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BIOMD0000000264 - Fujita2010_Akt_Signalling_EGFRinhib

 

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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: BIOMD0000000264.origin
Submitter: Kazuhiro Fujita
Submission ID: MODEL1004060003
Submission Date: 06 Apr 2010 07:59:37 UTC
Last Modification Date: 21 Feb 2014 16:40:08 UTC
Creation Date: 24 Aug 2010 13:34:45 UTC
Encoders:  Lukas Endler
   Kazuhiro Fujita
set #1
bqbiol:hasVersion Reactome REACT_12464.1
Reactome REACT_9417.3
Gene Ontology epidermal growth factor receptor signaling pathway
Gene Ontology protein kinase B signaling
Gene Ontology response to epidermal growth factor
bqbiol:occursIn Brenda Tissue Ontology PC-12 cell
set #2
bqbiol:hasTaxon Taxonomy Rattus norvegicus
Notes

Akt pathway model with EGFR inhibitor

made by Kazuhiro A. Fujita.

This is the Akt pathway model with an EGFR inhibitor 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 EGF_conc_pulse , EGF_conc_step and EGF_conc_ramp . Depending on which one is set unequal to 0, either a continous pulse with value EGF_conc_pulse , a 60 second step with EGF_conc_step or a signal increasing from 0 to EGF_conc_pulse over a time periode of 3600 seconds are used as input. In case more than one parameter are 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 07:59:37 UTC Last Modification Date: 21 Feb 2014 16:40:08 UTC Creation Date: 24 Aug 2010 13:34:45 UTC
Mathematical expressions
Reactions
EGF+EGFR pEGFR+Akt Akt_phosphorylation pEGFR_degradation
pAkt+S6 S6_phosphorylation pAkt_dephospho pS6_dephospho
EGFR_synthesis EGFR_phosphorylation EGFR_degradation EGFR+i
EGF_EGFR+i EGF+EGFR_i EGFR_i_degradation  
Rules
Assignment Rule (variable: pAkt_total) Assignment Rule (variable: pEGFR_total) Assignment Rule (variable: EGF) Assignment Rule (variable: pS6_total)
Physical entities
Compartments Species
Cell EGF EGFR pEGFR
pEGFR_Akt Akt pAkt
S6 pAkt_S6 pS6
pro_EGFR EGF_EGFR EGFR_i
EGF_EGFR_i Inhibitor  
Global parameters
pEGFR_total pAkt_total pEGFR_scaleFactor pAkt_scaleFactor
pS6_scaleFactor pS6_total EGF_conc_step EGF_conc_pulse
EGF_conc_ramp EGFR_turnover EGF_binding_kf EGF_binding_kb
inhibitor_binding_kf inhibitor_binding_kb pulse_time ramp_time
Reactions (15)
 
 EGF+EGFR [EGF] + [EGFR] ↔ [EGF_EGFR];  
 
 pEGFR+Akt [pEGFR] + [Akt] ↔ [pEGFR_Akt];  
 
 Akt_phosphorylation [pEGFR_Akt] → [pEGFR] + [pAkt];  
 
 pEGFR_degradation [pEGFR] → ;  
 
 pAkt+S6 [pAkt] + [S6] ↔ [pAkt_S6];  
 
 S6_phosphorylation [pAkt_S6] → [pAkt] + [pS6];  
 
 pAkt_dephospho [pAkt] → [Akt];  
 
 pS6_dephospho [pS6] → [S6];  
 
 EGFR_synthesis [pro_EGFR] → [EGFR];  
 
 EGFR_phosphorylation [EGF_EGFR] → [pEGFR];  
 
 EGFR_degradation [EGFR] → ;  
 
 EGFR+i [Inhibitor] + [EGFR] ↔ [EGFR_i];  
 
 EGF_EGFR+i [Inhibitor] + [EGF_EGFR] ↔ [EGF_EGFR_i];  
 
 EGF+EGFR_i [EGF] + [EGFR_i] ↔ [EGF_EGFR_i];  
 
 EGFR_i_degradation [EGFR_i] → ;  
 
Rules (4)
 
 Assignment Rule (name: pAkt_total) pAkt_total = (pAkt+pAkt_S6)*pAkt_scaleFactor
 
 Assignment Rule (name: pEGFR_total) pEGFR_total = (pEGFR+pEGFR_Akt)*pEGFR_scaleFactor
 
 Assignment Rule (name: EGF) EGF = EGF_conc_step+piecewise(EGF_conc_pulse, time <= pulse_time, 0)+EGF_conc_ramp*time/ramp_time
 
 Assignment Rule (name: pS6_total) pS6_total = pS6*pS6_scaleFactor
 
 Cell Spatial dimensions: 3.0  Compartment size: 1.0
 
  EGF
Compartment: Cell
Initial concentration: 30.0  (Units: ng)
 
 EGFR
Compartment: Cell
Initial concentration: 68190.2000000002
 
 pEGFR
Compartment: Cell
Initial concentration: 0.0
 
 pEGFR_Akt
Compartment: Cell
Initial concentration: 0.0
 
 Akt
Compartment: Cell
Initial concentration: 0.043309
 
 pAkt
Compartment: Cell
Initial concentration: 0.0
 
 S6
Compartment: Cell
Initial concentration: 3.54317
 
 pAkt_S6
Compartment: Cell
Initial concentration: 0.0
 
 pS6
Compartment: Cell
Initial concentration: 0.0
 
 pro_EGFR
Compartment: Cell
Initial concentration: 68190.2000000002
Constant
 
 EGF_EGFR
Compartment: Cell
Initial concentration: 0.0
 
 EGFR_i
Compartment: Cell
Initial concentration: 0.0
 
 EGF_EGFR_i
Compartment: Cell
Initial concentration: 0.0
 
 Inhibitor
Compartment: Cell
Initial concentration: 0.0
Constant
 
Global Parameters (16)
 
  pEGFR_total  
 
  pAkt_total  
 
   pEGFR_scaleFactor
Value: 1.81735E-4   (Units: ng)
Constant
 
   pAkt_scaleFactor
Value: 60.0588   (Units: ng)
Constant
 
   pS6_scaleFactor
Value: 49886.2   (Units: ng)
Constant
 
  pS6_total  
 
   EGF_conc_step
Value: 30.0   (Units: ng_per_ml)
Constant
 
   EGF_conc_pulse
Constant
 
   EGF_conc_ramp
Constant
 
   EGFR_turnover
Value: 1.06386E-4   (Units: per second)
Constant
 
   EGF_binding_kf
Value: 0.00673816   (Units: ml_per_ng_per_sec)
Constant
 
   EGF_binding_kb
Value: 0.040749   (Units: per second)
Constant
 
   inhibitor_binding_kf
Value: 2.43466029020655E-5   (Units: per conc per second)
Constant
 
   inhibitor_binding_kb
Value: 5.25096686262403E-5   (Units: per second)
Constant
 
   pulse_time
Value: 60.0   (Units: seconds)
Constant
 
   ramp_time
Value: 3600.0   (Units: seconds)
Constant
 
pEGFR+Akt (2)
 
   k1
Value: 1.5543E-5   (Units: per conc per second)
Constant
 
   k2
Value: 0.00517473   (Units: per second)
Constant
 
Akt_phosphorylation (1)
 
   k1
Value: 0.0528141   (Units: per second)
Constant
 
pEGFR_degradation (1)
 
   k1
Value: 0.0997194   (Units: per second)
Constant
 
pAkt+S6 (2)
 
   k1
Value: 2.10189E-6   (Units: per conc per second)
Constant
 
   k2
Value: 5.1794E-15   (Units: per second)
Constant
 
S6_phosphorylation (1)
 
   k1
Value: 0.00121498   (Units: per second)
Constant
 
pAkt_dephospho (1)
 
   k1
Value: 0.0327962   (Units: per second)
Constant
 
pS6_dephospho (1)
 
   k1
Value: 0.00113102   (Units: per second)
Constant
 
EGFR_phosphorylation (1)
 
   k1
Value: 0.0192391   (Units: per second)
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000264

Curator's comment: (updated: 24 Aug 2010 14:34:17 BST)

Reproduction of figure 7B from the original article using SBML ODESolver (cvs October 2009).
To obtain the the various results the parameter EGF_conc_pulse was set to 30 and the concentration of inhibitor was varied.

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