MODEL9079179924
type: SBMLModel
reaction: 920825
species: 918725
reaction: 920685
reaction: 920465
species: 917865
species: 919145
reaction: 919525
reaction: 920845
species: 918305
reaction: 920485
reaction: 920205
species: 918225
reaction: 919545
reaction: 920865
species: 918645
reaction: 919725
species: 918325
species: 917685
species: 918745
reaction: 919745
species: 919185
reaction: 920125
species: 918665
reaction: 920425
reaction: 919765
species: 918526
units def: 190250
reaction: 920145
species: 918025
species: 917725
species: 918465
units def: 190336
species: 919085
reaction: 919785
reaction: 919445
species: 918705
reaction: 919605
species: 918125
reaction: 919925
species: 917905
species: 917925
species: 918565
species: 918065
reaction: 919625
species: 918905
reaction: 920005
reaction: 919565
species: 918205
compartment: 917631
species: 918165
reaction: 919645
species: 918265
reaction: 920025
species: 917965
reaction: 919585
reaction: 920105
length unit: length
species: 918405
reaction: 919665
species: 918945
species: 918365
reaction: 919845
reaction: 920785
species: 918505
reaction: 919865
name: Bhalla2002_MAPK-bistability-fig1c
species: 917985
reaction: 919885
species: 919245
species: 919025
species: 918485
species: 918605
species: 918965
species: 919125
species: 918585
curated: false
reaction: 920665
reaction: 920385
reaction: 920765

920825
type: Reaction
kinetic law: 193996
product: 193984
reactant: 193972
reactant: 193959
notes: 22 Apr 2001: Based on MKP1 parms. The original kinetics have been modified to obey the k2 = 4 * k3 rule, while keeping kcat and Km fixed. The only constraining data point is the time course of MAPK dephosphorylation, which this model satisfies. The rates are treated as the same as for MKP-1, based on Chu et al 1995 JBC 271(11):6497-6501
fast: false
reversible: true

193996
type: KineticLaw
local parameters: 115494
local parameters: 115492
notes: k1*MAPK_slash_MAPK_minus_tyr*MKP_minus_2-k2*MKP_minus_2_slash_MKP2_minus_tyr_minus_deph_slash_MKP2_minus_tyr_minus_deph_cplx

115494
type: LocalParameter
units: 190250
value: 4.0E-12

190275
type: SBMLUnit
exponent: -1.0
scale: 0
multipler: 1.0
kind: SECOND

190262
type: SBMLUnit
exponent: 1.0
scale: 0
multipler: 1.0
kind: LITRE

115492
type: LocalParameter
units: 190287
value: 7.5E-11

190323
type: SBMLUnit
exponent: -1.0
scale: 0
multipler: 1.0
kind: SECOND

190311
type: SBMLUnit
exponent: -1.0
scale: -6
multipler: 1.0
kind: MOLE

190299
type: SBMLUnit
exponent: 2.0
scale: 0
multipler: 1.0
kind: LITRE

193984
type: SpeciesReference
stoichiometry: 1.0
species: 919105

919105
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

917645
type: Compartment
constant: true
size: 1.0E-12
spatial dimensions: 3.0

193972
type: SpeciesReference
stoichiometry: 1.0
species: 919085

919085
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0024
initial amount: NaN
in compartment: 917645

193959
type: SpeciesReference
stoichiometry: 1.0
species: 918205

918205
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

918725
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

920685
type: Reaction
kinetic law: 193655
product: 193643
product: 193631
reactant: 193619
fast: false
reversible: false

193655
type: KineticLaw
local parameters: 115481
notes: k3*PLA2_slash_PLA2_star__minus_Ca_slash_kenz_slash_kenz_cplx

115481
type: LocalParameter
units: 190250
value: 1.2E-10

193643
type: SpeciesReference
stoichiometry: 1.0
species: 918745

918745
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

193631
type: SpeciesReference
stoichiometry: 1.0
species: 918025

918025
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 6.12
initial amount: NaN
in compartment: 917645

193619
type: SpeciesReference
stoichiometry: 1.0
species: 918765

918765
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

920465
type: Reaction
kinetic law: 193123
product: 193111
reactant: 193099
reactant: 193087
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 assumed to be PP2A.
fast: false
reversible: true

115459
type: LocalParameter
units: 190250
value: 2.5E-11

115458
type: LocalParameter
units: 190287
value: 1.98E-12

193111
type: SpeciesReference
stoichiometry: 1.0
species: 918545

918545
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

193099
type: SpeciesReference
stoichiometry: 1.0
species: 918485

918485
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.224
initial amount: NaN
in compartment: 917645

193087
type: SpeciesReference
stoichiometry: 1.0
species: 918185

918185
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

917865
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 1.3896E-17
initial amount: NaN
in compartment: 917645

919145
type: Species
notes: Baseline in model is 11.661 uM. DAG is pretty nasty to estimate. In this model we just hold it fixed at this baseline level. Data sources are many and varied and sometimes difficult to reconcile. Welsh and Cabot 1987 JCB 35:231-245: DAG degradation Bocckino et al JBC 260(26):14201-14207: hepatocytes stim with vasopressin: 190 uM. Bocckino et al 1987 JBC 262(31):15309-15315: DAG rises from 70 to 200 ng/mg wet weight, approx 150 to 450 uM. Prescott and Majerus 1983 JBC 258:764-769: Platelets: 6 uM. Also see Rittenhouse-Simmons 1979 J Clin Invest 63. Sano et al JBC 258(3):2010-2013: Report a nearly 10 fold rise. Habenicht et al 1981 JBC 256(23)12329-12335: 3T3 cells with PDGF stim: 27 uM Cornell and Vance 1987 BBA 919:23-36: 10x rise from 10 to 100 uM. Summary: I see much lower rises in my PLC models, but the baseline could be anywhere from 5 to 100 uM. I have chosen about 11 uM based on the stimulus -response characteristics from the Schaechter and Benowitz paper and the Shinomura et al papers.
constant: true
boundary condition: true
has only substance units: false
initial concentration: 11.661
initial amount: NaN
in compartment: 917645

919525
type: Reaction
kinetic law: 190919
product: 190907
reactant: 190895
reactant: 190883
notes: Binding of PKC to DAG, non-Ca dependent. Kf based on Shinomura et al PNAS 88 5149-5153 1991 Tau estimated as fast and here it is about the same time-course as the formation of DAG so it will not be rate-limiting.
fast: false
reversible: true

190919
type: KineticLaw
local parameters: 115336
local parameters: 115334
notes: kf*PKC_slash_PKC_minus_cytosolic*DAG-kb*PKC_slash_PKC_minus_DAG

115336
type: LocalParameter
units: 190250
value: 1.0E-13

115334
type: LocalParameter
units: 190287
value: 6.0E-16

190907
type: SpeciesReference
stoichiometry: 1.0
species: 917965

917965
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

190895
type: SpeciesReference
stoichiometry: 1.0
species: 919145

190883
type: SpeciesReference
stoichiometry: 1.0
species: 918005

918005
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 1.0
initial amount: NaN
in compartment: 917645

920845
type: Reaction
kinetic law: 194044
product: 194032
product: 194020
reactant: 194008
fast: false
reversible: false

194044
type: KineticLaw
local parameters: 115496
notes: k3*MKP_minus_2_slash_MKP2_minus_tyr_minus_deph_slash_MKP2_minus_tyr_minus_deph_cplx

115496
type: LocalParameter
units: 190250
value: 1.0E-12

194032
type: SpeciesReference
stoichiometry: 1.0
species: 919085

194020
type: SpeciesReference
stoichiometry: 1.0
species: 918165

918165
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.36
initial amount: NaN
in compartment: 917645

194008
type: SpeciesReference
stoichiometry: 1.0
species: 919105

918305
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

920485
type: Reaction
kinetic law: 193171
product: 193159
product: 193147
reactant: 193135
fast: false
reversible: false

115460
type: LocalParameter
units: 190250
value: 6.0E-12

193159
type: SpeciesReference
stoichiometry: 1.0
species: 918485

193147
type: SpeciesReference
stoichiometry: 1.0
species: 918125

918125
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

193135
type: SpeciesReference
stoichiometry: 1.0
species: 918545

920205
type: Reaction
kinetic law: 192493
product: 192480
product: 192468
reactant: 192456
fast: false
reversible: false

192493
type: KineticLaw
local parameters: 115436
notes: k3*MAPK_slash_Raf_star__minus_GTP_minus_Ras_slash_Raf_star__minus_GTP_minus_Ras_dot_1_slash_Raf_star__minus_GTP_minus_Ras_dot_1_cplx

115436
type: LocalParameter
units: 190250
value: 1.05E-13

192480
type: SpeciesReference
stoichiometry: 1.0
species: 918365

918365
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

192468
type: SpeciesReference
stoichiometry: 1.0
species: 918285

918285
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

192456
type: SpeciesReference
stoichiometry: 1.0
species: 918385

918385
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

918225
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

919545
type: Reaction
kinetic law: 190967
product: 190955
reactant: 190943
reactant: 190931
notes: This is one of the more interesting steps. Mechanistically it does not seem necessary at first glance. Turns out that one needs this step to quantitatively match the curves in Schaechter and Benowitz 1993 J Neurosci 13(10):4361 and Shinomura et al 1991 PNAS 88:5149-5153. There is a synergy between DAG and AA activation even at low Ca levels, which is most simply represented by this reaction. Tau is assumed to be fast. Kd comes from matching the experimental curves.
fast: false
reversible: true

190967
type: KineticLaw
local parameters: 115340
local parameters: 115338
notes: kf*PKC_slash_PKC_minus_DAG*AA-kb*PKC_slash_PKC_minus_DAG_minus_AA

115340
type: LocalParameter
units: 190250
value: 2.0E-12

115338
type: LocalParameter
units: 190287
value: 1.8E-14

190955
type: SpeciesReference
stoichiometry: 1.0
species: 917985

917985
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 2.51883333333333E-19
initial amount: NaN
in compartment: 917645

190943
type: SpeciesReference
stoichiometry: 1.0
species: 918025

190931
type: SpeciesReference
stoichiometry: 1.0
species: 917965

920865
type: Reaction
kinetic law: 194092
product: 194080
reactant: 194068
reactant: 194056
notes: See MKP2-tyr-deph
fast: false
reversible: true

194092
type: KineticLaw
local parameters: 115498
local parameters: 115497
notes: k1*MAPK_star_*MKP_minus_2-k2*MKP_minus_2_slash_MKP2_minus_thr_minus_deph_slash_MKP2_minus_thr_minus_deph_cplx

115498
type: LocalParameter
units: 190250
value: 4.0E-12

115497
type: LocalParameter
units: 190287
value: 7.5E-11

194080
type: SpeciesReference
stoichiometry: 1.0
species: 919125

919125
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

194068
type: SpeciesReference
stoichiometry: 1.0
species: 919085

194056
type: SpeciesReference
stoichiometry: 1.0
species: 918425

918425
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

918645
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

919725
type: Reaction
kinetic law: 191375
product: 191362
reactant: 191349
notes: This rate is based on the known ratio of GDP-Ras to GTP-Ras. Basal: Ras.GTP = 7% Stimulated 15% Time course is within 10 min, probably much faster as not all early data points are there. See Gibbs et al JBC 265(33):20437-20422
fast: false
reversible: true

191375
type: KineticLaw
local parameters: 115376
local parameters: 115374
notes: kf*Ras_slash_GEF_star_-kb*Ras_slash_inact_minus_GEF

115376
type: LocalParameter
units: 190250
value: 0.0

115374
type: LocalParameter
units: 190250
value: 1.0E-13

191362
type: SpeciesReference
stoichiometry: 1.0
species: 918805

918805
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.1
initial amount: NaN
in compartment: 917645

191349
type: SpeciesReference
stoichiometry: 1.0
species: 918825

918825
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

918325
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

917685
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

919745
type: Reaction
kinetic law: 191414
product: 191401
reactant: 191388
notes: This is extremely slow (kf = 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 There is no back reaction as we assume this to be a regular irreversible Michaelis-Menten zeroth order hydrolysis.
fast: false
reversible: true

191414
type: KineticLaw
local parameters: 115380
local parameters: 115378
notes: kf*Ras_slash_GTP_minus_Ras-kb*Ras_slash_GDP_minus_Ras

115380
type: LocalParameter
units: 190250
value: 0.0

115378
type: LocalParameter
units: 190250
value: 1.0E-16

191401
type: SpeciesReference
stoichiometry: 1.0
species: 918885

918885
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.2
initial amount: NaN
in compartment: 917645

191388
type: SpeciesReference
stoichiometry: 1.0
species: 918865

918865
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

919185
type: Species
notes: arachodonylphosphatidylcholine is the favoured substrate from Wijkander and Sundler, JBC 202 pp 873-880, 1991. Their assay used 30 uM substrate, which is what the kinetics in this model are based on. For the later model we should locate a more realistic value for APC. For now it is treated as a buffered metabolite.
constant: true
boundary condition: true
has only substance units: false
initial concentration: 30.0
initial amount: NaN
in compartment: 917645

920125
type: Reaction
kinetic law: 192297
product: 192285
product: 192273
reactant: 192260
fast: false
reversible: false

192297
type: KineticLaw
local parameters: 115427
notes: k3*MAPK_slash_RGR_slash_RGR_dot_1_slash_RGR_dot_1_cplx

115427
type: LocalParameter
units: 190250
value: 1.05E-13

192285
type: SpeciesReference
stoichiometry: 1.0
species: 918305

192273
type: SpeciesReference
stoichiometry: 1.0
species: 918285

192260
type: SpeciesReference
stoichiometry: 1.0
species: 918325

918665
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

920425
type: Reaction
kinetic law: 193027
product: 193015
reactant: 193003
reactant: 192990
notes: See parent PPhostphatase2A description for rate details
fast: false
reversible: true

115456
type: LocalParameter
units: 190250
value: 2.5E-11

115455
type: LocalParameter
units: 190287
value: 1.98E-12

193015
type: SpeciesReference
stoichiometry: 1.0
species: 918526

918526
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

193003
type: SpeciesReference
stoichiometry: 1.0
species: 918485

192990
type: SpeciesReference
stoichiometry: 1.0
species: 918285

919765
type: Reaction
kinetic law: 191450
product: 191438
reactant: 191426
notes: Assume a reasonably good rate for dephosphorylating it, 0.1/sec. This fits well with resting levels of active kinase and the degree of activation as well as time-course of turnoff of Ras activation, but data is quite indirect.
fast: false
reversible: true

191450
type: KineticLaw
local parameters: 115384
local parameters: 115382
notes: kf*Ras_slash_GAP_star_-kb*Ras_slash_GAP

115384
type: LocalParameter
units: 190250
value: 0.0

115382
type: LocalParameter
units: 190250
value: 1.0E-13

191438
type: SpeciesReference
stoichiometry: 1.0
species: 918925

918925
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.002
initial amount: NaN
in compartment: 917645

191426
type: SpeciesReference
stoichiometry: 1.0
species: 918905

918905
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

920145
type: Reaction
kinetic law: 192346
product: 192334
reactant: 192322
reactant: 192309
notes: Same kinetics as other c-raf activated forms. See Force et al PNAS 91 1270-1274 1994. k1 = 5.5e-6, k2 = .42, k3 = 0.105
fast: false
reversible: true

192346
type: KineticLaw
local parameters: 115429
local parameters: 115428
notes: k1*MAPK_slash_MAPKK_minus_ser*MAPK_slash_RGR-k2*MAPK_slash_RGR_slash_RGR_dot_2_slash_RGR_dot_2_cplx

115429
type: LocalParameter
units: 190250
value: 4.2E-13

115428
type: LocalParameter
units: 190287
value: 3.3E-12

192334
type: SpeciesReference
stoichiometry: 1.0
species: 918345

918345
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

192322
type: SpeciesReference
stoichiometry: 1.0
species: 918305

192309
type: SpeciesReference
stoichiometry: 1.0
species: 918285

917725
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 1.0
initial amount: NaN
in compartment: 917645

918465
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

190348
type: SBMLUnit
exponent: 1.0
scale: -6
multipler: 1.0
kind: MOLE

919785
type: Reaction
kinetic law: 191499
product: 191487
reactant: 191475
reactant: 191462
notes: Based on rates of Ras-act-craf which has Kf=60, Kb= 0.5. This reaction was introduced to account for the PKC-independent activation of MAPK. This reac should have less affinity but similar tau as compared to the Ras-cat-craf, since the phosphorylated Raf form has a greater effect on MAPK.
fast: false
reversible: true

191499
type: KineticLaw
local parameters: 115388
local parameters: 115386
notes: kf*MAPK_slash_craf_minus_1*Ras_slash_GTP_minus_Ras-kb*MAPK_slash_RGR

115388
type: LocalParameter
units: 190250
value: 1.0E-12

115386
type: LocalParameter
units: 190287
value: 6.0E-12

191487
type: SpeciesReference
stoichiometry: 1.0
species: 918305

191475
type: SpeciesReference
stoichiometry: 1.0
species: 918865

191462
type: SpeciesReference
stoichiometry: 1.0
species: 918105

918105
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.2
initial amount: NaN
in compartment: 917645

919445
type: Reaction
kinetic law: 190749
product: 190737
reactant: 190725
reactant: 190713
notes: Ca-dependent AA activation of PKC. Note that this step combines the AA activation and also the membrane translocation. From Schaechter and Benowitz 1993 J Neurosci 13(10):4361
fast: false
reversible: true

190749
type: KineticLaw
local parameters: 115320
local parameters: 115318
notes: kf*PKC_slash_PKC_minus_Ca*AA-kb*PKC_slash_PKC_minus_Ca_minus_AA_star_

115320
type: LocalParameter
units: 190250
value: 1.0E-13

115318
type: LocalParameter
units: 190287
value: 1.2E-15

190737
type: SpeciesReference
stoichiometry: 1.0
species: 917845

917845
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 1.75E-16
initial amount: NaN
in compartment: 917645

190725
type: SpeciesReference
stoichiometry: 1.0
species: 918025

190713
type: SpeciesReference
stoichiometry: 1.0
species: 917805

917805
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 3.72083333333333E-17
initial amount: NaN
in compartment: 917645

918705
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

919605
type: Reaction
kinetic law: 191113
product: 191101
reactant: 191089
reactant: 191077
notes: Activation of PLA2 by PIP2. From Leslie and Channon 1990 BBA 1045:261 the stimulation of PLA2 activity by high PIP2 is 7x. In this model we don\'t really expect any PIP2 stimulus.
fast: false
reversible: true

191113
type: KineticLaw
local parameters: 115352
local parameters: 115350
notes: kf*temp_minus_PIP2*PLA2_slash_PLA2_minus_cytosolic-kb*PLA2_slash_PIP2_minus_PLA2_star_

115352
type: LocalParameter
units: 190250
value: 5.0E-13

115350
type: LocalParameter
units: 190287
value: 1.2E-15

191101
type: SpeciesReference
stoichiometry: 1.0
species: 918625

918625
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

191089
type: SpeciesReference
stoichiometry: 1.0
species: 918565

918565
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.4
initial amount: NaN
in compartment: 917645

191077
type: SpeciesReference
stoichiometry: 1.0
species: 919205

919205
type: Species
notes: This is a steady PIP2 input to PLA2. The sensitivity of PLA2 to PIP2 discussed below does not match with the reported free levels which are used by the phosphlipase Cs. My understanding is that there may be different pools of PIP2 available for stimulating PLA2 as opposed to being substrates for PLCs. For that reason I have given this PIP2 pool a separate identity. As it is a steady input this is not a problem in this model. Majerus et al Cell 37:701-703 report a brain concentration of 0.1 - 0.2 mole % Majerus et al Science 234:1519-1526 report a huge range of concentrations: from 1 to 10% of PI content, which is in turn 2-8% of cell lipid. This gives 2e-4 to 8e-3 of cell lipid. In concentrations in total volume of cell (a somewhat strange number given the compartmental considerations) this comes to anywhere from 4 uM to 200 uM. PLA2 is stim 7x by PIP2 (Leslie and Channon BBA 1045:261(1990) Leslie and Channon say PIP2 is present at 0.1 - 0.2mol% range in membs, so I\'ll use a value at the lower end of the scale for basal PIP2.
constant: true
boundary condition: true
has only substance units: false
initial concentration: 2.5
initial amount: NaN
in compartment: 917645

919925
type: Reaction
kinetic law: 191812
product: 191800
product: 191788
reactant: 191776
fast: false
reversible: false

191812
type: KineticLaw
local parameters: 115409
notes: k3*PKC_minus_active_slash_PKC_minus_act_minus_raf_slash_PKC_minus_act_minus_raf_cplx

115409
type: LocalParameter
units: 190250
value: 4.0E-12

191800
type: SpeciesReference
stoichiometry: 1.0
species: 919245

919245
type: Species
constant: false
boundary condition: true
has only substance units: false
initial concentration: 0.02
initial amount: NaN
in compartment: 917645

191788
type: SpeciesReference
stoichiometry: 1.0
species: 918125

191776
type: SpeciesReference
stoichiometry: 1.0
species: 918045

918045
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

917905
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.02
initial amount: NaN
in compartment: 917645

917925
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 1.81333333333333E-17
initial amount: NaN
in compartment: 917645

918065
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

919625
type: Reaction
kinetic law: 191162
product: 191150
reactant: 191138
reactant: 191126
notes: Synergistic activation of PLA2 by Ca and PIP2. Again from Leslie and Channon 1990 BBA 1045:261
fast: false
reversible: true

191162
type: KineticLaw
local parameters: 115356
local parameters: 115354
notes: kf*temp_minus_PIP2*PLA2_slash_PLA2_minus_Ca_star_-kb*PLA2_slash_PIP2_minus_Ca_minus_PLA2_star_

115356
type: LocalParameter
units: 190250
value: 1.0E-13

115354
type: LocalParameter
units: 190287
value: 1.2E-14

191150
type: SpeciesReference
stoichiometry: 1.0
species: 918665

191138
type: SpeciesReference
stoichiometry: 1.0
species: 918585

918585
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

191126
type: SpeciesReference
stoichiometry: 1.0
species: 919205

920005
type: Reaction
kinetic law: 192007
product: 191995
product: 191982
reactant: 191969
fast: false
reversible: false

192007
type: KineticLaw
local parameters: 115415
notes: k3*PKC_minus_active_slash_PKC_minus_act_minus_GEF_slash_PKC_minus_act_minus_GEF_cplx

115415
type: LocalParameter
units: 190250
value: 4.0E-12

191995
type: SpeciesReference
stoichiometry: 1.0
species: 919245

191982
type: SpeciesReference
stoichiometry: 1.0
species: 918825

191969
type: SpeciesReference
stoichiometry: 1.0
species: 918085

918085
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

919565
type: Reaction
kinetic law: 191016
product: 191004
reactant: 190992
reactant: 190980
notes: Assume binding is fast and limited only by available Ras*. 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 about 1e-4, giving a Kf of 60 for Kb of 0.5 and a tau of approx 2 sec. Based on: Hallberg et al JBC 269:6 3913-3916 1994, 3% of cellular Raf is complexed with Ras. This step needed to memb-anchor and activate Raf: Leevers et al Nature 369 411-414. Also see Koide et al 1993 PNAS USA 90(18):8683-8686
fast: false
reversible: true

191016
type: KineticLaw
local parameters: 115344
local parameters: 115342
notes: kf*MAPK_slash_craf_minus_1_star_*Ras_slash_GTP_minus_Ras-kb*MAPK_slash_Raf_star__minus_GTP_minus_Ras

115344
type: LocalParameter
units: 190250
value: 5.0E-13

115342
type: LocalParameter
units: 190287
value: 6.0E-11

191004
type: SpeciesReference
stoichiometry: 1.0
species: 918365

190992
type: SpeciesReference
stoichiometry: 1.0
species: 918865

190980
type: SpeciesReference
stoichiometry: 1.0
species: 918125

917631
type: Compartment
constant: true
size: 1.0E-18
spatial dimensions: 3.0

919645
type: Reaction
kinetic law: 191211
product: 191199
reactant: 191186
reactant: 191174
notes: Synergistic activation of PLA2 by Ca and DAG. Based on Leslie and Channon 1990 BBA 1045:261 The Kd is rather large and may reflect the complications in measuring DAG. For this model it is not critical since DAG is held fixed.
fast: false
reversible: true

191211
type: KineticLaw
local parameters: 115360
local parameters: 115358
notes: kf*DAG*PLA2_slash_PLA2_minus_Ca_star_-kb*PLA2_slash_DAG_minus_Ca_minus_PLA2_star_

115360
type: LocalParameter
units: 190250
value: 4.0E-12

115358
type: LocalParameter
units: 190287
value: 3.0E-15

191199
type: SpeciesReference
stoichiometry: 1.0
species: 918705

191186
type: SpeciesReference
stoichiometry: 1.0
species: 918585

191174
type: SpeciesReference
stoichiometry: 1.0
species: 919145

918265
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

920025
type: Reaction
kinetic law: 192055
product: 192043
reactant: 192031
reactant: 192019
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, ratio of 4 to get k2=0.6. k1=0.75/46.6nM=2.7e-5 In terms of Michaelis-Menten rates, Km = 0.046, Vmax = 0.15, ratio = 4.
fast: false
reversible: true

192055
type: KineticLaw
local parameters: 115419
local parameters: 115417
notes: k1*MAPK_slash_MAPK*MAPK_slash_MAPKK_star_-k2*MAPK_slash_MAPKK_star__slash_MAPKKtyr_slash_MAPKKtyr_cplx

115419
type: LocalParameter
units: 190250
value: 6.0E-13

115417
type: LocalParameter
units: 190287
value: 1.62E-11

192043
type: SpeciesReference
stoichiometry: 1.0
species: 918245

918245
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

192031
type: SpeciesReference
stoichiometry: 1.0
species: 918225

192019
type: SpeciesReference
stoichiometry: 1.0
species: 918165

919585
type: Reaction
kinetic law: 191065
product: 191053
reactant: 191041
reactant: 191029
notes: Direct activation of PLA2 by Ca. From Leslie and Channon BBA 1045 (1990) 261-270 fig6 pp267.
fast: false
reversible: true

191065
type: KineticLaw
local parameters: 115348
local parameters: 115346
notes: kf*PLA2_slash_PLA2_minus_cytosolic*Ca-kb*PLA2_slash_PLA2_minus_Ca_star_

115348
type: LocalParameter
units: 190250
value: 1.0E-13

115346
type: LocalParameter
units: 190287
value: 1.00002E-12

191053
type: SpeciesReference
stoichiometry: 1.0
species: 918585

191041
type: SpeciesReference
stoichiometry: 1.0
species: 919165

919165
type: Species
notes: This calcium pool is treated as being buffered to a steady 0.08 uM, which is the resting level.
constant: true
boundary condition: true
has only substance units: false
initial concentration: 0.08
initial amount: NaN
in compartment: 917645

191029
type: SpeciesReference
stoichiometry: 1.0
species: 918565

920105
type: Reaction
kinetic law: 192248
product: 192236
reactant: 192224
reactant: 192212
notes: Kinetics are the same as for the craf-1* activity, ie., k1=5.5e-6, k2=.42, k3 =0.105 These are based on Force et al PNAS USA 91 1270-1274 1994.
fast: false
reversible: true

192248
type: KineticLaw
local parameters: 115426
local parameters: 115425
notes: k1*MAPK_slash_MAPKK*MAPK_slash_RGR-k2*MAPK_slash_RGR_slash_RGR_dot_1_slash_RGR_dot_1_cplx

115426
type: LocalParameter
units: 190250
value: 4.2E-13

115425
type: LocalParameter
units: 190287
value: 3.3E-12

192236
type: SpeciesReference
stoichiometry: 1.0
species: 918325

192224
type: SpeciesReference
stoichiometry: 1.0
species: 918305

192212
type: SpeciesReference
stoichiometry: 1.0
species: 918145

918145
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.18
initial amount: NaN
in compartment: 917645

918405
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

919665
type: Reaction
kinetic law: 191248
product: 191235
reactant: 191223
notes: Degradation pathway for AA. APC is a convenient buffered pool to dump it back into, though the actual metabolism is probably far more complex. For the purposes of the full model we use a rate of degradation of 0.4/sec to give a dynamic range of AA comparable to what is seen experimentally. Wijkander and Sundler 1991 Eur J Biochem 202:873 Leslie and Channon 1990 BBA 1045:261
fast: false
reversible: true

191248
type: KineticLaw
local parameters: 115364
local parameters: 115362
notes: kf*AA-kb*PLA2_slash_APC

115364
type: LocalParameter
units: 190250
value: 0.0

115362
type: LocalParameter
units: 190250
value: 4.0E-13

191235
type: SpeciesReference
stoichiometry: 1.0
species: 919185

191223
type: SpeciesReference
stoichiometry: 1.0
species: 918025

918945
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

919845
type: Reaction
kinetic law: 191619
product: 191607
reactant: 191595
notes: Original model derived from EGFR model. 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 26 apr 2001: Keq too low for the PDGF model. Now Kf=0.001,Kb=0.00066 The previously calculated internalization equilibrium led to very high internalization which shifted the effective dependence of the receptor on PDGF so it looked like the receptor binding was higher affinity than experimentally determined. Used two constraining factors: 1. Time course of SHC phosphorylation/dephosphorylation which is fast on, but 10-20 minutes off. 2. Conc dependence of MAPK on PDGF has a halfmax around 3ng/ml. See Brondello et al 1997 JBC 272(2):1368-1376 and Brondello et al 1999 Science 286:2514-1517.
fast: false
reversible: true

191619
type: KineticLaw
local parameters: 115400
local parameters: 115398
notes: kf*PDGFR_slash_L_dot_PDGFR-kb*PDGFR_slash_Internal_L_dot_PDGFR

115400
type: LocalParameter
units: 190250
value: 6.6E-16

115398
type: LocalParameter
units: 190250
value: 1.0E-15

191607
type: SpeciesReference
stoichiometry: 1.0
species: 919065

919065
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

191595
type: SpeciesReference
stoichiometry: 1.0
species: 918985

918985
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

920785
type: Reaction
kinetic law: 193897
product: 193884
reactant: 193872
reactant: 193860
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. Tau 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. 27 Apr 2001: Lowered k3 to 0.05 to fix conc-effect of SHC phosph by PDGF. This gives results for downstream effects in agreement with other papers, e.g., the Brondello papers.
fast: false
reversible: true

193897
type: KineticLaw
local parameters: 115489
local parameters: 115488
notes: k1*PDGFR_slash_SHC*PDGFR_slash_L_dot_PDGFR-k2*PDGFR_slash_L_dot_PDGFR_slash_phosph_Shc_slash_phosph_Shc_cplx

115489
type: LocalParameter
units: 190250
value: 2.0E-13

115488
type: LocalParameter
units: 190287
value: 3.0E-13

193884
type: SpeciesReference
stoichiometry: 1.0
species: 919005

919005
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

193872
type: SpeciesReference
stoichiometry: 1.0
species: 918985

193860
type: SpeciesReference
stoichiometry: 1.0
species: 919025

919025
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.5
initial amount: NaN
in compartment: 917645

918505
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

919865
type: Reaction
kinetic law: 191667
product: 191655
reactant: 191643
reactant: 191631
notes: Rates from Orita et al JBC 268(34):25542-25546
fast: false
reversible: true

191667
type: KineticLaw
local parameters: 115404
local parameters: 115402
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

115404
type: LocalParameter
units: 190250
value: 8.0E-14

115402
type: LocalParameter
units: 190287
value: 1.98E-13

191655
type: SpeciesReference
stoichiometry: 1.0
species: 917685

191643
type: SpeciesReference
stoichiometry: 1.0
species: 917665

917665
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

191631
type: SpeciesReference
stoichiometry: 1.0
species: 918885

919885
type: Reaction
kinetic law: 191716
product: 191704
product: 191691
reactant: 191679
fast: false
reversible: false

191716
type: KineticLaw
local parameters: 115406
notes: k3*Shc_star__dot_Sos_dot_Grb2_slash_Sos_dot_Ras_GEF_slash_Sos_dot_Ras_GEF_cplx

115406
type: LocalParameter
units: 190250
value: 2.0E-14

191704
type: SpeciesReference
stoichiometry: 1.0
species: 917665

191691
type: SpeciesReference
stoichiometry: 1.0
species: 918865

191679
type: SpeciesReference
stoichiometry: 1.0
species: 917685

918605
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

918965
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.108333333333333
initial amount: NaN
in compartment: 917645

920665
type: Reaction
kinetic law: 193607
product: 193594
reactant: 193582
reactant: 193570
notes: This form should be 3 to 6 times as fast as the Ca-only form, from Lin et al 1993 Cell 269-278 Nemenoff et al 1993 JBC 268:1960 Several forms contribute to the Ca-stimulated form, so this rate has to be a factor larger than their total contribution. I assign Vmax as the scale factor here because there is lots of APC substrate, so all the PLA2 complex enzymes are limited primarily by Vmax.
fast: false
reversible: true

193607
type: KineticLaw
local parameters: 115479
local parameters: 115477
notes: k1*PLA2_slash_APC*PLA2_slash_PLA2_star__minus_Ca-k2*PLA2_slash_PLA2_star__minus_Ca_slash_kenz_slash_kenz_cplx

115479
type: LocalParameter
units: 190250
value: 4.8E-10

115477
type: LocalParameter
units: 190287
value: 3.0E-11

193594
type: SpeciesReference
stoichiometry: 1.0
species: 918765

193582
type: SpeciesReference
stoichiometry: 1.0
species: 918745

193570
type: SpeciesReference
stoichiometry: 1.0
species: 919185

920385
type: Reaction
kinetic law: 192929
product: 192916
reactant: 192904
reactant: 192892
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

115453
type: LocalParameter
units: 190250
value: 2.5E-11

115452
type: LocalParameter
units: 190287
value: 1.98E-12

192916
type: SpeciesReference
stoichiometry: 1.0
species: 918525

918525
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

192904
type: SpeciesReference
stoichiometry: 1.0
species: 918485

192892
type: SpeciesReference
stoichiometry: 1.0
species: 918225

920765
type: Reaction
kinetic law: 193848
product: 193836
product: 193824
reactant: 193811
fast: false
reversible: false

193848
type: KineticLaw
local parameters: 115487
notes: k3*Ras_slash_GAP_slash_GAP_minus_inact_minus_ras_slash_GAP_minus_inact_minus_ras_cplx

115487
type: LocalParameter
units: 190250
value: 1.0E-11

193836
type: SpeciesReference
stoichiometry: 1.0
species: 918925

193824
type: SpeciesReference
stoichiometry: 1.0
species: 918885

193811
type: SpeciesReference
stoichiometry: 1.0
species: 918945

920545
type: Reaction
kinetic law: 193316
product: 193303
reactant: 193291
reactant: 193279
notes: Based on Leslie and Channon 1990 BBA 1045:261.
fast: false
reversible: true

193316
type: KineticLaw
local parameters: 115468
local parameters: 115467
notes: k1*PLA2_slash_APC*PLA2_slash_PIP2_minus_PLA2_star_-k2*PLA2_slash_PIP2_minus_PLA2_star__slash_kenz_slash_kenz_cplx

115468
type: LocalParameter
units: 190250
value: 4.416E-11

115467
type: LocalParameter
units: 190287
value: 2.76E-12

193303
type: SpeciesReference
stoichiometry: 1.0
species: 918645

193291
type: SpeciesReference
stoichiometry: 1.0
species: 918625

193279
type: SpeciesReference
stoichiometry: 1.0
species: 919185

920065
type: Reaction
kinetic law: 192151
product: 192139
reactant: 192127
reactant: 192115
notes: Rate consts same as for MAPKKtyr.
fast: false
reversible: true

192151
type: KineticLaw
local parameters: 115423
local parameters: 115422
notes: k1*MAPK_slash_MAPK_minus_tyr*MAPK_slash_MAPKK_star_-k2*MAPK_slash_MAPKK_star__slash_MAPKKthr_slash_MAPKKthr_cplx

115423
type: LocalParameter
units: 190250
value: 6.0E-13

115422
type: LocalParameter
units: 190287
value: 1.62E-11

192139
type: SpeciesReference
stoichiometry: 1.0
species: 918265

192127
type: SpeciesReference
stoichiometry: 1.0
species: 918225

192115
type: SpeciesReference
stoichiometry: 1.0
species: 918205

918845
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

920885
type: Reaction
kinetic law: 194140
product: 194128
product: 194116
reactant: 194104
fast: false
reversible: false

194140
type: KineticLaw
local parameters: 115499
notes: k3*MKP_minus_2_slash_MKP2_minus_thr_minus_deph_slash_MKP2_minus_thr_minus_deph_cplx

115499
type: LocalParameter
units: 190250
value: 1.0E-12

194128
type: SpeciesReference
stoichiometry: 1.0
species: 919085

194116
type: SpeciesReference
stoichiometry: 1.0
species: 918205

194104
type: SpeciesReference
stoichiometry: 1.0
species: 919125

920085
type: Reaction
kinetic law: 192200
product: 192188
product: 192176
reactant: 192164
fast: false
reversible: false

192200
type: KineticLaw
local parameters: 115424
notes: k3*MAPK_slash_MAPKK_star__slash_MAPKKthr_slash_MAPKKthr_cplx

115424
type: LocalParameter
units: 190250
value: 1.5E-13

192188
type: SpeciesReference
stoichiometry: 1.0
species: 918225

192176
type: SpeciesReference
stoichiometry: 1.0
species: 918425

192164
type: SpeciesReference
stoichiometry: 1.0
species: 918265

919705
type: Reaction
kinetic law: 191336
product: 191323
reactant: 191310
notes: Dephosphorylation reaction to balance MAPK phosphorylation of PLA2. This is probably mediated by PP2A. Rates determined to keep the balance of phosphorylated and non-phosphorylated PLA2 reasonable. The constraining factor is the fold activation of PLA2 by MAPK.
fast: false
reversible: true

191336
type: KineticLaw
local parameters: 115372
local parameters: 115370
notes: kf*PLA2_slash_PLA2_star_-kb*PLA2_slash_PLA2_minus_cytosolic

115372
type: LocalParameter
units: 190250
value: 0.0

115370
type: LocalParameter
units: 190250
value: 1.7E-13

191323
type: SpeciesReference
stoichiometry: 1.0
species: 918565

191310
type: SpeciesReference
stoichiometry: 1.0
species: 918785

918785
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

917705
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

920265
type: Reaction
kinetic law: 192638
product: 192626
reactant: 192614
reactant: 192602
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

192638
type: KineticLaw
local parameters: 115441
local parameters: 115440
notes: k1*MAPK_slash_craf_minus_1_star_*MAPK_star_-k2*MAPK_star__slash_MAPK_star__minus_feedback_slash_MAPK_star__minus_feedback_cplx

115441
type: LocalParameter
units: 190250
value: 4.0E-11

115440
type: LocalParameter
units: 190287
value: 1.95E-12

192626
type: SpeciesReference
stoichiometry: 1.0
species: 918445

918445
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

192614
type: SpeciesReference
stoichiometry: 1.0
species: 918425

192602
type: SpeciesReference
stoichiometry: 1.0
species: 918125

919405
type: Reaction
kinetic law: 190665
product: 190652
reactant: 190640
notes: Membrane translocation is a standard step in PKC activation. It also turns out to be necessary to replicate the curves from Schaechter and Benowitz 1993 J Neurosci 13(10):4361 and Shonomura et al 1991 PNAS 88:5149-5153. These rates are constrained by matching the curves in the above papers and by fixing a rather fast (sub-second) tau for PKC activation.
fast: false
reversible: true

190665
type: KineticLaw
local parameters: 115312
local parameters: 115310
notes: kf*PKC_slash_PKC_minus_Ca-kb*PKC_slash_PKC_minus_Ca_minus_memb_star_

115312
type: LocalParameter
units: 190250
value: 3.5026E-12

115310
type: LocalParameter
units: 190250
value: 1.2705E-12

190652
type: SpeciesReference
stoichiometry: 1.0
species: 917865

190640
type: SpeciesReference
stoichiometry: 1.0
species: 917805

920645
type: Reaction
kinetic law: 193557
product: 193545
product: 193533
reactant: 193521
fast: false
reversible: false

193557
type: KineticLaw
local parameters: 115475
notes: k3*PLA2_slash_DAG_minus_Ca_minus_PLA2_star__slash_kenz_slash_kenz_cplx

115475
type: LocalParameter
units: 190250
value: 6.0E-11

193545
type: SpeciesReference
stoichiometry: 1.0
species: 918705

193533
type: SpeciesReference
stoichiometry: 1.0
species: 918025

193521
type: SpeciesReference
stoichiometry: 1.0
species: 918725

919345
type: Reaction
kinetic law: 190531
product: 190518
reactant: 190506
reactant: 190494
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. Porfiri and McCormick JBC 271 also have related data. After comparing with the time-course of 1 min and the efficacy of activation of Ras, settle on Kd of 0.672 which is close to the Chook et al value.
fast: false
reversible: true

190531
type: KineticLaw
local parameters: 115300
local parameters: 115298
notes: kf*Sos_slash_Grb2*Sos_slash_Sos-kb*Sos_slash_Sos_dot_Grb2

115300
type: LocalParameter
units: 190250
value: 1.68E-14

115298
type: LocalParameter
units: 190287
value: 2.50002E-14

190518
type: SpeciesReference
stoichiometry: 1.0
species: 917745

917745
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

190506
type: SpeciesReference
stoichiometry: 1.0
species: 917785

917785
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.1
initial amount: NaN
in compartment: 917645

190494
type: SpeciesReference
stoichiometry: 1.0
species: 917725

918685
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

920285
type: Reaction
kinetic law: 192686
product: 192674
product: 192662
reactant: 192650
fast: false
reversible: false

192686
type: KineticLaw
local parameters: 115442
notes: k3*MAPK_star__slash_MAPK_star__minus_feedback_slash_MAPK_star__minus_feedback_cplx

115442
type: LocalParameter
units: 190250
value: 1.0E-11

192674
type: SpeciesReference
stoichiometry: 1.0
species: 918425

192662
type: SpeciesReference
stoichiometry: 1.0
species: 918185

192650
type: SpeciesReference
stoichiometry: 1.0
species: 918445

919425
type: Reaction
kinetic law: 190701
product: 190689
reactant: 190677
notes: membrane translocation step for Ca.DAG.PKC complex. Rates constrained from Shinomura et al 1991 PNAS 88:5149-5153 and Schaechter and Benowitz 1993 J Neurosci 13(10):4361 as derived in the references cited in PKC general notes.
fast: false
reversible: true

190701
type: KineticLaw
local parameters: 115316
local parameters: 115314
notes: kf*PKC_slash_PKC_minus_Ca_minus_DAG-kb*PKC_slash_PKC_minus_DAG_minus_memb_star_

115316
type: LocalParameter
units: 190250
value: 1.0E-13

115314
type: LocalParameter
units: 190250
value: 1.0E-12

190689
type: SpeciesReference
stoichiometry: 1.0
species: 917885

917885
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 9.43516666666667E-21
initial amount: NaN
in compartment: 917645

190677
type: SpeciesReference
stoichiometry: 1.0
species: 917945

917945
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 8.46316666666667E-23
initial amount: NaN
in compartment: 917645

919285
type: Reaction
kinetic law: 190397
product: 190385
reactant: 190372
reactant: 190360
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

190397
type: KineticLaw
local parameters: 115289
local parameters: 115288
notes: kf*Sos_slash_Sos_dot_Grb2*PDGFR_slash_SHC_star_-kb*Shc_star__dot_Sos_dot_Grb2

115289
type: LocalParameter
units: 190250
value: 1.0E-13

115288
type: LocalParameter
units: 190287
value: 4.9998E-13

190385
type: SpeciesReference
stoichiometry: 1.0
species: 917665

190372
type: SpeciesReference
stoichiometry: 1.0
species: 919045

919045
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

190360
type: SpeciesReference
stoichiometry: 1.0
species: 917745

919365
type: Reaction
kinetic law: 190579
product: 190567
reactant: 190555
reactant: 190543
notes: This Kd is a straightforward result from the Schaechter and Benowitz 1993 J Neurosci 13(10):4361 curves. The time-course is based on the known rapid activation of PKC and also the fact that Ca association with proteins is typically quite fast. My guess is that this tau of 2 sec is quite conservative and the actualy rate may be much faster. The parameter is quite insensitive for most stimuli.
fast: false
reversible: true

190579
type: KineticLaw
local parameters: 115304
local parameters: 115302
notes: kf*PKC_slash_PKC_minus_cytosolic*Ca-kb*PKC_slash_PKC_minus_Ca

115304
type: LocalParameter
units: 190250
value: 5.0E-13

115302
type: LocalParameter
units: 190287
value: 6.0E-13

190567
type: SpeciesReference
stoichiometry: 1.0
species: 917805

190555
type: SpeciesReference
stoichiometry: 1.0
species: 919165

190543
type: SpeciesReference
stoichiometry: 1.0
species: 918005

919905
type: Reaction
kinetic law: 191764
product: 191752
reactant: 191740
reactant: 191728
notes: Rate consts from Chen et al Biochem 32, 1032 (1993) k3 = 4 Km for this substrate is trickier. Specific substrates are in the uM range, so we use a higher Km here. This may be too conservative in which case PKC would have a still higher effect on raf. The presence of this phosphorylation and activation step is from Kolch et al 1993 Nature 364:249
fast: false
reversible: true

191764
type: KineticLaw
local parameters: 115408
local parameters: 115407
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

115408
type: LocalParameter
units: 190250
value: 1.6E-11

115407
type: LocalParameter
units: 190287
value: 3.0E-13

191752
type: SpeciesReference
stoichiometry: 1.0
species: 918045

191740
type: SpeciesReference
stoichiometry: 1.0
species: 919245

191728
type: SpeciesReference
stoichiometry: 1.0
species: 918105

919385
type: Reaction
kinetic law: 190628
product: 190615
reactant: 190603
reactant: 190591
notes: Ca.PKC interaction with DAG is modeled by this reaction. Kf based on Shinomura et al PNAS 88 5149-5153 1991 and Schaechter and Benowitz 1993 J Neurosci 13(10):4361 and uses the constraining procedure referred to in the general notes for PKC.
fast: false
reversible: true

190628
type: KineticLaw
local parameters: 115308
local parameters: 115306
notes: kf*DAG*PKC_slash_PKC_minus_Ca-kb*PKC_slash_PKC_minus_Ca_minus_DAG

115308
type: LocalParameter
units: 190250
value: 8.6348E-12

115306
type: LocalParameter
units: 190287
value: 7.9998E-15

190615
type: SpeciesReference
stoichiometry: 1.0
species: 917945

190603
type: SpeciesReference
stoichiometry: 1.0
species: 917805

190591
type: SpeciesReference
stoichiometry: 1.0
species: 919145

917765
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

919805
type: Reaction
kinetic law: 191547
product: 191535
reactant: 191523
reactant: 191511
notes: From Heidaran et al JBC268(13):9287 Fig 5. Kd is ~0.5 nM
fast: false
reversible: true

191547
type: KineticLaw
local parameters: 115392
local parameters: 115390
notes: kf*PDGFR_slash_PDGFR*PDGFR_slash_PDGF-kb*PDGFR_slash_L_dot_PDGFR

115392
type: LocalParameter
units: 190250
value: 1.0E-13

115390
type: LocalParameter
units: 190287
value: 1.99998E-10

191535
type: SpeciesReference
stoichiometry: 1.0
species: 918985

191523
type: SpeciesReference
stoichiometry: 1.0
species: 919225

919225
type: Species
notes: Platelet-derived growth factor. Heterodimer Mol wt. is approx 30 KDa Deuel et al 1985 Cancer Surv. 4(4):633-53 Conc of 50 ng/ml is close to saturating, and is used by P. Ram (personal communication). Other refs use 65 ng/ml Weise RJ et al 1995 JBC 270(7):3442-3446 A stimulus of 5 min is commonly used. Conversion factor: 1ng/ml = (1e-9/30K)* 1000 Moles/litre = 3e-11M = 3e-5 uM So 50 ng/ml ~ 1.5 nM.
constant: true
boundary condition: true
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 917645

191511
type: SpeciesReference
stoichiometry: 1.0
species: 918965

919825
type: Reaction
kinetic law: 191583
product: 191571
reactant: 191559
notes: Time course of decline of phosph is 20 min from Sasaoka et al 1994 JBC 269(51):32621. Part of this is the turnoff time of the EGFR itself. Lets assume a tau of 10 min for this dephosphorylation as a first pass. 27 Apr 2001: Dephosph too slow, shifts SHC balance over to phosphorylated form. Increase Kf to 0.01. This gives a reasonable overall time-course.
fast: false
reversible: true

191583
type: KineticLaw
local parameters: 115396
local parameters: 115394
notes: kf*PDGFR_slash_SHC_star_-kb*PDGFR_slash_SHC

115396
type: LocalParameter
units: 190250
value: 0.0

115394
type: LocalParameter
units: 190250
value: 1.0E-14

191571
type: SpeciesReference
stoichiometry: 1.0
species: 919025

191559
type: SpeciesReference
stoichiometry: 1.0
species: 919045

920165
type: Reaction
kinetic law: 192394
product: 192382
product: 192370
reactant: 192358
fast: false
reversible: false

192394
type: KineticLaw
local parameters: 115430
notes: k3*MAPK_slash_RGR_slash_RGR_dot_2_slash_RGR_dot_2_cplx

115430
type: LocalParameter
units: 190250
value: 1.05E-13

192382
type: SpeciesReference
stoichiometry: 1.0
species: 918305

192370
type: SpeciesReference
stoichiometry: 1.0
species: 918225

192358
type: SpeciesReference
stoichiometry: 1.0
species: 918345

919465
type: Reaction
kinetic law: 190785
product: 190773
reactant: 190761
notes: Membrane translocation step for PKC-DAG-AA complex. Rates from matching concentration-effect data in our two main references: Schaechter and Benowitz 1993 J Neurosci 13(10):4361 and Shinomura et al 1988 PNAS 88: 5149-5153
fast: false
reversible: true

190785
type: KineticLaw
local parameters: 115324
local parameters: 115322
notes: kf*PKC_slash_PKC_minus_DAG_minus_AA-kb*PKC_slash_PKC_minus_DAG_minus_AA_star_

115324
type: LocalParameter
units: 190250
value: 2.0E-13

115322
type: LocalParameter
units: 190250
value: 2.0E-12

190773
type: SpeciesReference
stoichiometry: 1.0
species: 917825

917825
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 4.91366666666667E-18
initial amount: NaN
in compartment: 917645

190761
type: SpeciesReference
stoichiometry: 1.0
species: 917985

920185
type: Reaction
kinetic law: 192444
product: 192431
reactant: 192418
reactant: 192406
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. They report Km for MAPKK of 0.8 uM. and a Vmax of ~500 fm/min/ug. These parms cannot reach the observed 4X stimulation of MAPK. So we increase the affinity, ie, raise k1 5x to 5.5e-6 which is equivalent to 5-fold reduction in Km to about 0.16. This is, of course, dependent on the amount of MAPKK present.
fast: false
reversible: true

192444
type: KineticLaw
local parameters: 115434
local parameters: 115432
notes: k1*MAPK_slash_MAPKK*MAPK_slash_Raf_star__minus_GTP_minus_Ras-k2*MAPK_slash_Raf_star__minus_GTP_minus_Ras_slash_Raf_star__minus_GTP_minus_Ras_dot_1_slash_Raf_star__minus_GTP_minus_Ras_dot_1_cplx

115434
type: LocalParameter
units: 190250
value: 4.2E-13

115432
type: LocalParameter
units: 190287
value: 3.3E-12

192431
type: SpeciesReference
stoichiometry: 1.0
species: 918385

192418
type: SpeciesReference
stoichiometry: 1.0
species: 918365

192406
type: SpeciesReference
stoichiometry: 1.0
species: 918145

919945
type: Reaction
kinetic law: 191860
product: 191848
reactant: 191836
reactant: 191824
notes: Rate consts are PKC generic rates. This reaction inactivates GAP. The reaction is from the Boguski and McCormick 1993 review in Nature 366:643-654 The phosphorylation Vmax is 6x higher to account for balance of GDP-Ras:GDP-Ras.
fast: false
reversible: true

191860
type: KineticLaw
local parameters: 115411
local parameters: 115410
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

115411
type: LocalParameter
units: 190250
value: 1.0E-10

115410
type: LocalParameter
units: 190287
value: 1.875E-12

191848
type: SpeciesReference
stoichiometry: 1.0
species: 918065

191836
type: SpeciesReference
stoichiometry: 1.0
species: 919245

191824
type: SpeciesReference
stoichiometry: 1.0
species: 918925

919485
type: Reaction
kinetic law: 190823
product: 190810
reactant: 190798
notes: Basal activity of PKC is quite high, about 10% of max. See Schaechter and Benowitz 1993 J Neurosci 13(10):4361 and Shinomura et al 1991 PNAS 88:5149-5153. This is partly due to basal levels of DAG, AA and Ca, but even when these are taken into account (see the derivations as per the PKC general notes) there is a small basal activity still to be accounted for. This reaction handles it by giving a 2% activity at baseline.
fast: false
reversible: true

190823
type: KineticLaw
local parameters: 115328
local parameters: 115326
notes: kf*PKC_slash_PKC_minus_cytosolic-kb*PKC_slash_PKC_minus_basal_star_

115328
type: LocalParameter
units: 190250
value: 5.0E-11

115326
type: LocalParameter
units: 190250
value: 1.0E-12

190810
type: SpeciesReference
stoichiometry: 1.0
species: 917905

190798
type: SpeciesReference
stoichiometry: 1.0
species: 918005

920705
type: Reaction
kinetic law: 193703
product: 193691
reactant: 193679
reactant: 193667
notes: Kinetics from Orita et al JBC 268(34):25542-25546. Note that the Vmax is slow, but it does match the slow GTP hydrolysis rates.
fast: false
reversible: true

193703
type: KineticLaw
local parameters: 115483
local parameters: 115482
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

115483
type: LocalParameter
units: 190250
value: 8.0E-14

115482
type: LocalParameter
units: 190287
value: 1.98E-13

193691
type: SpeciesReference
stoichiometry: 1.0
species: 918845

193679
type: SpeciesReference
stoichiometry: 1.0
species: 918825

193667
type: SpeciesReference
stoichiometry: 1.0
species: 918885

919965
type: Reaction
kinetic law: 191908
product: 191896
product: 191884
reactant: 191872
fast: false
reversible: false

191908
type: KineticLaw
local parameters: 115412
notes: k3*PKC_minus_active_slash_PKC_minus_inact_minus_GAP_slash_PKC_minus_inact_minus_GAP_cplx

115412
type: LocalParameter
units: 190250
value: 2.5E-11

191896
type: SpeciesReference
stoichiometry: 1.0
species: 919245

191884
type: SpeciesReference
stoichiometry: 1.0
species: 918905

191872
type: SpeciesReference
stoichiometry: 1.0
species: 918065

920345
type: Reaction
kinetic law: 192831
product: 192818
reactant: 192806
reactant: 192794
notes: See parent PPhosphatase2A for parms
fast: false
reversible: true

115449
type: LocalParameter
units: 190250
value: 2.5E-11

115447
type: LocalParameter
units: 190287
value: 1.98E-12

192818
type: SpeciesReference
stoichiometry: 1.0
species: 918505

192806
type: SpeciesReference
stoichiometry: 1.0
species: 918485

192794
type: SpeciesReference
stoichiometry: 1.0
species: 918125

920725
type: Reaction
kinetic law: 193751
product: 193739
product: 193727
reactant: 193715
fast: false
reversible: false

193751
type: KineticLaw
local parameters: 115484
notes: k3*Ras_slash_GEF_star__slash_GEF_star__minus_act_minus_ras_slash_GEF_star__minus_act_minus_ras_cplx

115484
type: LocalParameter
units: 190250
value: 2.0E-14

193739
type: SpeciesReference
stoichiometry: 1.0
species: 918825

193727
type: SpeciesReference
stoichiometry: 1.0
species: 918865

193715
type: SpeciesReference
stoichiometry: 1.0
species: 918845

920505
type: Reaction
kinetic law: 193219
product: 193207
reactant: 193195
reactant: 193183
notes: Based on Leslie and Channon 1990 BBA 1045:261, in relation to the other PLA2 inputs (not including MAPK). Ca alone is rather a weak input.
fast: false
reversible: true

193219
type: KineticLaw
local parameters: 115464
local parameters: 115462
notes: k1*PLA2_slash_APC*PLA2_slash_PLA2_minus_Ca_star_-k2*PLA2_slash_PLA2_minus_Ca_star__slash_kenz_slash_kenz_cplx

115464
type: LocalParameter
units: 190250
value: 2.16E-11

115462
type: LocalParameter
units: 190287
value: 1.35E-12

193207
type: SpeciesReference
stoichiometry: 1.0
species: 918605

193195
type: SpeciesReference
stoichiometry: 1.0
species: 918585

193183
type: SpeciesReference
stoichiometry: 1.0
species: 919185

919985
type: Reaction
kinetic law: 191957
product: 191945
reactant: 191932
reactant: 191920
notes: Rate constants are generic PKC rates. See Chen et al 1993 Biochem 32:1032 This reaction activates GEF. Gives >= 2X stim of ras, and a 2X stim of MAPK over amount from direct phosph of c-raf. Note that it is a push-pull reaction, and also get effect through phosph and inact of GAPs.
fast: false
reversible: true

191957
type: KineticLaw
local parameters: 115414
local parameters: 115413
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

115414
type: LocalParameter
units: 190250
value: 1.6E-11

115413
type: LocalParameter
units: 190287
value: 3.0E-13

191945
type: SpeciesReference
stoichiometry: 1.0
species: 918085

191932
type: SpeciesReference
stoichiometry: 1.0
species: 919245

191920
type: SpeciesReference
stoichiometry: 1.0
species: 918805

920045
type: Reaction
kinetic law: 192103
product: 192091
product: 192079
reactant: 192067
fast: false
reversible: false

192103
type: KineticLaw
local parameters: 115421
notes: k3*MAPK_slash_MAPKK_star__slash_MAPKKtyr_slash_MAPKKtyr_cplx

115421
type: LocalParameter
units: 190250
value: 1.5E-13

192091
type: SpeciesReference
stoichiometry: 1.0
species: 918225

192079
type: SpeciesReference
stoichiometry: 1.0
species: 918205

192067
type: SpeciesReference
stoichiometry: 1.0
species: 918245

920365
type: Reaction
kinetic law: 192880
product: 192868
product: 192855
reactant: 192843
fast: false
reversible: false

115451
type: LocalParameter
units: 190250
value: 6.0E-12

192868
type: SpeciesReference
stoichiometry: 1.0
species: 918485

192855
type: SpeciesReference
stoichiometry: 1.0
species: 918105

192843
type: SpeciesReference
stoichiometry: 1.0
species: 918505

920745
type: Reaction
kinetic law: 193799
product: 193787
reactant: 193775
reactant: 193763
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%). The two sets of values are reasonably close. k1 = 1.666e-3/sec, k2 = 1000/sec, k3 = 10/sec (note k3 is rate-limiting) This is one of the rare cases where we have direct info on the k3 being rate-limiting. Hence the ratio I use for the k2:k3 rates is 100 rather than the usual 4.
fast: false
reversible: true

193799
type: KineticLaw
local parameters: 115486
local parameters: 115485
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

115486
type: LocalParameter
units: 190250
value: 1.0E-9

115485
type: LocalParameter
units: 190287
value: 9.996E-10

193787
type: SpeciesReference
stoichiometry: 1.0
species: 918945

193775
type: SpeciesReference
stoichiometry: 1.0
species: 918925

193763
type: SpeciesReference
stoichiometry: 1.0
species: 918865

920525
type: Reaction
kinetic law: 193267
product: 193255
product: 193243
reactant: 193231
fast: false
reversible: false

193267
type: KineticLaw
local parameters: 115466
notes: k3*PLA2_slash_PLA2_minus_Ca_star__slash_kenz_slash_kenz_cplx

115466
type: LocalParameter
units: 190250
value: 5.4E-12

193255
type: SpeciesReference
stoichiometry: 1.0
species: 918585

193243
type: SpeciesReference
stoichiometry: 1.0
species: 918025

193231
type: SpeciesReference
stoichiometry: 1.0
species: 918605

919685
type: Reaction
kinetic law: 191297
product: 191285
reactant: 191273
reactant: 191261
notes: Nemenoff et al 1993 JBC 268:1960 report a 2X to 4x activation of PLA2 by MAPK, which seems dependent on Ca as well. This reaction represents this activation. Rates are scaled to give appropriate fold activation.
fast: false
reversible: true

191297
type: KineticLaw
local parameters: 115368
local parameters: 115366
notes: kf*PLA2_slash_PLA2_star_*Ca-kb*PLA2_slash_PLA2_star__minus_Ca

115368
type: LocalParameter
units: 190250
value: 1.0E-13

115366
type: LocalParameter
units: 190287
value: 6.0E-12

191285
type: SpeciesReference
stoichiometry: 1.0
species: 918745

191273
type: SpeciesReference
stoichiometry: 1.0
species: 919165

191261
type: SpeciesReference
stoichiometry: 1.0
species: 918785

920565
type: Reaction
kinetic law: 193365
product: 193352
product: 193340
reactant: 193328
fast: false
reversible: false

193365
type: KineticLaw
local parameters: 115469
notes: k3*PLA2_slash_PIP2_minus_PLA2_star__slash_kenz_slash_kenz_cplx

115469
type: LocalParameter
units: 190250
value: 1.104E-11

193352
type: SpeciesReference
stoichiometry: 1.0
species: 918625

193340
type: SpeciesReference
stoichiometry: 1.0
species: 918025

193328
type: SpeciesReference
stoichiometry: 1.0
species: 918645

920585
type: Reaction
kinetic law: 193413
product: 193401
reactant: 193389
reactant: 193377
notes: Based on AA generation by different stimuli according to Leslie and Channon 1990 BBA 1045:261
fast: false
reversible: true

193413
type: KineticLaw
local parameters: 115471
local parameters: 115470
notes: k1*PLA2_slash_APC*PLA2_slash_PIP2_minus_Ca_minus_PLA2_star_-k2*PLA2_slash_PIP2_minus_Ca_minus_PLA2_star__slash_kenz_slash_kenz_cplx

115471
type: LocalParameter
units: 190250
value: 1.44E-10

115470
type: LocalParameter
units: 190287
value: 9.0E-12

193401
type: SpeciesReference
stoichiometry: 1.0
species: 918685

193389
type: SpeciesReference
stoichiometry: 1.0
species: 918665

193377
type: SpeciesReference
stoichiometry: 1.0
species: 919185

920225
type: Reaction
kinetic law: 192542
product: 192530
reactant: 192518
reactant: 192505
notes: Same kinetics as other c-raf activated forms. See Force et al PNAS 91 1270-1274 1994.
fast: false
reversible: true

192542
type: KineticLaw
local parameters: 115438
local parameters: 115437
notes: k1*MAPK_slash_MAPKK_minus_ser*MAPK_slash_Raf_star__minus_GTP_minus_Ras-k2*MAPK_slash_Raf_star__minus_GTP_minus_Ras_slash_Raf_star__minus_GTP_minus_Ras_dot_2_slash_Raf_star__minus_GTP_minus_Ras_dot_2_cplx

115438
type: LocalParameter
units: 190250
value: 4.2E-13

115437
type: LocalParameter
units: 190287
value: 3.3E-12

192530
type: SpeciesReference
stoichiometry: 1.0
species: 918405

192518
type: SpeciesReference
stoichiometry: 1.0
species: 918365

192505
type: SpeciesReference
stoichiometry: 1.0
species: 918285

920305
type: Reaction
kinetic law: 192734
product: 192722
reactant: 192710
reactant: 192698
notes: Km = 25uM @ 50 uM ATP and 1mg/ml MBP (huge XS of substrate) Vmax = 4124 pmol/min/ml at a conc of 125 pmol/ml of enz. Numbers are from Sanghera et al JBC 265 pp 52 , 1990. From Nemenoff et al 1993 JBC 268(3):1960-1964 - using Sanghera\'s 1e-4 ratio of MAPK to protein, we get k3 = 7/sec from 1000 pmol/min/mg total protein in fig 5 I take the Vmax to be higher for PLA2 given the fold activation of PLA2 by MAPK. This is actually a balance term between MAPK and the dephosphorylation step.
fast: false
reversible: true

192734
type: KineticLaw
local parameters: 115444
local parameters: 115443
notes: k1*PLA2_slash_PLA2_minus_cytosolic*MAPK_star_-k2*MAPK_star__slash_MAPK_star__slash_MAPK_star__cplx

115444
type: LocalParameter
units: 190250
value: 8.0E-11

115443
type: LocalParameter
units: 190287
value: 3.9E-12

192722
type: SpeciesReference
stoichiometry: 1.0
species: 918465

192710
type: SpeciesReference
stoichiometry: 1.0
species: 918425

192698
type: SpeciesReference
stoichiometry: 1.0
species: 918565

919305
type: Reaction
kinetic law: 190445
product: 190433
reactant: 190421
reactant: 190409
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 phosphorylation.
fast: false
reversible: true

190445
type: KineticLaw
local parameters: 115292
local parameters: 115290
notes: kf*Sos_slash_Sos_star_*Sos_slash_Grb2-kb*Sos_slash_Sos_star__dot_Grb2

115292
type: LocalParameter
units: 190250
value: 1.68E-14

115290
type: LocalParameter
units: 190287
value: 2.50002E-14

190433
type: SpeciesReference
stoichiometry: 1.0
species: 917705

190421
type: SpeciesReference
stoichiometry: 1.0
species: 917725

190409
type: SpeciesReference
stoichiometry: 1.0
species: 917765

920605
type: Reaction
kinetic law: 193461
product: 193449
product: 193437
reactant: 193425
fast: false
reversible: false

193461
type: KineticLaw
local parameters: 115472
notes: k3*PLA2_slash_PIP2_minus_Ca_minus_PLA2_star__slash_kenz_slash_kenz_cplx

115472
type: LocalParameter
units: 190250
value: 3.6E-11

193449
type: SpeciesReference
stoichiometry: 1.0
species: 918665

193437
type: SpeciesReference
stoichiometry: 1.0
species: 918025

193425
type: SpeciesReference
stoichiometry: 1.0
species: 918685

920245
type: Reaction
kinetic law: 192590
product: 192578
product: 192566
reactant: 192554
fast: false
reversible: false

192590
type: KineticLaw
local parameters: 115439
notes: k3*MAPK_slash_Raf_star__minus_GTP_minus_Ras_slash_Raf_star__minus_GTP_minus_Ras_dot_2_slash_Raf_star__minus_GTP_minus_Ras_dot_2_cplx

115439
type: LocalParameter
units: 190250
value: 1.05E-13

192578
type: SpeciesReference
stoichiometry: 1.0
species: 918365

192566
type: SpeciesReference
stoichiometry: 1.0
species: 918225

192554
type: SpeciesReference
stoichiometry: 1.0
species: 918405

920325
type: Reaction
kinetic law: 192782
product: 192770
product: 192758
reactant: 192746
fast: false
reversible: false

192782
type: KineticLaw
local parameters: 115445
notes: k3*MAPK_star__slash_MAPK_star__slash_MAPK_star__cplx

115445
type: LocalParameter
units: 190250
value: 2.0E-11

192770
type: SpeciesReference
stoichiometry: 1.0
species: 918425

192758
type: SpeciesReference
stoichiometry: 1.0
species: 918785

192746
type: SpeciesReference
stoichiometry: 1.0
species: 918465

919325
type: Reaction
kinetic law: 190482
product: 190469
reactant: 190457
notes: The best 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

190482
type: KineticLaw
local parameters: 115296
local parameters: 115294
notes: kf*Sos_slash_Sos_star_-kb*Sos_slash_Sos

115296
type: LocalParameter
units: 190250
value: 0.0

115294
type: LocalParameter
units: 190250
value: 1.0E-15

190469
type: SpeciesReference
stoichiometry: 1.0
species: 917785

190457
type: SpeciesReference
stoichiometry: 1.0
species: 917765

920625
type: Reaction
kinetic law: 193509
product: 193497
reactant: 193485
reactant: 193473
notes: Based on Leslie and Channon 1990 BBA 1045:261.
fast: false
reversible: true

193509
type: KineticLaw
local parameters: 115474
local parameters: 115473
notes: k1*PLA2_slash_APC*PLA2_slash_DAG_minus_Ca_minus_PLA2_star_-k2*PLA2_slash_DAG_minus_Ca_minus_PLA2_star__slash_kenz_slash_kenz_cplx

115474
type: LocalParameter
units: 190250
value: 2.4E-10

115473
type: LocalParameter
units: 190287
value: 1.5E-11

193497
type: SpeciesReference
stoichiometry: 1.0
species: 918725

193485
type: SpeciesReference
stoichiometry: 1.0
species: 918705

193473
type: SpeciesReference
stoichiometry: 1.0
species: 919185

920405
type: Reaction
kinetic law: 192978
product: 192966
product: 192954
reactant: 192942
fast: false
reversible: false

115454
type: LocalParameter
units: 190250
value: 6.0E-12

192966
type: SpeciesReference
stoichiometry: 1.0
species: 918485

192954
type: SpeciesReference
stoichiometry: 1.0
species: 918285

192942
type: SpeciesReference
stoichiometry: 1.0
species: 918525

920805
type: Reaction
kinetic law: 193947
product: 193935
product: 193922
reactant: 193909
fast: false
reversible: false

193947
type: KineticLaw
local parameters: 115490
notes: k3*PDGFR_slash_L_dot_PDGFR_slash_phosph_Shc_slash_phosph_Shc_cplx

115490
type: LocalParameter
units: 190250
value: 5.0E-14

193935
type: SpeciesReference
stoichiometry: 1.0
species: 918985

193922
type: SpeciesReference
stoichiometry: 1.0
species: 919045

193909
type: SpeciesReference
stoichiometry: 1.0
species: 919005

920445
type: Reaction
kinetic law: 193075
product: 193063
product: 193051
reactant: 193039
fast: false
reversible: false

115457
type: LocalParameter
units: 190250
value: 6.0E-12

193063
type: SpeciesReference
stoichiometry: 1.0
species: 918485

193051
type: SpeciesReference
stoichiometry: 1.0
species: 918145

193039
type: SpeciesReference
stoichiometry: 1.0
species: 918526

919505
type: Reaction
kinetic law: 190871
product: 190859
reactant: 190847
reactant: 190835
notes: AA stimulates PKC activity even at rather low Ca. Schaechter and Benowitz 1993 J Neurosci 13(10):4361 Note that this one reaction combines the initial interaction and also membrane translocation.
fast: false
reversible: true

190871
type: KineticLaw
local parameters: 115332
local parameters: 115330
notes: kf*AA*PKC_slash_PKC_minus_cytosolic-kb*PKC_slash_PKC_minus_AA_star_

115332
type: LocalParameter
units: 190250
value: 1.0E-13

115330
type: LocalParameter
units: 190287
value: 1.2E-16

190859
type: SpeciesReference
stoichiometry: 1.0
species: 917925

190847
type: SpeciesReference
stoichiometry: 1.0
species: 918005

190835
type: SpeciesReference
stoichiometry: 1.0
species: 918025