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BIOMD0000000343 - Brannmark2010_InsulinSignalling_Mifamodel

 

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Reference Publication
Publication ID: 20421297
Brännmark C, Palmér R, Glad ST, Cedersund G, Strålfors P.
Mass and information feedbacks through receptor endocytosis govern insulin signaling as revealed using a parameter-free modeling framework.
J. Biol. Chem. 2010 Jun; 285(26): 20171-20179
Division of Cell Biology, Department of Clinical and Experimental Medicine, Laboratory of Diabetes and Integrated Systems Biology, Linköping University, SE58185 Linköping, Sweden.  [more]
Model
Original Model: BIOMD0000000343.origin
Submitter: Ishan Ajmera
Submission ID: MODEL1107140000
Submission Date: 14 Jul 2011 14:06:25 UTC
Last Modification Date: 08 Apr 2016 18:01:02 UTC
Creation Date: 14 Jul 2011 15:54:55 UTC
Encoders:  Ishan Ajmera
set #1
bqbiol:hasProperty Human Disease Ontology diabetes mellitus
set #2
bqbiol:isVersionOf Gene Ontology insulin receptor internalization
set #3
bqbiol:occursIn Brenda Tissue Ontology adipocyte
set #4
bqbiol:isPartOf Gene Ontology insulin receptor signaling pathway
set #5
bqbiol:hasTaxon Taxonomy Homo sapiens
Notes

This model is from the article:
Mass and information feedbacks through receptor endocytosis govern insulin signaling as revealed using a parameter-free modeling framework.
Brannmark C, Palmer R, Glad ST, Cedersund G, Stralfors P. J Biol Chem.2010 Jun 25;285(26):20171-9. 20421297,
Abstract:
Insulin and other hormones control target cells through a network of signal-mediating molecules. Such networks are extremely complex due to multiple feedback loops in combination with redundancy, shared signal mediators, and cross-talk between signal pathways. We present a novel framework that integrates experimental work and mathematical modeling to quantitatively characterize the role and relation between co-existing submechanisms in complex signaling networks. The approach is independent of knowing or uniquely estimating model parameters because it only relies on (i) rejections and (ii) core predictions (uniquely identified properties in unidentifiable models). The power of our approach is demonstrated through numerous iterations between experiments, model-based data analyses, and theoretical predictions to characterize the relative role of co-existing feedbacks governing insulin signaling. We examined phosphorylation of the insulin receptor and insulin receptor substrate-1 and endocytosis of the receptor in response to various different experimental perturbations in primary human adipocytes. The analysis revealed that receptor endocytosis is necessary for two identified feedback mechanisms involving mass and information transfer, respectively. Experimental findings indicate that interfering with the feedback may substantially increase overall signaling strength, suggesting novel therapeutic targets for insulin resistance and type 2 diabetes. Because the central observations are present in other signaling networks, our results may indicate a general mechanism in hormonal control.

Model
Publication ID: 20421297 Submission Date: 14 Jul 2011 14:06:25 UTC Last Modification Date: 08 Apr 2016 18:01:02 UTC Creation Date: 14 Jul 2011 15:54:55 UTC
Mathematical expressions
Rules
Assignment Rule (variable: measanna) Assignment Rule (variable: measdosR) Assignment Rule (variable: measdoublestep) Assignment Rule (variable: V1a)
Assignment Rule (variable: V1b) Assignment Rule (variable: V1c) Assignment Rule (variable: V1d) Assignment Rule (variable: V1e)
Assignment Rule (variable: V1g) Assignment Rule (variable: v1r) Assignment Rule (variable: V2) Assignment Rule (variable: Vm2)
Assignment Rule (variable: V3) Assignment Rule (variable: Vm3) Assignment Rule (variable: simXp) Assignment Rule (variable: intamount)
Rate Rule (variable: IR) Rate Rule (variable: IRins) Rate Rule (variable: IRp) Rate Rule (variable: IRip)
Rate Rule (variable: IRi) Rate Rule (variable: IRS) Rate Rule (variable: IRSip) Rate Rule (variable: X)
Rate Rule (variable: Xp)      
Physical entities
Compartments Species
compartemnt 1 IR IRins IRp
IRip IRi IRS
IRSip X Xp
V1a V1b V1c
V1d V1e V1g
v1r V2 Vm2
V3 Vm3 simXp
intamount measIRp measdoublestep
measanna measdosR  
Global parameters
k1a k1abasic k1b k1e
k1f k1g k1r k21
k22 km2 k3 km3
ky1 ky2 kyanna kyDosR
ins k1c k1d  
Reactions (0)
Rules (25)
 
 Assignment Rule (name: measanna) measanna = kyanna*IRSip
 
 Assignment Rule (name: measdosR) measdosR = kyDosR*IRSip
 
 Assignment Rule (name: measdoublestep) measdoublestep = ky2*IRSip
 
 Assignment Rule (name: V1a) V1a = k1a*ins*IR+k1abasic*IR
 
 Assignment Rule (name: V1b) V1b = k1b*IRins
 
 Assignment Rule (name: V1c) V1c = k1c*IRins
 
 Assignment Rule (name: V1d) V1d = k1d*IRp
 
 Assignment Rule (name: V1e) V1e = IRip*(k1e+k1f*Xp/(1+Xp))
 
 Assignment Rule (name: V1g) V1g = k1g*IRp
 
 Assignment Rule (name: V1r) v1r = k1r*IRi
 
 Assignment Rule (name: V2) V2 = k21*(IRp+k22*IRip)*IRS
 
 Assignment Rule (name: Vm2) Vm2 = km2*IRSip
 
 Assignment Rule (name: V3) V3 = k3*X*IRSip
 
 Assignment Rule (name: Vm3) Vm3 = km3*Xp
 
 Assignment Rule (name: simXP) simXp = Xp
 
 Assignment Rule (name: intamount) intamount = (IRi+IRip)/10
 
 Rate Rule (name: IR) d [ IR] / d t= (-V1a)+V1b+V1r+V1g
 
 Rate Rule (name: IRins) d [ IRins] / d t= (V1a-V1b)-V1c
 
 Rate Rule (name: IRp) d [ IRp] / d t= (V1c-V1d)-V1g
 
 Rate Rule (name: IRip) d [ IRip] / d t= V1d-V1e
 
 Rate Rule (name: IRi) d [ IRi] / d t= V1e-V1r
 
 Rate Rule (name: IRS) d [ IRS] / d t= (-V2)+Vm2
 
 Rate Rule (name: IRSip) d [ IRSip] / d t= V2-Vm2
 
 Rate Rule (name: X) d [ X] / d t= (-V3)+Vm3
 
 Rate Rule (name: Xp) d [ Xp] / d t= V3-Vm3
 
   compartemnt 1 Spatial dimensions: 3.0  Compartment size: 1.0
 
 IR
Compartment: compartemnt 1
Initial amount: 10.0
 
 IRins
Compartment: compartemnt 1
Initial amount: 0.0
 
 IRp
Compartment: compartemnt 1
Initial amount: 0.0
 
 IRip
Compartment: compartemnt 1
Initial amount: 0.0
 
 IRi
Compartment: compartemnt 1
Initial amount: 0.0
 
 IRS
Compartment: compartemnt 1
Initial concentration: 10.0
 
 IRSip
Compartment: compartemnt 1
Initial amount: 0.0
 
 X
Compartment: compartemnt 1
Initial amount: 10.0
 
 Xp
Compartment: compartemnt 1
Initial amount: 0.0
 
   V1a
Compartment: compartemnt 1
Initial concentration: 389.41271264
 
   V1b
Compartment: compartemnt 1
Initial concentration: 0.0
 
   V1c
Compartment: compartemnt 1
Initial concentration: 0.0
 
   V1d
Compartment: compartemnt 1
Initial concentration: 0.0
 
   V1e
Compartment: compartemnt 1
Initial concentration: 0.0
 
   V1g
Compartment: compartemnt 1
Initial concentration: 0.0
 
   v1r
Compartment: compartemnt 1
Initial concentration: 0.0
 
   V2
Compartment: compartemnt 1
Initial concentration: 0.0
 
   Vm2
Compartment: compartemnt 1
Initial concentration: 0.0
 
   V3
Compartment: compartemnt 1
Initial concentration: 0.0
 
   Vm3
Compartment: compartemnt 1
Initial concentration: 0.0
 
   simXp
Compartment: compartemnt 1
Initial concentration: 0.0
 
   intamount
Compartment: compartemnt 1
Initial concentration: 0.0
 
 measIRp
Compartment: compartemnt 1
Initial concentration: 1.0
 
   measdoublestep
Compartment: compartemnt 1
Initial concentration: 0.0
 
   measanna
Compartment: compartemnt 1
Initial concentration: 0.0
 
   measdosR
Compartment: compartemnt 1
Initial concentration: 0.0
 
Global Parameters (19)
 
 k1a
Value: 0.3892881852
Constant
 
 k1abasic
Value: 0.012452744
Constant
 
 k1b
Value: 0.02000224505
Constant
 
 k1e
Value: 4.38334E-5
Constant
 
 k1f
Value: 20.0726035037
Constant
 
 k1g
Value: 286.6994648072
Constant
 
 k1r
Value: 3.6327773442
Constant
 
 k21
Value: 1.6722503302
Constant
 
 k22
Value: 0.036381619
Constant
 
 km2
Value: 32.5942371891
Constant
 
 k3
Value: 1.6286590231
Constant
 
 km3
Value: 0.1131073982
Constant
 
 ky1
Value: 152.9631668536
Constant
 
 ky2
Value: 8936.219557405
Constant
 
 kyanna
Value: 16760.1203140926
Constant
 
 kyDosR
Value: 13740.4321729991
Constant
 
 ins
Value: 100.0
Constant
 
 k1c
Value: 0.3635167928
Constant
 
 k1d
Value: 1580.6782649401
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000343

Curator's comment: (updated: 15 Jul 2011 23:09:48 GMT)

The model produced fig 5 of the reference publication.
Plot G corresponds to the blocked internalization (kd1=0).
An event function representing two step addition of insulin is included in the model to produce plot D. A separate SBML file with event function is provided in the supporting file section.

Additional file(s)
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