {MK-PP_P2}
 
 20 [MK-PP_P2] → [MK-P] + [P2];   {MK-PP_P2}
 
 21 [MK-P] + [P2] ↔ [MK-P_P2];   {MK-P} , {P2} , {MK-P_P2}
 
 22 [MK-P_P2] → [MK_P2];   {MK-P_P2}
 
 23 [MK_P2] ↔ [MK] + [P2];   {MK_P2} , {MK} , {P2}
 
 6 [MKK] + [MKKK-P] ↔ [MKK_MKKK-P];   {MKK} , {MKKK-P} , {MKK_MKKK-P}
 
 7 [MKK_MKKK-P] → [MKK-P] + [MKKK-P];   {MKK_MKKK-P}
 
 8 [MKK-P] + [MKKK-P] ↔ [MKK-P_MKKK-P];   {MKK-P} , {MKKK-P} , {MKK-P_MKKK-P}
 
 9 [MKK-P_MKKK-P] → [MKK-PP] + [MKKK-P];   {MKK-P_MKKK-P}
 
 10_P2 [MKK-PP] + [P2] ↔ [MKK-PP_P2];   {MKK-PP} , {P2} , {MKK-PP_P2}
 
 11_P2 [MKK-PP_P2] → [MKK-P] + [P2];   {MKK-PP_P2}
 
 12_P2 [MKK-P] + [P2] ↔ [MKK-P_P2];   {MKK-P} , {P2} , {MKK-P_P2}
 
 13_P2 [MKK-P_P2] → [MKK_P2];   {MKK-P_P2}
 
 14_P2 [MKK_P2] ↔ [MKK] + [P2];   {MKK_P2} , {MKK} , {P2}
 
 1 [MKKK] + [Sig] ↔ [MKKK_Sig];   {MKKK} , {Sig} , {MKKK_Sig}
 
 2 [MKKK_Sig] → [MKKK-P] + [Sig];   {MKKK_Sig}
 
 3 [MKKK-P] + [P1] ↔ [MKKK-P_P1];   {MKKK-P} , {P1} , {MKKK-P_P1}
 
 4 [MKKK-P_P1] → [MKKK_P1];   {MKKK-P_P1}
 
 10_P1 [MKK-PP] + [P1] ↔ [MKK-PP_P1];   {MKK-PP} , {P1} , {MKK-PP_P1}
 
 11_P1 [MKK-PP_P1] → [MKK-P] + [P1];   {MKK-PP_P1}
 
 12_P1 [MKK-P] + [P1] ↔ [MKK-P_P1];   {MKK-P} , {P1} , {MKK-P_P1}
 
 13_P1 [MKK-P_P1] → [MKK_P1];   {MKK-P_P1}
 
 14_P1 [MKK_P1] ↔ [MKK] + [P1];   {MKK_P1} , {MKK} , {P1}
 
 5 [MKKK_P1] ↔ [MKKK] + [P1];   {MKKK_P1} , {MKKK} , {P1}
 
 compartment Spatial dimensions: 3.0  Compartment size: 1.0
 
 MK
Compartment: compartment
Initial concentration: 1200.0
 
 MKK-PP
Compartment: compartment
Initial concentration: 0.0
 
 MK_MKK-PP
Compartment: compartment
Initial concentration: 0.0
 
 MK-P
Compartment: compartment
Initial concentration: 0.0
 
 MK-P_MKK-PP
Compartment: compartment
Initial concentration: 0.0
 
 MK-PP
Compartment: compartment
Initial concentration: 0.0
 
 MKK
Compartment: compartment
Initial concentration: 1200.0
 
 MKKK-P
Compartment: compartment
Initial concentration: 0.0
 
 MKK_MKKK-P
Compartment: compartment
Initial concentration: 0.0
 
 MKK-P
Compartment: compartment
Initial concentration: 0.0
 
 MKK-P_MKKK-P
Compartment: compartment
Initial concentration: 0.0
 
 MKK-PP_P2
Compartment: compartment
Initial concentration: 0.0
 
 P2
Compartment: compartment
Initial concentration: 200.0
 
 MKK-P_P2
Compartment: compartment
Initial concentration: 0.0
 
 MKK_P2
Compartment: compartment
Initial concentration: 0.0
 
 MKKK
Compartment: compartment
Initial concentration: 300.0
 
 MKKK_Sig
Compartment: compartment
Initial concentration: 0.0
 
 Sig
Compartment: compartment
Initial concentration: 10.0
 
 MKKK-P_P1
Compartment: compartment
Initial concentration: 0.0
 
 P1
Compartment: compartment
Initial concentration: 100.0
 
 MK-PP_P2
Compartment: compartment
Initial concentration: 0.0
 
 MK-P_P2
Compartment: compartment
Initial concentration: 0.0
 
 MK_P2
Compartment: compartment
Initial concentration: 0.0
 
 MKK-PP_P1
Compartment: compartment
Initial concentration: 0.0
 
 MKK-P_P1
Compartment: compartment
Initial concentration: 0.0
 
 MKK_P1
Compartment: compartment
Initial concentration: 0.0
 
 MKKK_P1
Compartment: compartment
Initial concentration: 0.0
 
Global Parameters (1)
 
 quantity_1
Constant
 
15 (2)
 
   k1
Value: 0.02
Constant
 
   k2
Value: 1.0
Constant
 
16 (1)
 
   k1
Value: 0.01
Constant
 
17 (2)
 
   k1
Value: 0.032
Constant
 
   k2
Value: 1.0
Constant
 
18 (1)
 
   k1
Value: 15.0
Constant
 
19 (2)
 
   k1
Value: 0.045
Constant
 
   k2
Value: 1.0
Constant
 
20 (1)
 
   k1
Value: 0.092
Constant
 
21 (2)
 
   k1
Value: 0.01
Constant
 
   k2
Value: 1.0
Constant
 
22 (1)
 
   k1
Value: 0.5
Constant
 
23 (2)
 
   k1
Value: 0.086
Constant
 
   k2
Value: 0.0050
Constant
 
6 (2)
 
   k1
Value: 0.02
Constant
 
   k2
Value: 1.0
Constant
 
7 (1)
 
   k1
Value: 0.01
Constant
 
8 (2)
 
   k1
Value: 0.032
Constant
 
   k2
Value: 1.0
Constant
 
9 (1)
 
   k1
Value: 15.0
Constant
 
10_P2 (2)
 
   k1
Value: 0.045
Constant
 
   k2
Value: 1.0
Constant
 
11_P2 (1)
 
   k1
Value: 0.092
Constant
 
12_P2 (2)
 
   k1
Value: 0.01
Constant
 
   k2
Value: 1.0
Constant
 
13_P2 (1)
 
   k1
Value: 0.5
Constant
 
14_P2 (2)
 
   k1
Value: 0.086
Constant
 
   k2
Value: 0.0050
Constant
 
1 (2)
 
   k1
Value: 0.02
Constant
 
   k2
Value: 1.0
Constant
 
2 (1)
 
   k1
Value: 1.0
Constant
 
3 (2)
 
   k1
Value: 0.02
Constant
 
   k2
Value: 1.0
Constant
 
4 (1)
 
   k1
Value: 0.5
Constant
 
10_P1 (2)
 
   k1
Value: 0.045
Constant
 
   k2
Value: 1.0
Constant
 
11_P1 (1)
 
   k1
Value: 0.092
Constant
 
12_P1 (2)
 
   k1
Value: 0.01
Constant
 
   k2
Value: 1.0
Constant
 
13_P1 (1)
 
   k1
Value: 0.5
Constant
 
14_P1 (2)
 
   k1
Value: 0.086
Constant
 
   k2
Value: 0.0050
Constant
 
5 (2)
 
   k1
Value: 0.086
Constant
 
   k2
Value: 0.0050
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000431

Curator's comment: (updated: 23 Nov 2012 16:10:58 GMT)

The model [M4_K2_PSEQ] correspond to type M4 with mass-action kinetics K2, in PSEQ (sequestrated ) condition. Figure 5b is reproduced by setting P2=5nM and 1000nM.
The simulation was done using SBML odeSolver and the plot was generated using Gnuplot.

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