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is described by: http://identifiers.org/pubmed/15298883
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units def: 247220
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reaction: 983789
reaction: 983449
reaction: 983069
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species: 982389
reaction: 983049
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notes: Model of MAPK activation by EGFR in the synapse. Demonstration programs using this model are available here. Primary citation:Bhalla US. Biophys J. (2004) 87(2):745-53. This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. 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. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
species: 982029
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reaction: 983189
reaction: 982989
reaction: 982969
reaction: 983589
time units: 131570
compartment: 981456
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species: 982229
species: 982529

982849
type: Reaction
kinetic law: 247696
product: 247683
reactant: 247671
notes: See Helin and Beguinot JBC 266:13 1991 pg 8363-8368. In Fig 3 they have internalization tau about 10 min, equil at about 20% EGF available. So kf = 4x kb, and 1/(kf + kb) = 600 sec so kb = 1/3K = 3.3e-4, and kf = 1.33e-3. This doesn\'t take into account the unbound receptor, so we need to push the kf up a bit, to 0.002
fast: false
reversible: true

247696
type: KineticLaw
local parameters: 900822
local parameters: 900821
notes: kf*EGFR_slash_L_dot_EGFR-kb*EGFR_slash_Internal_L_dot_EGFR

900822
type: LocalParameter
units: 247184
value: 3.3E-16

247208
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exponent: -1.0
scale: 0
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kind: SECOND

247196
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exponent: 1.0
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kind: LITRE

900821
type: LocalParameter
units: 247184
value: 2.0E-15

247683
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species: 982449

982449
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constant: false
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981469
type: Compartment
constant: true
size: 1.0E-12
spatial dimensions: 3.0

247671
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stoichiometry: 1.0
species: 982369

982369
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constant: false
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982349
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.166666666666667
initial amount: NaN
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983009
type: Reaction
kinetic law: 248070
product: 248058
product: 248046
reactant: 248033
fast: false
reversible: false

248070
type: KineticLaw
local parameters: 900839
notes: k3*PKC_minus_active_slash_PKC_minus_inact_minus_GAP_slash_PKC_minus_inact_minus_GAP_cplx

900839
type: LocalParameter
units: 247184
value: 4.0E-12

248058
type: SpeciesReference
stoichiometry: 1.0
species: 982569

982569
type: Species
constant: true
boundary condition: true
has only substance units: false
initial concentration: 0.09
initial amount: NaN
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248046
type: SpeciesReference
stoichiometry: 1.0
species: 982169

982169
type: Species
constant: false
boundary condition: false
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initial concentration: 0.0
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248033
type: SpeciesReference
stoichiometry: 1.0
species: 981509

981509
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

981529
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

982269
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

981949
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

981989
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

981729
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

983709
type: Reaction
kinetic law: 249763
product: 249751
reactant: 249739
reactant: 249727
notes: This pathway inhibits Ras when cAMP is elevated. See: Hordijk et al JBC 269:5 3534-3538 1994 Burgering et al EMBO J 12:11 4211-4220 1993 The rates are the same as used in PKA-phosph-I1
fast: false
reversible: true

249763
type: KineticLaw
local parameters: 900967
local parameters: 900964
notes: k1*Ras_slash_inact_minus_GEF*PKA_minus_active-k2*PKA_minus_active_slash_PKA_minus_phosph_minus_GEF_slash_PKA_minus_phosph_minus_GEF_cplx

900967
type: LocalParameter
units: 247184
value: 3.6E-11

900964
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units: 247220
value: 6.0E-12

247257
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scale: 0
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kind: SECOND

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scale: -6
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kind: MOLE

247232
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exponent: 2.0
scale: 0
multipler: 1.0
kind: LITRE

249751
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stoichiometry: 1.0
species: 982289

982289
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constant: false
boundary condition: false
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249739
type: SpeciesReference
stoichiometry: 1.0
species: 982609

982609
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constant: true
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has only substance units: false
initial concentration: 0.015
initial amount: NaN
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249727
type: SpeciesReference
stoichiometry: 1.0
species: 982069

982069
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982649
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constant: true
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981489
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constant: false
boundary condition: false
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initial concentration: 0.0
initial amount: NaN
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983169
type: Reaction
kinetic law: 248460
product: 248448
product: 248436
reactant: 248424
fast: false
reversible: false

248460
type: KineticLaw
local parameters: 900863
notes: k3*MAPK_slash_MAPKK_star__slash_MAPKKtyr_slash_MAPKKtyr_cplx

900863
type: LocalParameter
units: 247184
value: 1.5E-13

248448
type: SpeciesReference
stoichiometry: 1.0
species: 981729

248436
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stoichiometry: 1.0
species: 981709

981709
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constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

248424
type: SpeciesReference
stoichiometry: 1.0
species: 981749

981749
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constant: false
boundary condition: false
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initial concentration: 0.0
initial amount: NaN
in compartment: 981469

983149
type: Reaction
kinetic law: 248412
product: 248400
reactant: 248388
reactant: 248376
notes: The actual MAPKK is 2 forms from Seger et al JBC 267:20 14373(1992) Vmax = 150nmol/min/mg From Haystead et al FEBS 306(1):17-22 we get Km=46.6nM for at least one of the phosphs. Putting these together: k3=0.15/sec, scale to get k2=0.6. k1=0.75/46.6nM=2.7e-5
fast: false
reversible: true

248412
type: KineticLaw
local parameters: 900862
local parameters: 900859
notes: k1*MAPK_slash_MAPK*MAPK_slash_MAPKK_star_-k2*MAPK_slash_MAPKK_star__slash_MAPKKtyr_slash_MAPKKtyr_cplx

900862
type: LocalParameter
units: 247184
value: 6.0E-13

900859
type: LocalParameter
units: 247220
value: 1.62E-11

248400
type: SpeciesReference
stoichiometry: 1.0
species: 981749

248388
type: SpeciesReference
stoichiometry: 1.0
species: 981729

248376
type: SpeciesReference
stoichiometry: 1.0
species: 981669

981669
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.36
initial amount: NaN
in compartment: 981469

982949
type: Reaction
kinetic law: 247924
product: 247912
reactant: 247900
reactant: 247888
notes: Rate consts from Chen et al Biochem 32, 1032 (1993) k3 = k2 = 4 k1 = 9e-5 recalculated gives 1.666e-5, which is not very different. Looks like k3 is rate-limiting in this case: there is a huge amount of craf locked up in the enz complex. Let us assume a 10x higher Km, ie, lower affinity. k1 drops by 10x. Also changed k2 to 4x k3. Lowerd k1 to 1e-6 to balance 10X DAG sensitivity of PKC
fast: false
reversible: true

247924
type: KineticLaw
local parameters: 900832
local parameters: 900831
notes: k1*MAPK_slash_craf_minus_1*PKC_minus_active-k2*PKC_minus_active_slash_PKC_minus_act_minus_raf_slash_PKC_minus_act_minus_raf_cplx

900832
type: LocalParameter
units: 247184
value: 1.6E-11

900831
type: LocalParameter
units: 247220
value: 3.0E-13

247912
type: SpeciesReference
stoichiometry: 1.0
species: 981489

247900
type: SpeciesReference
stoichiometry: 1.0
species: 982569

247888
type: SpeciesReference
stoichiometry: 1.0
species: 981609

981609
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.2
initial amount: NaN
in compartment: 981469

982929
type: Reaction
kinetic law: 247876
product: 247864
reactant: 247852
reactant: 247840
notes: As there are 2 SH3 domains, this reaction could be 2nd order. I have a Kd of 22 uM from peptide binding (Lemmon et al JBC 269:50 pg 31653). However, Chook et al JBC 271:48 pg30472 say it is 0.4uM with purified proteins, so we believe them. They say it is 1:1 binding.
fast: false
reversible: true

247876
type: KineticLaw
local parameters: 900830
local parameters: 900829
notes: kf*Sos_slash_Grb2*Sos_slash_Sos-kb*Sos_slash_Sos_dot_Grb2

900830
type: LocalParameter
units: 247184
value: 1.68E-14

900829
type: LocalParameter
units: 247220
value: 2.50002E-14

247864
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species: 982509

982509
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constant: false
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247852
type: SpeciesReference
stoichiometry: 1.0
species: 982549

982549
type: Species
constant: false
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initial concentration: 0.1
initial amount: NaN
in compartment: 981469

247840
type: SpeciesReference
stoichiometry: 1.0
species: 982489

982489
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constant: false
boundary condition: false
has only substance units: false
initial concentration: 1.0
initial amount: NaN
in compartment: 981469

982409
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.5
initial amount: NaN
in compartment: 981469

983569
type: Reaction
kinetic law: 249424
product: 249412
product: 249400
reactant: 249388
fast: false
reversible: false

249424
type: KineticLaw
local parameters: 900944
notes: k3*Ras_slash_GEF_minus_Gprot_minus_bg_slash_GEF_minus_bg_act_minus_ras_slash_GEF_minus_bg_act_minus_ras_cplx

900944
type: LocalParameter
units: 247184
value: 2.0E-14

249412
type: SpeciesReference
stoichiometry: 1.0
species: 982029

982029
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constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

249400
type: SpeciesReference
stoichiometry: 1.0
species: 982129

982129
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

249388
type: SpeciesReference
stoichiometry: 1.0
species: 982049

982049
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

983249
type: Reaction
kinetic law: 248653
product: 248641
product: 248629
reactant: 248617
fast: false
reversible: false

248653
type: KineticLaw
local parameters: 900875
notes: k3*MAPK_slash_Raf_minus_GTP_minus_Ras_star__slash_Raf_minus_GTP_minus_Ras_star__dot_1_slash_Raf_minus_GTP_minus_Ras_star__dot_1_cplx

900875
type: LocalParameter
units: 247184
value: 1.05E-13

248641
type: SpeciesReference
stoichiometry: 1.0
species: 981809

981809
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

248629
type: SpeciesReference
stoichiometry: 1.0
species: 981789

981789
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

248617
type: SpeciesReference
stoichiometry: 1.0
species: 981829

981829
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

983229
type: Reaction
kinetic law: 248605
product: 248592
reactant: 248580
reactant: 248568
notes: Kinetics are the same as for the craf-1* activity, ie., k1=1.1e-6, k2=.42, k3 =0.105 These are based on Force et al PNAS USA 91 1270-1274 1994. These parms cannot reach the observed 4X stim of MAPK. So lets increase the affinity, ie, raise k1 10X to 1.1e-5 Lets take it back down to where it was. Back up to 5X: 5.5e-6
fast: false
reversible: true

248605
type: KineticLaw
local parameters: 900874
local parameters: 900871
notes: k1*MAPK_slash_MAPKK*MAPK_slash_Raf_minus_GTP_minus_Ras_star_-k2*MAPK_slash_Raf_minus_GTP_minus_Ras_star__slash_Raf_minus_GTP_minus_Ras_star__dot_1_slash_Raf_minus_GTP_minus_Ras_star__dot_1_cplx

900874
type: LocalParameter
units: 247184
value: 4.2E-13

900871
type: LocalParameter
units: 247220
value: 3.3E-12

248592
type: SpeciesReference
stoichiometry: 1.0
species: 981829

248580
type: SpeciesReference
stoichiometry: 1.0
species: 981809

248568
type: SpeciesReference
stoichiometry: 1.0
species: 981649

981649
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.18
initial amount: NaN
in compartment: 981469

982689
type: Reaction
kinetic law: 247379
product: 247367
reactant: 247354
reactant: 247342
notes: SoS/GEF is present at 50 nM ie 3e4/cell. BetaGamma maxes out at 9e4. Assume we have 1/3 of the GEF active when the BetaGamma is 1.5e4. so 1e4 * kb = 2e4 * 1.5e4 * kf, so kf/kb = 3e-5. The rate of this equil should be reasonably fast, say 1/sec
fast: false
reversible: true

247379
type: KineticLaw
local parameters: 900806
local parameters: 900803
notes: kf*BetaGamma*Ras_slash_inact_minus_GEF-kb*Ras_slash_GEF_minus_Gprot_minus_bg

900806
type: LocalParameter
units: 247184
value: 1.0E-12

900803
type: LocalParameter
units: 247220
value: 6.0E-12

247367
type: SpeciesReference
stoichiometry: 1.0
species: 982029

247354
type: SpeciesReference
stoichiometry: 1.0
species: 982069

247342
type: SpeciesReference
stoichiometry: 1.0
species: 982589

982589
type: Species
notes: These exist in a nebulous sense in this model, basically only to balance the conservation equations. The details of their reassociation with G-GDP are not modeled Resting level =0.0094, stim level =.0236 from all42.g ish.
constant: true
boundary condition: true
has only substance units: false
initial concentration: 0.0094
initial amount: NaN
in compartment: 981469

982669
type: Reaction
kinetic law: 247329
product: 247317
reactant: 247305
reactant: 247293
notes: Assume the binding is fast and limited only by the amount of Ras* available. So kf=kb/[craf-1] If kb is 1/sec, then kf = 1/0.2 uM = 1/(0.2 * 6e5) = 8.3e-6 Later: Raise it by 10 X to 4e-5 From Hallberg et al JBC 269:6 3913-3916 1994, 3% of cellular Raf is complexed with Ras. So we raise kb 4x to 4 This step needed to memb-anchor and activate Raf: Leevers et al Nature 369 411-414 (I don\'t....
fast: false
reversible: true

247329
type: KineticLaw
local parameters: 900801
local parameters: 900800
notes: kf*MAPK_slash_craf_minus_1_star_*Ras_slash_GTP_minus_Ras-kb*MAPK_slash_Raf_minus_GTP_minus_Ras_star_

900801
type: LocalParameter
units: 247184
value: 5.0E-13

900800
type: LocalParameter
units: 247220
value: 2.4E-11

247317
type: SpeciesReference
stoichiometry: 1.0
species: 981809

247305
type: SpeciesReference
stoichiometry: 1.0
species: 982129

247293
type: SpeciesReference
stoichiometry: 1.0
species: 981629

981629
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

981689
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

983209
type: Reaction
kinetic law: 248556
product: 248544
product: 248532
reactant: 248520
fast: false
reversible: false

248556
type: KineticLaw
local parameters: 900869
notes: k3*MAPK_slash_MAPKK_star__slash_MAPKKthr_slash_MAPKKthr_cplx

900869
type: LocalParameter
units: 247184
value: 1.5E-13

248544
type: SpeciesReference
stoichiometry: 1.0
species: 981729

248532
type: SpeciesReference
stoichiometry: 1.0
species: 981549

981549
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

248520
type: SpeciesReference
stoichiometry: 1.0
species: 981769

981769
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

983529
type: Reaction
kinetic law: 249328
product: 249316
product: 249304
reactant: 249292
fast: false
reversible: false

900938
type: LocalParameter
units: 247184
value: 6.0E-12

249316
type: SpeciesReference
stoichiometry: 1.0
species: 981929

981929
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.224
initial amount: NaN
in compartment: 981469

249304
type: SpeciesReference
stoichiometry: 1.0
species: 981629

249292
type: SpeciesReference
stoichiometry: 1.0
species: 982009

982009
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

983509
type: Reaction
kinetic law: 249280
product: 249268
reactant: 249256
reactant: 249244
notes: Ueki et al JBC 269(22) pp 15756-15761 1994 show hyperphosphorylation of craf, so this is there to dephosphorylate it. Identity of phosphatase is not known to me, but it may be PP2A like the rest, so I have made it so.
fast: false
reversible: true

900937
type: LocalParameter
units: 247184
value: 2.5E-11

900934
type: LocalParameter
units: 247220
value: 1.98E-12

249268
type: SpeciesReference
stoichiometry: 1.0
species: 982009

249256
type: SpeciesReference
stoichiometry: 1.0
species: 981929

249244
type: SpeciesReference
stoichiometry: 1.0
species: 981689

981969
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

983609
type: Reaction
kinetic law: 249522
product: 249509
product: 249497
reactant: 249485
fast: false
reversible: false

249522
type: KineticLaw
local parameters: 900950
notes: k3*Ras_slash_GEF_star__slash_GEF_star__minus_act_minus_ras_slash_GEF_star__minus_act_minus_ras_cplx

900950
type: LocalParameter
units: 247184
value: 2.0E-14

249509
type: SpeciesReference
stoichiometry: 1.0
species: 982089

982089
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

249497
type: SpeciesReference
stoichiometry: 1.0
species: 982129

249485
type: SpeciesReference
stoichiometry: 1.0
species: 982109

982109
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

982769
type: Reaction
kinetic law: 247537
product: 247525
reactant: 247513
reactant: 247501
notes: We have no numbers for this. It is probably between the two extremes represented by the CaMKII phosph states, and I have used guesses based on this. kf=1e-4 kb=1 The reaction is based on Farnsworth et al Nature 376 524-527 1995
fast: false
reversible: true

247537
type: KineticLaw
local parameters: 900814
local parameters: 900813
notes: kf*Ras_slash_inact_minus_GEF*CaM_minus_Ca4-kb*Ras_slash_CaM_minus_GEF

900814
type: LocalParameter
units: 247184
value: 1.0E-12

900813
type: LocalParameter
units: 247220
value: 6.0E-11

247525
type: SpeciesReference
stoichiometry: 1.0
species: 982249

982249
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

247513
type: SpeciesReference
stoichiometry: 1.0
species: 982629

982629
type: Species
notes: Resting level is ~1e-5 uM, small enough to ignore.
constant: true
boundary condition: true
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

247501
type: SpeciesReference
stoichiometry: 1.0
species: 982069

982749
type: Reaction
kinetic law: 247489
product: 247476
reactant: 247464
notes: Assume a reasonably good rate for dephosphorylating it, 1/sec
fast: false
reversible: true

247489
type: KineticLaw
local parameters: 900812
local parameters: 900811
notes: kf*Ras_slash_GAP_star_-kb*Ras_slash_GAP

900812
type: LocalParameter
units: 247184
value: 0.0

900811
type: LocalParameter
units: 247184
value: 1.0E-13

247476
type: SpeciesReference
stoichiometry: 1.0
species: 982189

982189
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.002
initial amount: NaN
in compartment: 981469

247464
type: SpeciesReference
stoichiometry: 1.0
species: 982169

983389
type: Reaction
kinetic law: 248991
product: 248979
reactant: 248967
reactant: 248954
notes: See parent PPhosphatase2A for parms
fast: false
reversible: true

900920
type: LocalParameter
units: 247184
value: 2.5E-11

900919
type: LocalParameter
units: 247220
value: 1.98E-12

248979
type: SpeciesReference
stoichiometry: 1.0
species: 981949

248967
type: SpeciesReference
stoichiometry: 1.0
species: 981929

248954
type: SpeciesReference
stoichiometry: 1.0
species: 981629

983369
type: Reaction
kinetic law: 248942
product: 248930
product: 248918
reactant: 248906
fast: false
reversible: false

248942
type: KineticLaw
local parameters: 900915
notes: k3*MKP_minus_1_slash_MKP1_minus_thr_minus_deph_slash_MKP1_minus_thr_minus_deph_cplx

900915
type: LocalParameter
units: 247184
value: 1.0E-12

248930
type: SpeciesReference
stoichiometry: 1.0
species: 981869

981869
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0024
initial amount: NaN
in compartment: 981469

248918
type: SpeciesReference
stoichiometry: 1.0
species: 981709

248906
type: SpeciesReference
stoichiometry: 1.0
species: 981909

981909
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

983469
type: Reaction
kinetic law: 249184
product: 249172
reactant: 249160
reactant: 249148
fast: false
reversible: true

900931
type: LocalParameter
units: 247184
value: 2.5E-11

900928
type: LocalParameter
units: 247220
value: 1.98E-12

249172
type: SpeciesReference
stoichiometry: 1.0
species: 981989

249160
type: SpeciesReference
stoichiometry: 1.0
species: 981929

249148
type: SpeciesReference
stoichiometry: 1.0
species: 981789

983789
type: Reaction
kinetic law: 249956
product: 249944
reactant: 249932
reactant: 249920
notes: Rates from Okada et al JBC 270:35 pp 20737 1995 Km = 0.70 to 0.85 uM, Vmax = 4.4 to 5.0 pmol/min. Unfortunately the amount of enzyme is not known, the prep is only partially purified. Time course of phosph is max within 30 sec, falls back within 20 min. Ref: Sasaoka et al JBC 269:51 32621 1994. Use k3 = 0.1 based on this tau.
fast: false
reversible: true

249956
type: KineticLaw
local parameters: 900979
local parameters: 900976
notes: k1*EGFR_slash_SHC*EGFR_slash_L_dot_EGFR-k2*EGFR_slash_L_dot_EGFR_slash_phosph_Shc_slash_phosph_Shc_cplx

900979
type: LocalParameter
units: 247184
value: 8.0E-13

900976
type: LocalParameter
units: 247220
value: 1.2E-12

249944
type: SpeciesReference
stoichiometry: 1.0
species: 982389

982389
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

249932
type: SpeciesReference
stoichiometry: 1.0
species: 982369

249920
type: SpeciesReference
stoichiometry: 1.0
species: 982409

983449
type: Reaction
kinetic law: 249136
product: 249124
product: 249112
reactant: 249100
fast: false
reversible: false

900926
type: LocalParameter
units: 247184
value: 6.0E-12

249124
type: SpeciesReference
stoichiometry: 1.0
species: 981929

249112
type: SpeciesReference
stoichiometry: 1.0
species: 981789

249100
type: SpeciesReference
stoichiometry: 1.0
species: 981969

983069
type: Reaction
kinetic law: 248218
product: 248206
reactant: 248193
reactant: 248181
notes: Ueki et al JBC 269(22):15756-15761 show the presence of this step, but not the rate consts, which are derived from Sanghera et al JBC 265(1):52-57, 1990, see the deriv in the MAPK* notes.
fast: false
reversible: true

248218
type: KineticLaw
local parameters: 900850
local parameters: 900847
notes: k1*MAPK_slash_craf_minus_1_star_*MAPK_star_-k2*MAPK_star__slash_MAPK_star__minus_feedback_slash_MAPK_star__minus_feedback_cplx

900850
type: LocalParameter
units: 247184
value: 4.0E-11

900847
type: LocalParameter
units: 247220
value: 1.95E-12

248206
type: SpeciesReference
stoichiometry: 1.0
species: 981569

981569
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

248193
type: SpeciesReference
stoichiometry: 1.0
species: 981549

248181
type: SpeciesReference
stoichiometry: 1.0
species: 981629

982889
type: Reaction
kinetic law: 247792
product: 247780
reactant: 247768
reactant: 247756
notes: Same rates as Grb2_bind_Sos: Porfiri and McCormick JBC 271:10 pp 5871 1996 show that the binding is not affected by the phosph.
fast: false
reversible: true

247792
type: KineticLaw
local parameters: 900826
local parameters: 900825
notes: kf*Sos_slash_Sos_star_*Sos_slash_Grb2-kb*Sos_slash_Sos_star__dot_Grb2

900826
type: LocalParameter
units: 247184
value: 1.68E-14

900825
type: LocalParameter
units: 247220
value: 2.50002E-14

247780
type: SpeciesReference
stoichiometry: 1.0
species: 982469

982469
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

247768
type: SpeciesReference
stoichiometry: 1.0
species: 982489

247756
type: SpeciesReference
stoichiometry: 1.0
species: 982529

982529
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

983049
type: Reaction
kinetic law: 248168
product: 248156
product: 248144
reactant: 248132
fast: false
reversible: false

248168
type: KineticLaw
local parameters: 900845
notes: k3*PKC_minus_active_slash_PKC_minus_act_minus_GEF_slash_PKC_minus_act_minus_GEF_cplx

900845
type: LocalParameter
units: 247184
value: 4.0E-12

248156
type: SpeciesReference
stoichiometry: 1.0
species: 982569

248144
type: SpeciesReference
stoichiometry: 1.0
species: 982089

248132
type: SpeciesReference
stoichiometry: 1.0
species: 981529

982309
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

983749
type: Reaction
kinetic law: 249860
product: 249848
reactant: 249835
reactant: 249823
fast: false
reversible: true

249860
type: KineticLaw
local parameters: 900973
local parameters: 900970
notes: k1*Ras_slash_GDP_minus_Ras*Shc_star__dot_Sos_dot_Grb2-k2*Shc_star__dot_Sos_dot_Grb2_slash_Sos_dot_Ras_GEF_slash_Sos_dot_Ras_GEF_cplx

900973
type: LocalParameter
units: 247184
value: 8.0E-14

900970
type: LocalParameter
units: 247220
value: 1.98E-13

249848
type: SpeciesReference
stoichiometry: 1.0
species: 982329

982329
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

249835
type: SpeciesReference
stoichiometry: 1.0
species: 982309

249823
type: SpeciesReference
stoichiometry: 1.0
species: 982149

982149
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.2
initial amount: NaN
in compartment: 981469

983429
type: Reaction
kinetic law: 249088
product: 249076
reactant: 249064
reactant: 249052
notes: See: Kyriakis et al Nature 358 pp 417-421 1992 Ahn et al Curr Op Cell Biol 4:992-999 1992 for this pathway. See parent PPhosphatase2A for parms.
fast: false
reversible: true

900925
type: LocalParameter
units: 247184
value: 2.5E-11

900924
type: LocalParameter
units: 247220
value: 1.98E-12

249076
type: SpeciesReference
stoichiometry: 1.0
species: 981969

249064
type: SpeciesReference
stoichiometry: 1.0
species: 981929

249052
type: SpeciesReference
stoichiometry: 1.0
species: 981729

983409
type: Reaction
kinetic law: 249040
product: 249028
product: 249016
reactant: 249003
fast: false
reversible: false

900923
type: LocalParameter
units: 247184
value: 6.0E-12

249028
type: SpeciesReference
stoichiometry: 1.0
species: 981929

249016
type: SpeciesReference
stoichiometry: 1.0
species: 981609

249003
type: SpeciesReference
stoichiometry: 1.0
species: 981949

983729
type: Reaction
kinetic law: 249811
product: 249799
product: 249787
reactant: 249775
fast: false
reversible: false

249811
type: KineticLaw
local parameters: 900968
notes: k3*PKA_minus_active_slash_PKA_minus_phosph_minus_GEF_slash_PKA_minus_phosph_minus_GEF_cplx

900968
type: LocalParameter
units: 247184
value: 9.0E-12

249799
type: SpeciesReference
stoichiometry: 1.0
species: 982609

249787
type: SpeciesReference
stoichiometry: 1.0
species: 982229

982229
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

249775
type: SpeciesReference
stoichiometry: 1.0
species: 982289

983809
type: Reaction
kinetic law: 250004
product: 249992
product: 249980
reactant: 249968
fast: false
reversible: false

250004
type: KineticLaw
local parameters: 900980
notes: k3*EGFR_slash_L_dot_EGFR_slash_phosph_Shc_slash_phosph_Shc_cplx

900980
type: LocalParameter
units: 247184
value: 2.0E-13

249992
type: SpeciesReference
stoichiometry: 1.0
species: 982369

249980
type: SpeciesReference
stoichiometry: 1.0
species: 982429

982429
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

249968
type: SpeciesReference
stoichiometry: 1.0
species: 982389

983189
type: Reaction
kinetic law: 248508
product: 248496
reactant: 248484
reactant: 248472
notes: Rate consts same as for MAPKKtyr.
fast: false
reversible: true

248508
type: KineticLaw
local parameters: 900868
local parameters: 900865
notes: k1*MAPK_slash_MAPK_minus_tyr*MAPK_slash_MAPKK_star_-k2*MAPK_slash_MAPKK_star__slash_MAPKKthr_slash_MAPKKthr_cplx

900868
type: LocalParameter
units: 247184
value: 6.0E-13

900865
type: LocalParameter
units: 247220
value: 1.62E-11

248496
type: SpeciesReference
stoichiometry: 1.0
species: 981769

248484
type: SpeciesReference
stoichiometry: 1.0
species: 981729

248472
type: SpeciesReference
stoichiometry: 1.0
species: 981709

982989
type: Reaction
kinetic law: 248021
product: 248009
reactant: 247996
reactant: 247984
notes: Rate consts copied from PCK-act-raf This reaction inactivates GAP. The idea is from the Boguski and McCormick review.
fast: false
reversible: true

248021
type: KineticLaw
local parameters: 900838
local parameters: 900835
notes: k1*Ras_slash_GAP*PKC_minus_active-k2*PKC_minus_active_slash_PKC_minus_inact_minus_GAP_slash_PKC_minus_inact_minus_GAP_cplx

900838
type: LocalParameter
units: 247184
value: 1.6E-11

900835
type: LocalParameter
units: 247220
value: 6.0E-12

248009
type: SpeciesReference
stoichiometry: 1.0
species: 981509

247996
type: SpeciesReference
stoichiometry: 1.0
species: 982569

247984
type: SpeciesReference
stoichiometry: 1.0
species: 982189

982969
type: Reaction
kinetic law: 247972
product: 247960
product: 247948
reactant: 247936
fast: false
reversible: false

247972
type: KineticLaw
local parameters: 900833
notes: k3*PKC_minus_active_slash_PKC_minus_act_minus_raf_slash_PKC_minus_act_minus_raf_cplx

900833
type: LocalParameter
units: 247184
value: 4.0E-12

247960
type: SpeciesReference
stoichiometry: 1.0
species: 982569

247948
type: SpeciesReference
stoichiometry: 1.0
species: 981629

247936
type: SpeciesReference
stoichiometry: 1.0
species: 981489

983589
type: Reaction
kinetic law: 249473
product: 249460
reactant: 249448
reactant: 249436
notes: Kinetics same as GEF-bg-act-ras
fast: false
reversible: true

249473
type: KineticLaw
local parameters: 900949
local parameters: 900946
notes: k1*Ras_slash_GDP_minus_Ras*Ras_slash_GEF_star_-k2*Ras_slash_GEF_star__slash_GEF_star__minus_act_minus_ras_slash_GEF_star__minus_act_minus_ras_cplx

900949
type: LocalParameter
units: 247184
value: 8.0E-14

900946
type: LocalParameter
units: 247220
value: 1.98E-13

249460
type: SpeciesReference
stoichiometry: 1.0
species: 982109

249448
type: SpeciesReference
stoichiometry: 1.0
species: 982089

249436
type: SpeciesReference
stoichiometry: 1.0
species: 982149

981456
type: Compartment
constant: true
size: 1.0E-18
spatial dimensions: 3.0

983689
type: Reaction
kinetic law: 249715
product: 249703
product: 249691
reactant: 249679
fast: false
reversible: false

249715
type: KineticLaw
local parameters: 900962
notes: k3*Ras_slash_CaM_minus_GEF_slash_CaM_minus_GEF_minus_act_minus_ras_slash_CaM_minus_GEF_minus_act_minus_ras_cplx

900962
type: LocalParameter
units: 247184
value: 2.0E-14

249703
type: SpeciesReference
stoichiometry: 1.0
species: 982249

249691
type: SpeciesReference
stoichiometry: 1.0
species: 982129

249679
type: SpeciesReference
stoichiometry: 1.0
species: 982269

983289
type: Reaction
kinetic law: 248750
product: 248738
product: 248726
reactant: 248714
fast: false
reversible: false

248750
type: KineticLaw
local parameters: 900881
notes: k3*MAPK_slash_Raf_minus_GTP_minus_Ras_star__slash_Raf_minus_GTP_minus_Ras_star__dot_2_slash_Raf_minus_GTP_minus_Ras_star__dot_2_cplx

900881
type: LocalParameter
units: 247184
value: 1.05E-13

248738
type: SpeciesReference
stoichiometry: 1.0
species: 981809

248726
type: SpeciesReference
stoichiometry: 1.0
species: 981729

248714
type: SpeciesReference
stoichiometry: 1.0
species: 981849

981849
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

983549
type: Reaction
kinetic law: 249376
product: 249364
reactant: 249352
reactant: 249340
notes: Kinetics based on the activation of Gq by the receptor complex in the Gq model (in turn based on the Mahama and Linderman model) k1 = 2e-5, k2 = 1e-10, k3 = 10 (I do not know why they even bother with k2). Lets put k1 at 2e-6 to get a reasonable equilibrium More specific values from, eg.g: Orita et al JBC 268(34) 25542-25546 from rasGRF and smgGDS: k1=3.3e-7; k2 = 0.08, k3 = 0.02
fast: false
reversible: true

249376
type: KineticLaw
local parameters: 900943
local parameters: 900940
notes: k1*Ras_slash_GDP_minus_Ras*Ras_slash_GEF_minus_Gprot_minus_bg-k2*Ras_slash_GEF_minus_Gprot_minus_bg_slash_GEF_minus_bg_act_minus_ras_slash_GEF_minus_bg_act_minus_ras_cplx

900943
type: LocalParameter
units: 247184
value: 8.0E-14

900940
type: LocalParameter
units: 247220
value: 1.98E-13

249364
type: SpeciesReference
stoichiometry: 1.0
species: 982049

249352
type: SpeciesReference
stoichiometry: 1.0
species: 982029

249340
type: SpeciesReference
stoichiometry: 1.0
species: 982149

983269
type: Reaction
kinetic law: 248701
product: 248689
reactant: 248677
reactant: 248665
notes: Same kinetics as other c-raf activated forms. See Force et al PNAS 91 1270-1274 1994. k1 = 1.1e-6, k2 = .42, k3 = 1.05 raise k1 to 5.5e-6
fast: false
reversible: true

248701
type: KineticLaw
local parameters: 900880
local parameters: 900877
notes: k1*MAPK_slash_MAPKK_minus_ser*MAPK_slash_Raf_minus_GTP_minus_Ras_star_-k2*MAPK_slash_Raf_minus_GTP_minus_Ras_star__slash_Raf_minus_GTP_minus_Ras_star__dot_2_slash_Raf_minus_GTP_minus_Ras_star__dot_2_cplx

900880
type: LocalParameter
units: 247184
value: 4.2E-13

900877
type: LocalParameter
units: 247220
value: 3.3E-12

248689
type: SpeciesReference
stoichiometry: 1.0
species: 981849

248677
type: SpeciesReference
stoichiometry: 1.0
species: 981809

248665
type: SpeciesReference
stoichiometry: 1.0
species: 981789

983649
type: Reaction
kinetic law: 249618
product: 249606
product: 249594
reactant: 249582
fast: false
reversible: false

249618
type: KineticLaw
local parameters: 900956
notes: k3*Ras_slash_GAP_slash_GAP_minus_inact_minus_ras_slash_GAP_minus_inact_minus_ras_cplx

900956
type: LocalParameter
units: 247184
value: 1.0E-11

249606
type: SpeciesReference
stoichiometry: 1.0
species: 982189

249594
type: SpeciesReference
stoichiometry: 1.0
species: 982149

249582
type: SpeciesReference
stoichiometry: 1.0
species: 982209

982209
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

982829
type: Reaction
kinetic law: 247658
product: 247646
reactant: 247634
notes: Time course of decline of phosph is 20 min. Part of this is the turnoff time of the EGFR itself. Lets assume a tau of 10 min for this dephosph. It may be wildly off.
fast: false
reversible: true

247658
type: KineticLaw
local parameters: 900820
local parameters: 900819
notes: kf*EGFR_slash_SHC_star_-kb*EGFR_slash_SHC

900820
type: LocalParameter
units: 247184
value: 0.0

900819
type: LocalParameter
units: 247184
value: 1.6667E-15

247646
type: SpeciesReference
stoichiometry: 1.0
species: 982409

247634
type: SpeciesReference
stoichiometry: 1.0
species: 982429

982809
type: Reaction
kinetic law: 247622
product: 247610
reactant: 247598
reactant: 247586
notes: Affinity of EGFR for EGF is complex: depends on [EGFR]. We\'ll assume fixed [EGFR] and use exptal affinity ~20 nM (see Sherrill and Kyte Biochem 1996 35 5705-5718, Berkers et al JBC 266:2 922-927 1991, Sorokin et al JBC 269:13 9752-9759 1994). Tau =~2 min (Davis et al JBC 263:11 5373-5379 1988) or Berkers Kass = 6.2e5/M/sec, Kdiss=3.5e-4/sec. Sherrill and Kyte have Hill Coeff=1.7
fast: false
reversible: true

247622
type: KineticLaw
local parameters: 900818
local parameters: 900817
notes: kf*EGFR_slash_EGFR*EGFR_slash_EGF-kb*EGFR_slash_L_dot_EGFR

900818
type: LocalParameter
units: 247184
value: 2.5E-13

900817
type: LocalParameter
units: 247220
value: 4.2E-12

247610
type: SpeciesReference
stoichiometry: 1.0
species: 982369

247598
type: SpeciesReference
stoichiometry: 1.0
species: 982649

247586
type: SpeciesReference
stoichiometry: 1.0
species: 982349

983629
type: Reaction
kinetic law: 249570
product: 249558
reactant: 249546
reactant: 249534
notes: From Eccleston et al JBC 268(36)pp27012-19 get Kd < 2uM, kcat - 10/sec From Martin et al Cell 63 843-849 1990 get Kd ~ 250 nM, kcat = 20/min I will go with the Eccleston figures as there are good error bars (10%). In general the values are reasonably close. k1 = 1.666e-3/sec, k2 = 1000/sec, k3 = 10/sec (note k3 is rate-limiting) 5 Nov 2002: Changed ratio term to 4 from 100. Now we have k1=8.25e-5; k2=40, k3=10. k3 is still rate-limiting.
fast: false
reversible: true

249570
type: KineticLaw
local parameters: 900955
local parameters: 900952
notes: k1*Ras_slash_GTP_minus_Ras*Ras_slash_GAP-k2*Ras_slash_GAP_slash_GAP_minus_inact_minus_ras_slash_GAP_minus_inact_minus_ras_cplx

900955
type: LocalParameter
units: 247184
value: 4.0E-11

900952
type: LocalParameter
units: 247220
value: 4.94856E-11

249558
type: SpeciesReference
stoichiometry: 1.0
species: 982209

249546
type: SpeciesReference
stoichiometry: 1.0
species: 982189

249534
type: SpeciesReference
stoichiometry: 1.0
species: 982129

982789
type: Reaction
kinetic law: 247574
product: 247562
reactant: 247549
fast: false
reversible: true

247574
type: KineticLaw
local parameters: 900816
local parameters: 900815
notes: kf*Ras_slash_inact_minus_GEF_star_-kb*Ras_slash_inact_minus_GEF

900816
type: LocalParameter
units: 247184
value: 0.0

900815
type: LocalParameter
units: 247184
value: 1.0E-12

247562
type: SpeciesReference
stoichiometry: 1.0
species: 982069

247549
type: SpeciesReference
stoichiometry: 1.0
species: 982229

983489
type: Reaction
kinetic law: 249232
product: 249220
product: 249208
reactant: 249196
fast: false
reversible: false

900932
type: LocalParameter
units: 247184
value: 6.0E-12

249220
type: SpeciesReference
stoichiometry: 1.0
species: 981929

249208
type: SpeciesReference
stoichiometry: 1.0
species: 981649

249196
type: SpeciesReference
stoichiometry: 1.0
species: 981989

983129
type: Reaction
kinetic law: 248364
product: 248352
product: 248340
reactant: 248328
fast: false
reversible: false

248364
type: KineticLaw
local parameters: 900857
notes: k3*MAPK_star__slash_phosph_Sos_slash_phosph_Sos_cplx

900857
type: LocalParameter
units: 247184
value: 1.0E-11

248352
type: SpeciesReference
stoichiometry: 1.0
species: 981549

248340
type: SpeciesReference
stoichiometry: 1.0
species: 982529

248328
type: SpeciesReference
stoichiometry: 1.0
species: 981589

981589
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

983109
type: Reaction
kinetic law: 248316
product: 248304
reactant: 248291
reactant: 248279
notes: See Porfiri and McCormick JBC 271:10 pp5871 1996 for the existence of this step. We\'ll take the rates from the ones used for the phosph of Raf by MAPK. Sep 17 1997: The transient activation curve matches better with k1 up by 10 x.
fast: false
reversible: true

248316
type: KineticLaw
local parameters: 900856
local parameters: 900853
notes: k1*Sos_slash_Sos*MAPK_star_-k2*MAPK_star__slash_phosph_Sos_slash_phosph_Sos_cplx

900856
type: LocalParameter
units: 247184
value: 4.0E-11

900853
type: LocalParameter
units: 247220
value: 1.95E-11

248304
type: SpeciesReference
stoichiometry: 1.0
species: 981589

248291
type: SpeciesReference
stoichiometry: 1.0
species: 981549

248279
type: SpeciesReference
stoichiometry: 1.0
species: 982549

982909
type: Reaction
kinetic law: 247828
product: 247816
reactant: 247804
notes: The only clue I have to these rates is from the time courses of the EGF activation, which is around 1 to 5 min. The dephosph would be expected to be of the same order, perhaps a bit longer. Lets use 0.002 which is about 8 min. Sep 17: The transient activation curve matches better with kf = 0.001
fast: false
reversible: true

247828
type: KineticLaw
local parameters: 900828
local parameters: 900827
notes: kf*Sos_slash_Sos_star_-kb*Sos_slash_Sos

900828
type: LocalParameter
units: 247184
value: 0.0

900827
type: LocalParameter
units: 247184
value: 1.0E-15

247816
type: SpeciesReference
stoichiometry: 1.0
species: 982549

247804
type: SpeciesReference
stoichiometry: 1.0
species: 982529

983089
type: Reaction
kinetic law: 248267
product: 248255
product: 248243
reactant: 248230
fast: false
reversible: false

248267
type: KineticLaw
local parameters: 900851
notes: k3*MAPK_star__slash_MAPK_star__minus_feedback_slash_MAPK_star__minus_feedback_cplx

900851
type: LocalParameter
units: 247184
value: 1.0E-11

248255
type: SpeciesReference
stoichiometry: 1.0
species: 981549

248243
type: SpeciesReference
stoichiometry: 1.0
species: 981689

248230
type: SpeciesReference
stoichiometry: 1.0
species: 981569

983769
type: Reaction
kinetic law: 249908
product: 249896
product: 249884
reactant: 249872
fast: false
reversible: false

249908
type: KineticLaw
local parameters: 900974
notes: k3*Shc_star__dot_Sos_dot_Grb2_slash_Sos_dot_Ras_GEF_slash_Sos_dot_Ras_GEF_cplx

900974
type: LocalParameter
units: 247184
value: 2.0E-14

249896
type: SpeciesReference
stoichiometry: 1.0
species: 982309

249884
type: SpeciesReference
stoichiometry: 1.0
species: 982129

249872
type: SpeciesReference
stoichiometry: 1.0
species: 982329

982729
type: Reaction
kinetic law: 247452
product: 247440
reactant: 247428
notes: This is extremely slow (1e-4), but it is significant as so little GAP actually gets complexed with it that the total GTP turnover rises only by 2-3 X (see Gibbs et al, JBC 265(33) 20437-20422) and Eccleston et al JBC 268(36) 27012-27019 kf = 1e-4
fast: false
reversible: true

247452
type: KineticLaw
local parameters: 900810
local parameters: 900809
notes: kf*Ras_slash_GTP_minus_Ras-kb*Ras_slash_GDP_minus_Ras

900810
type: LocalParameter
units: 247184
value: 0.0

900809
type: LocalParameter
units: 247184
value: 1.0E-16

247440
type: SpeciesReference
stoichiometry: 1.0
species: 982149

247428
type: SpeciesReference
stoichiometry: 1.0
species: 982129

982709
type: Reaction
kinetic law: 247416
product: 247404
reactant: 247391
fast: false
reversible: true

247416
type: KineticLaw
local parameters: 900808
local parameters: 900807
notes: kf*Ras_slash_GEF_star_-kb*Ras_slash_inact_minus_GEF

900808
type: LocalParameter
units: 247184
value: 0.0

900807
type: LocalParameter
units: 247184
value: 1.0E-12

247404
type: SpeciesReference
stoichiometry: 1.0
species: 982069

247391
type: SpeciesReference
stoichiometry: 1.0
species: 982089

983349
type: Reaction
kinetic law: 248894
product: 248882
reactant: 248870
reactant: 248858
notes: See MKP1-tyr-deph
fast: false
reversible: true

248894
type: KineticLaw
local parameters: 900912
local parameters: 900911
notes: k1*MAPK_star_*MKP_minus_1-k2*MKP_minus_1_slash_MKP1_minus_thr_minus_deph_slash_MKP1_minus_thr_minus_deph_cplx

900912
type: LocalParameter
units: 247184
value: 4.0E-12

900911
type: LocalParameter
units: 247220
value: 7.5E-11

248882
type: SpeciesReference
stoichiometry: 1.0
species: 981909

248870
type: SpeciesReference
stoichiometry: 1.0
species: 981869

248858
type: SpeciesReference
stoichiometry: 1.0
species: 981549

983329
type: Reaction
kinetic law: 248846
product: 248834
product: 248822
reactant: 248810
fast: false
reversible: false

248846
type: KineticLaw
local parameters: 900909
notes: k3*MKP_minus_1_slash_MKP1_minus_tyr_minus_deph_slash_MKP1_minus_tyr_minus_deph_cplx

900909
type: LocalParameter
units: 247184
value: 1.0E-12

248834
type: SpeciesReference
stoichiometry: 1.0
species: 981869

248822
type: SpeciesReference
stoichiometry: 1.0
species: 981669

248810
type: SpeciesReference
stoichiometry: 1.0
species: 981889

981889
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469

983669
type: Reaction
kinetic law: 249667
product: 249655
reactant: 249643
reactant: 249631
notes: Kinetics same as GEF-bg_act-ras
fast: false
reversible: true

249667
type: KineticLaw
local parameters: 900961
local parameters: 900958
notes: k1*Ras_slash_GDP_minus_Ras*Ras_slash_CaM_minus_GEF-k2*Ras_slash_CaM_minus_GEF_slash_CaM_minus_GEF_minus_act_minus_ras_slash_CaM_minus_GEF_minus_act_minus_ras_cplx

900961
type: LocalParameter
units: 247184
value: 8.0E-14

900958
type: LocalParameter
units: 247220
value: 1.98E-13

249655
type: SpeciesReference
stoichiometry: 1.0
species: 982269

249643
type: SpeciesReference
stoichiometry: 1.0
species: 982249

249631
type: SpeciesReference
stoichiometry: 1.0
species: 982149

983309
type: Reaction
kinetic law: 248798
product: 248786
reactant: 248774
reactant: 248762
notes: The original kinetics have been modified to obey the k2 = 4 * k3 rule, while keeping kcat and Km fixed. As noted in the NOTES, the only constraining data point is the time course of MAPK dephosphorylation, which this model satisfies. It would be nice to have more accurate estimates of rate consts and MKP-1 levels from the literature. Effective Km : 67 nM kcat = 1.43 umol/min/mg
fast: false
reversible: true

248798
type: KineticLaw
local parameters: 900886
local parameters: 900883
notes: k1*MAPK_slash_MAPK_minus_tyr*MKP_minus_1-k2*MKP_minus_1_slash_MKP1_minus_tyr_minus_deph_slash_MKP1_minus_tyr_minus_deph_cplx

900886
type: LocalParameter
units: 247184
value: 4.0E-12

900883
type: LocalParameter
units: 247220
value: 7.5E-11

248786
type: SpeciesReference
stoichiometry: 1.0
species: 981889

248774
type: SpeciesReference
stoichiometry: 1.0
species: 981869

248762
type: SpeciesReference
stoichiometry: 1.0
species: 981709

983029
type: Reaction
kinetic law: 248119
product: 248107
reactant: 248095
reactant: 248082
notes: Rate consts from PKC-act-raf. This reaction activates GEF. It can lead to at least 2X stim of ras, and a 2X stim of MAPK over and above that obtained via direct phosph of c-raf. Note that it is a push-pull reaction, and there is also a contribution through the phosphorylation and inactivation of GAPs. The original PKC-act-raf rate consts are too fast. We lower K1 by 10 X
fast: false
reversible: true

248119
type: KineticLaw
local parameters: 900844
local parameters: 900841
notes: k1*Ras_slash_inact_minus_GEF*PKC_minus_active-k2*PKC_minus_active_slash_PKC_minus_act_minus_GEF_slash_PKC_minus_act_minus_GEF_cplx

900844
type: LocalParameter
units: 247184
value: 1.6E-11

900841
type: LocalParameter
units: 247220
value: 6.0E-12

248107
type: SpeciesReference
stoichiometry: 1.0
species: 981529

248095
type: SpeciesReference
stoichiometry: 1.0
species: 982569

248082
type: SpeciesReference
stoichiometry: 1.0
species: 982069

982869
type: Reaction
kinetic law: 247744
product: 247732
reactant: 247720
reactant: 247708
notes: Sasaoka et al JBC 269:51 pp 32621 1994, table on pg 32623 indicates that this pathway accounts for about 50% of the GEF activation. (88% - 39%). Error is large, about 20%. Fig 1 is most useful in constraining rates. Chook et al JBC 271:48 pp 30472, 1996 say that the Kd is 0.2 uM for Shc binding to EGFR. The Kd for Grb direct binding is 0.7, so we\'ll ignore it.
fast: false
reversible: true

247744
type: KineticLaw
local parameters: 900824
local parameters: 900823
notes: kf*Sos_slash_Sos_dot_Grb2*EGFR_slash_SHC_star_-kb*Shc_star__dot_Sos_dot_Grb2

900824
type: LocalParameter
units: 247184
value: 1.0E-13

900823
type: LocalParameter
units: 247220
value: 4.9998E-13

247732
type: SpeciesReference
stoichiometry: 1.0
species: 982309

247720
type: SpeciesReference
stoichiometry: 1.0
species: 982429

247708
type: SpeciesReference
stoichiometry: 1.0
species: 982509