249944
stoichiometry: 1.0
species: 982389
type: SpeciesReference

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

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

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

248255
stoichiometry: 1.0
species: 981549
type: SpeciesReference

981749
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469
type: Species

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

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

900828
units: 247184
value: 0.0
type: LocalParameter

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

247245
exponent: -1.0
scale: -6
multipler: 1.0
kind: MOLE
type: SBMLUnit

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

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

247756
stoichiometry: 1.0
species: 982529
type: SpeciesReference

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

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

248340
stoichiometry: 1.0
species: 982529
type: SpeciesReference

249691
stoichiometry: 1.0
species: 982129
type: SpeciesReference

247996
stoichiometry: 1.0
species: 982569
type: SpeciesReference

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

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

248206
stoichiometry: 1.0
species: 981569
type: SpeciesReference

248750
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
type: KineticLaw

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

982589
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
type: Species

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

249884
stoichiometry: 1.0
species: 982129
type: SpeciesReference

MODEL9085850385
reaction: 983029
reaction: 982849
species: 982349
reaction: 983009
curated: false
species: 981529
species: 982269
species: 981949
species: 981989
species: 981729
reaction: 983709
substance units: 247269
species: 982649
species: 981489
reaction: 983169
reaction: 983149
reaction: 982949
reaction: 982929
is described by: http://identifiers.org/pubmed/15298883
volume units: 679943
length unit: length
species: 982409
reaction: 983569
reaction: 983249
species: 982569
reaction: 983229
reaction: 982689
reaction: 982669
species: 982169
species: 981689
species: 982369
species: 981609
reaction: 983209
species: 981549
reaction: 983529
reaction: 983509
species: 981749
species: 981929
species: 982489
species: 981969
species: 982009
reaction: 983609
reaction: 982769
reaction: 982749
type: SBMLModel
reaction: 983389
reaction: 983369
units def: 247220
species: 982089
species: 982549
reaction: 983469
reaction: 983789
reaction: 983449
reaction: 983069
reaction: 982889
species: 982389
reaction: 983049
species: 982109
species: 981629
species: 982189
species: 982309
species: 981829
reaction: 983749
reaction: 983429
species: 981769
reaction: 983409
species: 981909
reaction: 983729
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
species: 982249
reaction: 983809
reaction: 983189
reaction: 982989
reaction: 982969
reaction: 983589
time units: 131570
compartment: 981456
compartment: 981469
species: 982229

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

247634
stoichiometry: 1.0
species: 982429
type: SpeciesReference

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

248107
stoichiometry: 1.0
species: 981529
type: SpeciesReference

248568
stoichiometry: 1.0
species: 981649
type: SpeciesReference

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

248822
stoichiometry: 1.0
species: 981669
type: SpeciesReference

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

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

248243
stoichiometry: 1.0
species: 981689
type: SpeciesReference

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

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

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

249956
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
type: KineticLaw

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

983149
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
type: Reaction

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

982069
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.1
initial amount: NaN
in compartment: 981469
type: Species

900816
units: 247184
value: 0.0
type: LocalParameter

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

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

248762
stoichiometry: 1.0
species: 981709
type: SpeciesReference

247257
exponent: -1.0
scale: 0
multipler: 1.0
kind: SECOND
type: SBMLUnit

248218
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
type: KineticLaw

249992
stoichiometry: 1.0
species: 982369
type: SpeciesReference

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

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

982929
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
type: Reaction

247984
stoichiometry: 1.0
species: 982189
type: SpeciesReference

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

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

248810
stoichiometry: 1.0
species: 981889
type: SpeciesReference

247342
stoichiometry: 1.0
species: 982589
type: SpeciesReference

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

983009
kinetic law: 248070
product: 248058
product: 248046
reactant: 248033
fast: false
reversible: false
type: Reaction

249896
stoichiometry: 1.0
species: 982309
type: SpeciesReference

247646
stoichiometry: 1.0
species: 982409
type: SpeciesReference

248009
stoichiometry: 1.0
species: 981509
type: SpeciesReference

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

247708
stoichiometry: 1.0
species: 982509
type: SpeciesReference

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

249316
stoichiometry: 1.0
species: 981929
type: SpeciesReference

982449
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469
type: Species

982509
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469
type: Species

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

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

249606
stoichiometry: 1.0
species: 982189
type: SpeciesReference

249920
stoichiometry: 1.0
species: 982409
type: SpeciesReference

249497
stoichiometry: 1.0
species: 982129
type: SpeciesReference

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

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

248132
stoichiometry: 1.0
species: 981529
type: SpeciesReference

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

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

248279
stoichiometry: 1.0
species: 982549
type: SpeciesReference

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

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

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

248412
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
type: KineticLaw

247610
stoichiometry: 1.0
species: 982369
type: SpeciesReference

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

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

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

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

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

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

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

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

248095
stoichiometry: 1.0
species: 982569
type: SpeciesReference

249980
stoichiometry: 1.0
species: 982429
type: SpeciesReference

249799
stoichiometry: 1.0
species: 982609
type: SpeciesReference

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

247960
stoichiometry: 1.0
species: 982569
type: SpeciesReference

247768
stoichiometry: 1.0
species: 982489
type: SpeciesReference

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

248082
stoichiometry: 1.0
species: 982069
type: SpeciesReference

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

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

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

248144
stoichiometry: 1.0
species: 982089
type: SpeciesReference

249932
stoichiometry: 1.0
species: 982369
type: SpeciesReference

249160
stoichiometry: 1.0
species: 981929
type: SpeciesReference

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

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

249485
stoichiometry: 1.0
species: 982109
type: SpeciesReference

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

248834
stoichiometry: 1.0
species: 981869
type: SpeciesReference

248181
stoichiometry: 1.0
species: 981629
type: SpeciesReference

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

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

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

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

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

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

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

900964
units: 247220
value: 6.0E-12
type: LocalParameter

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

248352
stoichiometry: 1.0
species: 981549
type: SpeciesReference

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

248388
stoichiometry: 1.0
species: 981729
type: SpeciesReference

982989
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
type: Reaction

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

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

248580
stoichiometry: 1.0
species: 981809
type: SpeciesReference

248304
stoichiometry: 1.0
species: 981589
type: SpeciesReference

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

247900
stoichiometry: 1.0
species: 982569
type: SpeciesReference

249715
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
type: KineticLaw

249388
stoichiometry: 1.0
species: 982049
type: SpeciesReference

247864
stoichiometry: 1.0
species: 982509
type: SpeciesReference

249028
stoichiometry: 1.0
species: 981929
type: SpeciesReference

248436
stoichiometry: 1.0
species: 981709
type: SpeciesReference

248193
stoichiometry: 1.0
species: 981549
type: SpeciesReference

249679
stoichiometry: 1.0
species: 982269
type: SpeciesReference

248954
stoichiometry: 1.0
species: 981629
type: SpeciesReference

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

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

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

248520
stoichiometry: 1.0
species: 981769
type: SpeciesReference

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

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

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

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

249208
stoichiometry: 1.0
species: 981649
type: SpeciesReference

249016
stoichiometry: 1.0
species: 981609
type: SpeciesReference

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

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

249064
stoichiometry: 1.0
species: 981929
type: SpeciesReference

249823
stoichiometry: 1.0
species: 982149
type: SpeciesReference

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

249376
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
type: KineticLaw

247912
stoichiometry: 1.0
species: 981489
type: SpeciesReference

249703
stoichiometry: 1.0
species: 982249
type: SpeciesReference

247852
stoichiometry: 1.0
species: 982549
type: SpeciesReference

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

248376
stoichiometry: 1.0
species: 981669
type: SpeciesReference

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

247562
stoichiometry: 1.0
species: 982069
type: SpeciesReference

248858
stoichiometry: 1.0
species: 981549
type: SpeciesReference

982949
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
type: Reaction

248291
stoichiometry: 1.0
species: 981549
type: SpeciesReference

248424
stoichiometry: 1.0
species: 981749
type: SpeciesReference

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

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

249667
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
type: KineticLaw

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

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

983169
kinetic law: 248460
product: 248448
product: 248436
reactant: 248424
fast: false
reversible: false
type: Reaction

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

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

249304
stoichiometry: 1.0
species: 981629
type: SpeciesReference

983029
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
type: Reaction

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

249076
stoichiometry: 1.0
species: 981969
type: SpeciesReference

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

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

982909
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
type: Reaction

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

249860
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
type: KineticLaw

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

248544
stoichiometry: 1.0
species: 981729
type: SpeciesReference

248906
stoichiometry: 1.0
species: 981909
type: SpeciesReference

247354
stoichiometry: 1.0
species: 982069
type: SpeciesReference

247293
stoichiometry: 1.0
species: 981629
type: SpeciesReference

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

249739
stoichiometry: 1.0
species: 982609
type: SpeciesReference

249003
stoichiometry: 1.0
species: 981949
type: SpeciesReference

249364
stoichiometry: 1.0
species: 982049
type: SpeciesReference

247840
stoichiometry: 1.0
species: 982489
type: SpeciesReference

248230
stoichiometry: 1.0
species: 981569
type: SpeciesReference

248979
stoichiometry: 1.0
species: 981949
type: SpeciesReference

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

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

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

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

248918
stoichiometry: 1.0
species: 981709
type: SpeciesReference

248119
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
type: KineticLaw

248448
stoichiometry: 1.0
species: 981729
type: SpeciesReference

249872
stoichiometry: 1.0
species: 982329
type: SpeciesReference

247281
exponent: 1.0
scale: -6
multipler: 1.0
kind: MOLE
type: SBMLUnit

249727
stoichiometry: 1.0
species: 982069
type: SpeciesReference

249352
stoichiometry: 1.0
species: 982029
type: SpeciesReference

247367
stoichiometry: 1.0
species: 982029
type: SpeciesReference

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

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

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

982629
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
type: Species

248967
stoichiometry: 1.0
species: 981929
type: SpeciesReference

249052
stoichiometry: 1.0
species: 981729
type: SpeciesReference

249292
stoichiometry: 1.0
species: 982009
type: SpeciesReference

249340
stoichiometry: 1.0
species: 982149
type: SpeciesReference

982649
constant: true
boundary condition: true
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469
type: Species

982369
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469
type: Species

248532
stoichiometry: 1.0
species: 981549
type: SpeciesReference

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

983509
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
type: Reaction

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

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

249848
stoichiometry: 1.0
species: 982329
type: SpeciesReference

247804
stoichiometry: 1.0
species: 982529
type: SpeciesReference

248653
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
type: KineticLaw

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

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

247780
stoichiometry: 1.0
species: 982469
type: SpeciesReference

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

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

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

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

248726
stoichiometry: 1.0
species: 981729
type: SpeciesReference

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

247586
stoichiometry: 1.0
species: 982349
type: SpeciesReference

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

249244
stoichiometry: 1.0
species: 981689
type: SpeciesReference

983549
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
type: Reaction

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

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

249631
stoichiometry: 1.0
species: 982149
type: SpeciesReference

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

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

248641
stoichiometry: 1.0
species: 981809
type: SpeciesReference

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

983229
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
type: Reaction

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

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

248738
stoichiometry: 1.0
species: 981809
type: SpeciesReference

982569
constant: true
boundary condition: true
has only substance units: false
initial concentration: 0.09
initial amount: NaN
in compartment: 981469
type: Species

247549
stoichiometry: 1.0
species: 982229
type: SpeciesReference

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

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

249256
stoichiometry: 1.0
species: 981929
type: SpeciesReference

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

249835
stoichiometry: 1.0
species: 982309
type: SpeciesReference

247683
stoichiometry: 1.0
species: 982449
type: SpeciesReference

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

982549
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.1
initial amount: NaN
in compartment: 981469
type: Species

982289
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469
type: Species

249460
stoichiometry: 1.0
species: 982109
type: SpeciesReference

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

982869
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
type: Reaction

249436
stoichiometry: 1.0
species: 982149
type: SpeciesReference

981489
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469
type: Species

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

982349
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.166666666666667
initial amount: NaN
in compartment: 981469
type: Species

249643
stoichiometry: 1.0
species: 982249
type: SpeciesReference

247208
exponent: -1.0
scale: 0
multipler: 1.0
kind: SECOND
type: SBMLUnit

982849
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
type: Reaction

247671
stoichiometry: 1.0
species: 982369
type: SpeciesReference

982889
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
type: Reaction

249220
stoichiometry: 1.0
species: 981929
type: SpeciesReference

249400
stoichiometry: 1.0
species: 982129
type: SpeciesReference

248592
stoichiometry: 1.0
species: 981829
type: SpeciesReference

248677
stoichiometry: 1.0
species: 981809
type: SpeciesReference

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

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

247816
stoichiometry: 1.0
species: 982549
type: SpeciesReference

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

982809
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
type: Reaction

249424
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
type: KineticLaw

983429
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
type: Reaction

982829
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
type: Reaction

247598
stoichiometry: 1.0
species: 982649
type: SpeciesReference

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

248930
stoichiometry: 1.0
species: 981869
type: SpeciesReference

249412
stoichiometry: 1.0
species: 982029
type: SpeciesReference

249655
stoichiometry: 1.0
species: 982269
type: SpeciesReference

249473
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
type: KineticLaw

249148
stoichiometry: 1.0
species: 981789
type: SpeciesReference

247888
stoichiometry: 1.0
species: 981609
type: SpeciesReference

248665
stoichiometry: 1.0
species: 981789
type: SpeciesReference

247525
stoichiometry: 1.0
species: 982249
type: SpeciesReference

248328
stoichiometry: 1.0
species: 981589
type: SpeciesReference

249787
stoichiometry: 1.0
species: 982229
type: SpeciesReference

247513
stoichiometry: 1.0
species: 982629
type: SpeciesReference

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

247317
stoichiometry: 1.0
species: 981809
type: SpeciesReference

982689
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
type: Reaction

983789
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
type: Reaction

982669
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
type: Reaction

248882
stoichiometry: 1.0
species: 981909
type: SpeciesReference

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

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

249509
stoichiometry: 1.0
species: 982089
type: SpeciesReference

249112
stoichiometry: 1.0
species: 981789
type: SpeciesReference

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

248472
stoichiometry: 1.0
species: 981709
type: SpeciesReference

248058
stoichiometry: 1.0
species: 982569
type: SpeciesReference

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

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

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

249751
stoichiometry: 1.0
species: 982289
type: SpeciesReference

248786
stoichiometry: 1.0
species: 981889
type: SpeciesReference

249558
stoichiometry: 1.0
species: 982209
type: SpeciesReference

247428
stoichiometry: 1.0
species: 982129
type: SpeciesReference

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

247936
stoichiometry: 1.0
species: 981489
type: SpeciesReference

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

249570
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
type: KineticLaw

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

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

248689
stoichiometry: 1.0
species: 981849
type: SpeciesReference

247501
stoichiometry: 1.0
species: 982069
type: SpeciesReference

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

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

247305
stoichiometry: 1.0
species: 982129
type: SpeciesReference

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

248046
stoichiometry: 1.0
species: 982169
type: SpeciesReference

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

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

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

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

247440
stoichiometry: 1.0
species: 982149
type: SpeciesReference

248894
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
type: KineticLaw

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

900820
units: 247184
value: 0.0
type: LocalParameter

248774
stoichiometry: 1.0
species: 981869
type: SpeciesReference

249124
stoichiometry: 1.0
species: 981929
type: SpeciesReference

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

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

249763
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
type: KineticLaw

900808
units: 247184
value: 0.0
type: LocalParameter

249172
stoichiometry: 1.0
species: 981989
type: SpeciesReference

983629
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
type: Reaction

983069
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
type: Reaction

248400
stoichiometry: 1.0
species: 981749
type: SpeciesReference

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

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

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

248156
stoichiometry: 1.0
species: 982569
type: SpeciesReference

248605
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
type: KineticLaw

249582
stoichiometry: 1.0
species: 982209
type: SpeciesReference

249968
stoichiometry: 1.0
species: 982389
type: SpeciesReference

247924
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
type: KineticLaw

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

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

249448
stoichiometry: 1.0
species: 982089
type: SpeciesReference

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

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

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

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

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

247476
stoichiometry: 1.0
species: 982189
type: SpeciesReference

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

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

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

248496
stoichiometry: 1.0
species: 981769
type: SpeciesReference

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

982169
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 981469
type: Species

249268
stoichiometry: 1.0
species: 982009
type: SpeciesReference

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

247391
stoichiometry: 1.0
species: 982089
type: SpeciesReference

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

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

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

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

247720
stoichiometry: 1.0
species: 982429
type: SpeciesReference

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

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

248021
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
type: KineticLaw

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

983109
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
type: Reaction

249594
stoichiometry: 1.0
species: 982149
type: SpeciesReference

983709
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
type: Reaction

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

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

983269
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
type: Reaction

983309
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
type: Reaction

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

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

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

248617
stoichiometry: 1.0
species: 981829
type: SpeciesReference

249775
stoichiometry: 1.0
species: 982289
type: SpeciesReference

249534
stoichiometry: 1.0
species: 982129
type: SpeciesReference

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

247404
stoichiometry: 1.0
species: 982069
type: SpeciesReference

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

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

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

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

247196
exponent: 1.0
scale: 0
multipler: 1.0
kind: LITRE
type: SBMLUnit

248484
stoichiometry: 1.0
species: 981729
type: SpeciesReference

249100
stoichiometry: 1.0
species: 981969
type: SpeciesReference

248870
stoichiometry: 1.0
species: 981869
type: SpeciesReference

247464
stoichiometry: 1.0
species: 982169
type: SpeciesReference

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

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

982769
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
type: Reaction

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

248714
stoichiometry: 1.0
species: 981849
type: SpeciesReference

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

900810
units: 247184
value: 0.0
type: LocalParameter

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

247329
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_
type: KineticLaw

982609
constant: true
boundary condition: true
has only substance units: false
initial concentration: 0.015
initial amount: NaN
in compartment: 981469
type: Species

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

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

900812
units: 247184
value: 0.0
type: LocalParameter

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

247948
stoichiometry: 1.0
species: 981629
type: SpeciesReference

247732
stoichiometry: 1.0
species: 982309
type: SpeciesReference

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

248033
stoichiometry: 1.0
species: 981509
type: SpeciesReference

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

248629
stoichiometry: 1.0
species: 981789
type: SpeciesReference

249546
stoichiometry: 1.0
species: 982189
type: SpeciesReference

248798
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
type: KineticLaw

248508
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
type: KineticLaw

982729
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
type: Reaction

248701
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
type: KineticLaw

249196
stoichiometry: 1.0
species: 981989
type: SpeciesReference