608682
stoichiometry: 1.0
species: 627723
type: SpeciesReference

627754
kinetic law: 609081
product: 609069
reactant: 609057
is version of: GO:0004672
is: SBO:0000216
fast: false
reversible: false
name: TrkA_phosphorylation
type: Reaction

627764
units: 608535
value: 5.23519
name: k2
type: LocalParameter

608792
stoichiometry: 1.0
species: 627726
type: SpeciesReference

608451
unit: 608475
unit: 608463
name: arbitrary_conc
type: SBMLUnitsDef

609093
stoichiometry: 1.0
species: 627724
type: SpeciesReference

627784
constant: true
units: 608560
value: 0.848783474941268
name: pTrkA_scaleFactor
type: Parameter

627748
kinetic law: 608937
type: Reaction
fast: false
is: SBO:0000216
reactant: 608900
product: 608924
is version of: GO:0004672
name: S6_phosphorylation
has version: REACT_12442
reversible: false
product: 608912

627765
units: 608535
value: 0.0056515
name: k1
type: LocalParameter

608657
exponent: -1.0
scale: 0
multipler: 1.0
kind: SECOND
type: SBMLUnit

627753
kinetic law: 609045
product: 609033
reactant: 609021
is version of: GO:0010467
is: SBO:0000184
fast: false
reversible: false
name: TrkA_synthesis
type: Reaction

609033
stoichiometry: 1.0
species: 627724
type: SpeciesReference

608743
stoichiometry: 1.0
species: 627728
type: SpeciesReference

627794
constant: true
units: 608585
value: 30.0
name: NGF_conc_ramp
type: Parameter

627733
initial concentration: 0.0
boundary condition: false
has version: Q63484
in compartment: 627721
constant: false
has version: C00562
is: SBO:0000297
type: Species
has version: P62755
name: pAkt_S6
has only substance units: false
initial amount: NaN

608535
unit: 608547
name: per second
type: SBMLUnitsDef

608499
exponent: 1.0
scale: 0
multipler: 1.0
kind: SECOND
type: SBMLUnit

608876
stoichiometry: 1.0
species: 627733
type: SpeciesReference

608585
unit: 608609
unit: 608597
name: ng_per_ml
type: SBMLUnitsDef

627785
constant: true
units: 608560
value: 2.42381211094508
name: pAkt_scaleFactor
type: Parameter

BIOMD0000000263
species: 627723
parameter: 627799
species: 627726
parameter: 627795
name: Fujita2010_Akt_Signalling_NGF
is: MODEL1004060002
length unit: length
species: 627727
parameter: 627790
parameter: 627780
species: 627731
curated: true
rule: 627773
reaction: 627739
units def: 608621
reaction: 627750
reaction: 627740
species: 627737
occurs in: http://identifiers.org/taxonomy/10116
reaction: 627755
parameter: 627788
parameter: 627789
units def: 608511
species: 627724
rule: 627776
compartment: 627721
area units: metaid_0000005
time units: 608487
parameter: 627794
parameter: 627784
parameter: 627785
reaction: 627754
has version: REACT_12056
substance units: 608426
modified:
  W3 CDTF: Wed Sep 21 09:38:41 BST 2011
parameter: 627798
species: 627728
has version: REACT 12464.1
species: 627732
parameter: 627793
is described by: http://identifiers.org/pubmed/20664065
reaction: 627744
reaction: 627745
rule: 627777
species: 627738
reaction: 627753
units def: 608487
volume units: 608511
parameter: 627783
units def: 608426
creator:
  ORG:
    orgname: EMBL-EBI
  n:
    given: Lukas
    family: Endler
type: SBMLModel
initial assignment: BIOMD0000000263#
creator:
  ORG:
    orgname: University of Tokyo
  n:
    given: Kazuhiro
    family: Fujita
reaction: 627748
reaction: 627749
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 in…
units def: 608451
has version: GO:0043491
created:
  W3 CDTF: Tue Aug 24 13:00:29 BST 2010
units def: 608560
has version: GO:0048011
species: 627733
reaction: 627743
units def: 608585
occurs in: BTO:0001009
species: 627736
rule: 627778
units def: 608535

627766
units: 608535
value: 1.28135
name: k1
type: LocalParameter

608828
stoichiometry: 1.0
species: 627726
type: SpeciesReference

627795
constant: true
units: 608535
value: 0.0011032440769796
name: TrkA_turnover
type: Parameter

608780
stoichiometry: 1.0
species: 627727
type: SpeciesReference

608694
stoichiometry: 1.0
species: 627724
type: SpeciesReference

627732
initial amount: NaN
is: SBO:0000252
in compartment: 627721
constant: false
is version of: P62755
type: Species
name: S6
has only substance units: false
boundary condition: false
initial concentration: 3.552336039555

608961
stoichiometry: 1.0
species: 627728
type: SpeciesReference

627762
units: 608535
value: 0.0684084
name: k1
type: LocalParameter

608609
exponent: -1.0
scale: -3
multipler: 1.0
kind: LITRE
type: SBMLUnit

609021
stoichiometry: 1.0
species: 627737
type: SpeciesReference

627727
has version: C00562
is: SBO:0000297
in compartment: 627721
has part: P35739
has part: Q63484
constant: false
type: Species
boundary condition: false
initial concentration: 0.0
initial amount: NaN
name: pTrkA_Akt
has only substance units: false

627731
in compartment: 627721
is version of: C00562
is homolog to: REACT_13319
initial concentration: 0.0
type: Species
is: SBO:0000297
constant: false
has only substance units: false
boundary condition: false
initial amount: NaN
name: pAkt

608573
exponent: 1.0
scale: -9
multipler: 1.0
kind: GRAM
type: SBMLUnit

627798
constant: true
units: 608487
value: 60.0
name: pulse_time
type: Parameter

608523
exponent: 1.0
scale: -3
multipler: 1.0
kind: LITRE
type: SBMLUnit

627721
is: GO:0005623
is: SBO:0000290
constant: true
size: 1.0
spatial dimensions: 3.0
name: Cell
type: Compartment

608487
unit: 608499
name: seconds
type: SBMLUnitsDef

627763
units: 608621
value: 68.3666
name: k1
type: LocalParameter

608560
unit: 608573
name: ng
type: SBMLUnitsDef

627750
kinetic law: 609009
product: 608997
reactant: 608985
is version of: GO:0004721
is: SBO:0000330
fast: false
reversible: false
name: pS6_dephospho
type: Reaction

627783
has version: Q63484
is version of: C00562
constant: false
units: 608585
value: 0.0
name: pAkt_total
type: Parameter

627728
in compartment: 627721
constant: false
name: Akt
type: Species
initial amount: NaN
has only substance units: false
is version of: Q63484
initial concentration: 1.15594897919397
is: SBO:0000297
boundary condition: false

627749
kinetic law: 608973
product: 608961
reactant: 608949
is version of: GO:0004721
is: SBO:0000330
fast: false
reversible: false
name: pAkt_dephospho
type: Reaction

627759
units: 608535
value: 1.47518E-10
name: k2
type: LocalParameter

608949
stoichiometry: 1.0
species: 627731
type: SpeciesReference

609069
stoichiometry: 1.0
species: 627726
type: SpeciesReference

627740
type: Reaction
kinetic law: 608768
reversible: true
reactant: 608731
is version of: GO:0005515
reactant: 608743
name: pTrkA+Akt
product: 608756
is: SBO:0000177
fast: false

608621
unit: 608657
unit: 608645
unit: 608633
name: per conc per second
type: SBMLUnitsDef

627724
in compartment: 627721
initial amount: NaN
name: TrkA
is: SBO:0000252
initial concentration: 8.52065090518276
has only substance units: false
boundary condition: false
is version of: P35739
constant: false
type: Species

627789
is version of: C00562
is version of: P62755
constant: false
units: 608585
value: 0.0
name: pS6_total
type: Parameter

609057
stoichiometry: 1.0
species: 627738
type: SpeciesReference

627760
value: 0.0202517
name: k1
type: LocalParameter

608924
stoichiometry: 1.0
species: 627736
type: SpeciesReference

627799
constant: true
units: 608487
value: 3600.0
name: ramp_time
type: Parameter

627770
units: 608535
value: 0.00833178
name: k1
type: LocalParameter

627738
has part: P35739
name: NGF_TrkA
initial concentration: 0.0
is: SBO:0000297
in compartment: 627721
constant: false
has part: P25427
initial amount: NaN
type: Species
boundary condition: false
has only substance units: false

627739
reactant: 608694
name: NGF+TrkA
kinetic law: 608719
is version of: GO:0005167
product: 608706
fast: false
is: SBO:0000177
reversible: true
is version of: REACT_10088
type: Reaction
reactant: 608682

608475
exponent: -1.0
scale: -3
multipler: 1.0
kind: LITRE
type: SBMLUnit

608511
unit: 608523
name: ml
type: SBMLUnitsDef

627758
units: 608621
value: 0.0882701
name: k1
type: LocalParameter

608997
stoichiometry: 1.0
species: 627732
type: SpeciesReference

608706
stoichiometry: 1.0
species: 627738
type: SpeciesReference

608864
stoichiometry: 1.0
species: 627732
type: SpeciesReference

627744
kinetic law: 608840
reactant: 608828
is version of: GO:0030163
is: SBO:0000179
fast: false
reversible: false
name: pTrkA_degradation
type: Reaction

608633
exponent: 1.0
scale: -3
multipler: 1.0
kind: LITRE
type: SBMLUnit

608731
stoichiometry: 1.0
species: 627726
type: SpeciesReference

627723
type: Species
boundary condition: true
initial concentration: 0.0
in compartment: 627721
substance units: 608560
initial amount: NaN
is version of: P25427
is: SBO:0000252
has only substance units: false
constant: false
name: NGF

627790
constant: true
units: 608585
value: 0.0
name: NGF_conc_step
type: Parameter

627780
is version of: C00562
is version of: P35739
is version of: GO:0048406
constant: false
units: 608585
value: 0.0
name: pTrkA_total
type: Parameter

627737
boundary condition: true
name: pro_TrkA
constant: true
initial concentration: 8.52065090518276
initial amount: NaN
type: Species
has only substance units: false
is: SBO:0000252
is version of: P35739
in compartment: 627721

608804
stoichiometry: 1.0
species: 627731
type: SpeciesReference

627757
value: 0.0133747
name: k2
type: LocalParameter

608756
stoichiometry: 1.0
species: 627727
type: SpeciesReference

608438
exponent: 1.0
scale: 0
multipler: 1.0
kind: DIMENSIONLESS
type: SBMLUnit

608426
unit: 608438
name: arbitrary_amount
type: SBMLUnitsDef

627743
reactant: 608780
reversible: false
is: SBO:0000216
product: 608804
product: 608792
name: Akt_phosphorylation
type: Reaction
fast: false
kinetic law: 608816
is version of: GO:0004672

608912
stoichiometry: 1.0
species: 627731
type: SpeciesReference

627793
constant: true
units: 608585
value: 0.0
name: NGF_conc_pulse
type: Parameter

627726
initial amount: NaN
boundary condition: false
has only substance units: false
type: Species
is version of: P35739
is: SBO:0000252
initial concentration: 0.0
in compartment: 627721
name: pTrkA
constant: false

627736
is version of: C00562
is version of: P62755
is: SBO:0000252
initial concentration: 0.0
name: pS6
in compartment: 627721
constant: false
type: Species
initial amount: NaN
has only substance units: false
boundary condition: false

627756
value: 0.00269408
name: k1
type: LocalParameter

608852
stoichiometry: 1.0
species: 627731
type: SpeciesReference

608463
exponent: 1.0
scale: 0
multipler: 1.0
kind: DIMENSIONLESS
type: SBMLUnit

608985
stoichiometry: 1.0
species: 627736
type: SpeciesReference

627788
constant: true
units: 608560
value: 0.525842718263069
name: pS6_scaleFactor
type: Parameter

627768
units: 608535
value: 2.93167E-4
name: k1
type: LocalParameter

608645
exponent: 1.0
scale: 0
multipler: 1.0
kind: DIMENSIONLESS
type: SBMLUnit

608597
exponent: 1.0
scale: -9
multipler: 1.0
kind: GRAM
type: SBMLUnit

608900
stoichiometry: 1.0
species: 627733
type: SpeciesReference

627755
kinetic law: 609105
reactant: 609093
is version of: GO:0030163
is: SBO:0000179
fast: false
reversible: false
name: TrkA_degradation
type: Reaction

608547
exponent: -1.0
scale: 0
multipler: 1.0
kind: SECOND
type: SBMLUnit

627745
name: pAkt+S6
is version of: GO:0005515
reactant: 608864
product: 608876
reactant: 608852
type: Reaction
kinetic law: 608888
is: SBO:0000177
fast: false
reversible: true
is version of: REACT_12442