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BIOMD0000000263 - Fujita2010_Akt_Signalling_NGF

 

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Reference Publication
Publication ID: 20664065
Fujita KA, Toyoshima Y, Uda S, Ozaki Y, Kubota H, Kuroda S.
Decoupling of receptor and downstream signals in the Akt pathway by its low-pass filter characteristics.
Sci Signal 2010; 3(132): ra56
Department of Computational Biology, Graduate School of Frontier Sciences, University of Tokyo, Kshiwanoha 5-1-5, Kashiwa, Chiba 277-8568, Japan.  [more]
Model
Original Model: BIOMD0000000263.origin
Submitter: Kazuhiro Fujita
Submission ID: MODEL1004060002
Submission Date: 06 Apr 2010 07:55:17 UTC
Last Modification Date: 21 Feb 2014 11:25:30 UTC
Creation Date: 24 Aug 2010 12:00:29 UTC
Encoders:  Lukas Endler
   Kazuhiro Fujita
set #1
bqbiol:hasVersion Reactome REACT_12464.1
Reactome REACT_12056
Gene Ontology neurotrophin TRK receptor signaling pathway
Gene Ontology protein kinase B signaling
bqbiol:occursIn Brenda Tissue Ontology PC-12 cell
set #2
bqbiol:hasTaxon Taxonomy Rattus norvegicus
Notes

NGF dependent Akt pathway model

made by Kazuhiro A. Fujita.

This is the NGF dependent Akt pathway model described in:
Decoupling of receptor and downstream signals in the Akt pathway by its low-pass filter characteristics.
Fujita KA, Toyoshima Y, Uda S, Ozaki Y, Kubota H, and Kuroda S. Sci Signal. 2010 Jul 27;3(132):ra56. PMID: 20664065 ; DOI: 10.1126/scisignal.2000810
Abstract:
In cellular signal transduction, the information in an external stimulus is encoded in temporal patterns in the activities of signaling molecules; for example, pulses of a stimulus may produce an increasing response or may produce pulsatile responses in the signaling molecules. Here, we show how the Akt pathway, which is involved in cell growth, specifically transmits temporal information contained in upstream signals to downstream effectors. We modeled the epidermal growth factor (EGF)–dependent Akt pathway in PC12 cells on the basis of experimental results. We obtained counterintuitive results indicating that the sizes of the peak amplitudes of receptor and downstream effector phosphorylation were decoupled; weak, sustained EGF receptor (EGFR) phosphorylation, rather than strong, transient phosphorylation, strongly induced phosphorylation of the ribosomal protein S6, a molecule downstream of Akt. Using frequency response analysis, we found that a three-component Akt pathway exhibited the property of a low-pass filter and that this property could explain decoupling of the peak amplitudes of receptor phosphorylation and that of downstream effectors. Furthermore, we found that lapatinib, an EGFR inhibitor used as an anticancer drug, converted strong, transient Akt phosphorylation into weak, sustained Akt phosphorylation, and, because of the low-pass filter characteristics of the Akt pathway, this led to stronger S6 phosphorylation than occurred in the absence of the inhibitor. Thus, an EGFR inhibitor can potentially act as a downstream activator of some effectors.

The different versions of input, step, pulse and ramp, can be simulated using the parameters NGF_conc_pulse , NGF_conc_step and NGF_conc_ramp . Depending on which one is set unequal to 0, either a continous pulse with value NGF_conc_pulse , a 60 second step with NGF_conc_step or a signal increasing from 0 to NGF_conc_pulse over a time periode of 3600 seconds are used as input. In case more than one parameter is set to values greater than 0 these input profiles are added to each other. The pulse time and the time over which the ramp input increases can be set by pulse_time and ramp_time .

This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2010 The BioModels Team.
For more information see the terms of use .
To cite BioModels Database, please use Le Novère N., Bornstein B., Broicher A., Courtot M., Donizelli M., Dharuri H., Li L., Sauro H., Schilstra M., Shapiro B., Snoep J.L., Hucka M. (2006) BioModels Database: A Free, Centralized Database of Curated, Published, Quantitative Kinetic Models of Biochemical and Cellular Systems Nucleic Acids Res., 34: D689-D691.

Model
Publication ID: 20664065 Submission Date: 06 Apr 2010 07:55:17 UTC Last Modification Date: 21 Feb 2014 11:25:30 UTC Creation Date: 24 Aug 2010 12:00:29 UTC
Mathematical expressions
Reactions
NGF+TrkA pTrkA+Akt Akt_phosphorylation pTrkA_degradation
pAkt+S6 S6_phosphorylation pAkt_dephospho pS6_dephospho
TrkA_synthesis TrkA_phosphorylation TrkA_degradation  
Rules
Assignment Rule (variable: pS6_total) Assignment Rule (variable: pAkt_total) Assignment Rule (variable: pTrkA_total) Assignment Rule (variable: NGF)
Physical entities
Compartments Species
Cell NGF TrkA pTrkA
pTrkA_Akt Akt pAkt
S6 pAkt_S6 pS6
pro_TrkA NGF_TrkA  
Global parameters
pTrkA_total pAkt_total pTrkA_scaleFactor pAkt_scaleFactor
pS6_scaleFactor pS6_total NGF_conc_step NGF_conc_pulse
NGF_conc_ramp TrkA_turnover pulse_time ramp_time
Reactions (11)
 
 NGF+TrkA [NGF] + [TrkA] ↔ [NGF_TrkA];  
 
 pTrkA+Akt [pTrkA] + [Akt] ↔ [pTrkA_Akt];  
 
 Akt_phosphorylation [pTrkA_Akt] → [pTrkA] + [pAkt];  
 
 pTrkA_degradation [pTrkA] → ;  
 
 pAkt+S6 [pAkt] + [S6] ↔ [pAkt_S6];  
 
 S6_phosphorylation [pAkt_S6] → [pAkt] + [pS6];  
 
 pAkt_dephospho [pAkt] → [Akt];  
 
 pS6_dephospho [pS6] → [S6];  
 
 TrkA_synthesis [pro_TrkA] → [TrkA];  
 
 TrkA_phosphorylation [NGF_TrkA] → [pTrkA];  
 
 TrkA_degradation [TrkA] → ;  
 
Rules (4)
 
 Assignment Rule (name: pS6_total) pS6_total = pS6*pS6_scaleFactor
 
 Assignment Rule (name: pAkt_total) pAkt_total = (pAkt+pAkt_S6)*pAkt_scaleFactor
 
 Assignment Rule (name: pTrkA_total) pTrkA_total = (pTrkA+pTrkA_Akt)*pTrkA_scaleFactor
 
 Assignment Rule (name: NGF) NGF = NGF_conc_step+piecewise(NGF_conc_pulse, time <= pulse_time, 0)+NGF_conc_ramp*time/ramp_time
 
 Cell Spatial dimensions: 3.0  Compartment size: 1.0
 
  NGF
Compartment: Cell
Initial concentration: 0.0  (Units: ng)
 
 TrkA
Compartment: Cell
Initial concentration: 8.52065090518276
 
 pTrkA
Compartment: Cell
Initial concentration: 0.0
 
 pTrkA_Akt
Compartment: Cell
Initial concentration: 0.0
 
 Akt
Compartment: Cell
Initial concentration: 1.15594897919397
 
 pAkt
Compartment: Cell
Initial concentration: 0.0
 
 S6
Compartment: Cell
Initial concentration: 3.552336039555
 
 pAkt_S6
Compartment: Cell
Initial concentration: 0.0
 
 pS6
Compartment: Cell
Initial concentration: 0.0
 
 pro_TrkA
Compartment: Cell
Initial concentration: 8.52065090518276
Constant
 
 NGF_TrkA
Compartment: Cell
Initial concentration: 0.0
 
Global Parameters (12)
 
  pTrkA_total  
 
  pAkt_total  
 
   pTrkA_scaleFactor
Value: 0.848783474941268   (Units: ng)
Constant
 
   pAkt_scaleFactor
Value: 2.42381211094508   (Units: ng)
Constant
 
   pS6_scaleFactor
Value: 0.525842718263069   (Units: ng)
Constant
 
  pS6_total  
 
   NGF_conc_step
Constant
 
   NGF_conc_pulse
Constant
 
   NGF_conc_ramp
Value: 30.0   (Units: ng_per_ml)
Constant
 
   TrkA_turnover
Value: 0.0011032440769796   (Units: per second)
Constant
 
   pulse_time
Value: 60.0   (Units: seconds)
Constant
 
   ramp_time
Value: 3600.0   (Units: seconds)
Constant
 
NGF+TrkA (2)
 
   k1
Value: 0.00269408
Constant
 
   k2
Value: 0.0133747
Constant
 
pTrkA+Akt (2)
 
   k1
Value: 0.0882701   (Units: per conc per second)
Constant
 
   k2
Value: 1.47518E-10   (Units: per second)
Constant
 
Akt_phosphorylation (1)
 
   k1
Value: 0.0202517
Constant
 
pTrkA_degradation (1)
 
   k1
Value: 0.0684084   (Units: per second)
Constant
 
pAkt+S6 (2)
 
   k1
Value: 68.3666   (Units: per conc per second)
Constant
 
   k2
Value: 5.23519   (Units: per second)
Constant
 
S6_phosphorylation (1)
 
   k1
Value: 0.0056515   (Units: per second)
Constant
 
pAkt_dephospho (1)
 
   k1
Value: 1.28135   (Units: per second)
Constant
 
pS6_dephospho (1)
 
   k1
Value: 2.93167E-4   (Units: per second)
Constant
 
TrkA_phosphorylation (1)
 
   k1
Value: 0.00833178   (Units: per second)
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000263

Curator's comment: (updated: 24 Aug 2010 13:00:06 BST)

Reproduction of figure S9 from the supplement of the original article using SBML ODESolver (cvs October 2009).
To obtain the the results the parameter NGF_conc_ramp was set to the desired final value of NGF.

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