MODEL9070467164
type: SBMLModel
reaction: 544871
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species: 542811
species: 541191
reaction: 543971
reaction: 544191
species: 541331
species: 542271
species: 541411
reaction: 543091
reaction: 544491
species: 542851
reaction: 543151
reaction: 544651
units def: 146908
reaction: 543471
species: 542531
species: 542251
reaction: 543951
reaction: 543811
reaction: 544971
species: 541151
species: 541831
is described by: http://identifiers.org/pubmed/12169734
species: 541351
compartment: 541094
species: 541431
reaction: 543991
species: 542051
reaction: 544211
species: 542691
reaction: 543331
species: 542171
species: 542011
reaction: 543391
reaction: 544891
species: 542031
reaction: 543651
reaction: 543731
species: 541931
reaction: 544171
reaction: 544251
reaction: 544411
species: 541531
species: 541516
reaction: 544631
reaction: 543171
reaction: 544451
reaction: 543111
reaction: 543511
species: 541731
reaction: 543571
species: 542211
reaction: 543831
reaction: 543911
reaction: 544931
species: 541171
compartment: 541111
species: 541311
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species: 541771
species: 542151
reaction: 544231
species: 542651
species: 542231
reaction: 544991
reaction: 543491
reaction: 543351
species: 541131
reaction: 543751
reaction: 543611
units def: 146981
reaction: 544271
reaction: 544131
species: 541791
species: 541231
species: 542431

544871
type: Reaction
kinetic law: 151263
product: 151250
reactant: 151238
reactant: 151226
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

151263
type: KineticLaw
local parameters: 353001
local parameters: 352999
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

353001
type: LocalParameter
units: 146944
value: 1.0E-9

146968
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exponent: -1.0
scale: 0
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kind: SECOND

146956
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exponent: 1.0
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kind: LITRE

352999
type: LocalParameter
units: 146981
value: 9.996E-10

147018
type: SBMLUnit
exponent: -1.0
scale: 0
multipler: 1.0
kind: SECOND

147006
type: SBMLUnit
exponent: -1.0
scale: -6
multipler: 1.0
kind: MOLE

146994
type: SBMLUnit
exponent: 2.0
scale: 0
multipler: 1.0
kind: LITRE

151250
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species: 542571

542571
type: Species
constant: false
boundary condition: false
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initial concentration: 0.0
initial amount: NaN
in compartment: 541094

541094
type: Compartment
constant: true
size: 1.0E-12
spatial dimensions: 3.0

151238
type: SpeciesReference
stoichiometry: 1.0
species: 542551

542551
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.002
initial amount: NaN
in compartment: 541094

151226
type: SpeciesReference
stoichiometry: 1.0
species: 542491

542491
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

541971
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

542511
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.2
initial amount: NaN
in compartment: 541094

542711
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

542811
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: 541094

541191
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 1.0
initial amount: NaN
in compartment: 541094

543971
type: Reaction
kinetic law: 149084
product: 149072
product: 149060
reactant: 149048
fast: false
reversible: false

149084
type: KineticLaw
local parameters: 352893
notes: k3*MAPK_slash_MAPKK_star__slash_MAPKKtyr_slash_MAPKKtyr_cplx

352893
type: LocalParameter
units: 146944
value: 1.5E-13

149072
type: SpeciesReference
stoichiometry: 1.0
species: 541691

541691
type: Species
constant: false
boundary condition: false
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149060
type: SpeciesReference
stoichiometry: 1.0
species: 541671

541671
type: Species
constant: false
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initial concentration: 0.0
initial amount: NaN
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149048
type: SpeciesReference
stoichiometry: 1.0
species: 541711

541711
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

544191
type: Reaction
kinetic law: 149618
product: 149606
reactant: 149594
reactant: 149582
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

149618
type: KineticLaw
local parameters: 352915
local parameters: 352914
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

352915
type: LocalParameter
units: 146944
value: 4.2E-13

352914
type: LocalParameter
units: 146981
value: 3.3E-12

149606
type: SpeciesReference
stoichiometry: 1.0
species: 541951

541951
type: Species
constant: false
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149594
type: SpeciesReference
stoichiometry: 1.0
species: 541931

541931
type: Species
constant: false
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initial amount: NaN
in compartment: 541094

149582
type: SpeciesReference
stoichiometry: 1.0
species: 541611

541611
type: Species
constant: false
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has only substance units: false
initial concentration: 0.18
initial amount: NaN
in compartment: 541094

541331
type: Species
constant: false
boundary condition: false
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initial concentration: 1.3896E-17
initial amount: NaN
in compartment: 541094

542271
type: Species
constant: false
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in compartment: 541094

541411
type: Species
constant: false
boundary condition: false
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initial concentration: 8.46316666666667E-23
initial amount: NaN
in compartment: 541094

543091
type: Reaction
kinetic law: 147184
product: 147172
reactant: 147160
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

147184
type: KineticLaw
local parameters: 352638
local parameters: 352636
notes: kf*Sos_slash_Sos_star_-kb*Sos_slash_Sos

352638
type: LocalParameter
units: 146944
value: 0.0

352636
type: LocalParameter
units: 146944
value: 1.0E-15

147172
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species: 541251

541251
type: Species
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147160
type: SpeciesReference
stoichiometry: 1.0
species: 541231

541231
type: Species
constant: false
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initial amount: NaN
in compartment: 541094

544491
type: Reaction
kinetic law: 150345
product: 150333
product: 150321
reactant: 150309
fast: false
reversible: false

352953
type: LocalParameter
units: 146944
value: 6.0E-12

150333
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stoichiometry: 1.0
species: 542091

542091
type: Species
constant: false
boundary condition: false
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initial concentration: 0.224
initial amount: NaN
in compartment: 541094

150321
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stoichiometry: 1.0
species: 541571

541571
type: Species
constant: false
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initial concentration: 0.2
initial amount: NaN
in compartment: 541094

150309
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stoichiometry: 1.0
species: 542111

542111
type: Species
constant: false
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initial concentration: 0.0
initial amount: NaN
in compartment: 541094

542851
type: Species
notes: Infinite supply assumed for formation of mRNA.
constant: true
boundary condition: true
has only substance units: false
initial concentration: 0.1
initial amount: NaN
in compartment: 541111

541111
type: Compartment
constant: true
size: 2.0E-13
spatial dimensions: 3.0

543151
type: Reaction
kinetic law: 147328
product: 147316
reactant: 147304
reactant: 147292
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

147328
type: KineticLaw
local parameters: 352650
local parameters: 352648
notes: kf*DAG*PKC_slash_PKC_minus_Ca-kb*PKC_slash_PKC_minus_Ca_minus_DAG

352650
type: LocalParameter
units: 146944
value: 8.6348E-12

352648
type: LocalParameter
units: 146981
value: 7.9998E-15

147316
type: SpeciesReference
stoichiometry: 1.0
species: 541411

147304
type: SpeciesReference
stoichiometry: 1.0
species: 541271

541271
type: Species
constant: false
boundary condition: false
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initial concentration: 3.72083333333333E-17
initial amount: NaN
in compartment: 541094

147292
type: SpeciesReference
stoichiometry: 1.0
species: 542791

542791
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: 541094

544651
type: Reaction
kinetic law: 150731
product: 150719
product: 150707
reactant: 150695
fast: false
reversible: false

150731
type: KineticLaw
local parameters: 352973
notes: k3*PLA2_slash_PLA2_minus_Ca_star__slash_kenz_slash_kenz_cplx

352973
type: LocalParameter
units: 146944
value: 5.4E-12

150719
type: SpeciesReference
stoichiometry: 1.0
species: 542211

542211
type: Species
constant: false
boundary condition: false
has only substance units: false
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initial amount: NaN
in compartment: 541094

150707
type: SpeciesReference
stoichiometry: 1.0
species: 541491

541491
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 6.12
initial amount: NaN
in compartment: 541094

150695
type: SpeciesReference
stoichiometry: 1.0
species: 542231

542231
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

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scale: -6
multipler: 1.0
kind: MOLE

146920
type: SBMLUnit
exponent: -1.0
scale: 0
multipler: 1.0
kind: LITRE

543471
type: Reaction
kinetic law: 147955
product: 147943
reactant: 147931
notes: This is a \'black box\' approximation to the process of translation. I assume that there is unity stoichiometry, that is, a single RNA gives a single protein. This is obviously wrong, but since the RNA level itself is just a ratio against baseline, the conversion factor is absorbed there.
fast: false
reversible: true

147955
type: KineticLaw
local parameters: 352810
local parameters: 352809
notes: kf*MAPK_slash_MKP1_minus_RNA-kb*MKP_minus_1

352810
type: LocalParameter
units: 146944
value: 0.0

352809
type: LocalParameter
units: 146944
value: 4.0E-16

147943
type: SpeciesReference
stoichiometry: 1.0
species: 542072

542072
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 4.0E-4
initial amount: NaN
in compartment: 541094

147931
type: SpeciesReference
stoichiometry: 1.0
species: 541911

541911
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 1.0E-4
initial amount: NaN
in compartment: 541111

542531
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

542251
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

543951
type: Reaction
kinetic law: 149036
product: 149024
reactant: 149012
reactant: 149000
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

149036
type: KineticLaw
local parameters: 352891
local parameters: 352889
notes: k1*MAPK_slash_MAPK*MAPK_slash_MAPKK_star_-k2*MAPK_slash_MAPKK_star__slash_MAPKKtyr_slash_MAPKKtyr_cplx

352891
type: LocalParameter
units: 146944
value: 6.0E-13

352889
type: LocalParameter
units: 146981
value: 1.62E-11

149024
type: SpeciesReference
stoichiometry: 1.0
species: 541711

149012
type: SpeciesReference
stoichiometry: 1.0
species: 541691

149000
type: SpeciesReference
stoichiometry: 1.0
species: 541631

541631
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.36
initial amount: NaN
in compartment: 541094

543811
type: Reaction
kinetic law: 148695
product: 148683
product: 148671
reactant: 148659
fast: false
reversible: false

148695
type: KineticLaw
local parameters: 352873
notes: k3*Shc_star__dot_Sos_dot_Grb2_slash_Sos_dot_Ras_GEF_slash_Sos_dot_Ras_GEF_cplx

352873
type: LocalParameter
units: 146944
value: 2.0E-14

148683
type: SpeciesReference
stoichiometry: 1.0
species: 541131

541131
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

148671
type: SpeciesReference
stoichiometry: 1.0
species: 542491

148659
type: SpeciesReference
stoichiometry: 1.0
species: 541151

541151
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

544971
type: Reaction
kinetic law: 151505
product: 151493
product: 151481
reactant: 151469
fast: false
reversible: false

151505
type: KineticLaw
local parameters: 353013
notes: k3*MKP_minus_2_slash_MKP2_minus_tyr_minus_deph_slash_MKP2_minus_tyr_minus_deph_cplx

353013
type: LocalParameter
units: 146944
value: 1.0E-12

151493
type: SpeciesReference
stoichiometry: 1.0
species: 542731

542731
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.002
initial amount: NaN
in compartment: 541094

151481
type: SpeciesReference
stoichiometry: 1.0
species: 541631

151469
type: SpeciesReference
stoichiometry: 1.0
species: 542751

542751
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

541831
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

541351
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 9.43516666666667E-21
initial amount: NaN
in compartment: 541094

541431
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

543991
type: Reaction
kinetic law: 149133
product: 149121
reactant: 149108
reactant: 149096
notes: Rate consts same as for MAPKKtyr.
fast: false
reversible: true

149133
type: KineticLaw
local parameters: 352896
local parameters: 352894
notes: k1*MAPK_slash_MAPK_minus_tyr*MAPK_slash_MAPKK_star_-k2*MAPK_slash_MAPKK_star__slash_MAPKKthr_slash_MAPKKthr_cplx

352896
type: LocalParameter
units: 146944
value: 6.0E-13

352894
type: LocalParameter
units: 146981
value: 1.62E-11

149121
type: SpeciesReference
stoichiometry: 1.0
species: 541731

541731
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

149108
type: SpeciesReference
stoichiometry: 1.0
species: 541691

149096
type: SpeciesReference
stoichiometry: 1.0
species: 541671

542051
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

544211
type: Reaction
kinetic law: 149667
product: 149654
product: 149642
reactant: 149630
fast: false
reversible: false

149667
type: KineticLaw
local parameters: 352916
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

352916
type: LocalParameter
units: 146944
value: 1.05E-13

149654
type: SpeciesReference
stoichiometry: 1.0
species: 541931

149642
type: SpeciesReference
stoichiometry: 1.0
species: 541751

541751
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

149630
type: SpeciesReference
stoichiometry: 1.0
species: 541951

542691
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

543331
type: Reaction
kinetic law: 147703
product: 147691
reactant: 147679
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

147703
type: KineticLaw
local parameters: 352686
local parameters: 352684
notes: kf*AA-kb*PLA2_slash_APC

352686
type: LocalParameter
units: 146944
value: 0.0

352684
type: LocalParameter
units: 146944
value: 4.0E-13

147691
type: SpeciesReference
stoichiometry: 1.0
species: 542871

542871
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: 541094

147679
type: SpeciesReference
stoichiometry: 1.0
species: 541491

542171
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

542011
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

543391
type: Reaction
kinetic law: 147811
product: 147799
reactant: 147787
notes: Rate of turnover of phosph form of MKP1 is from Brondello et al Science 286:2514 1999. Tau is about 150 min though it is not a clean exponential falloff.
fast: false
reversible: true

147811
type: KineticLaw
local parameters: 352698
local parameters: 352696
notes: kf*MAPK_slash_MKP_minus_1_minus_ser359_star_-kb*MAPK_slash_Ubiquitination

352698
type: LocalParameter
units: 146944
value: 0.0

352696
type: LocalParameter
units: 146944
value: 1.0E-16

147799
type: SpeciesReference
stoichiometry: 1.0
species: 542831

542831
type: Species
notes: This is a representation of generic ubiquitination followed by degradation. Since this pool is buffered to zero, anything that ends up here is removed from the model.
constant: true
boundary condition: true
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

147787
type: SpeciesReference
stoichiometry: 1.0
species: 541831

544891
type: Reaction
kinetic law: 151311
product: 151299
product: 151287
reactant: 151275
fast: false
reversible: false

151311
type: KineticLaw
local parameters: 353003
notes: k3*Ras_slash_GAP_slash_GAP_minus_inact_minus_ras_slash_GAP_minus_inact_minus_ras_cplx

353003
type: LocalParameter
units: 146944
value: 1.0E-11

151299
type: SpeciesReference
stoichiometry: 1.0
species: 542551

151287
type: SpeciesReference
stoichiometry: 1.0
species: 542511

151275
type: SpeciesReference
stoichiometry: 1.0
species: 542571

542031
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

543651
type: Reaction
kinetic law: 148357
product: 148345
reactant: 148333
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

148357
type: KineticLaw
local parameters: 352843
local parameters: 352841
notes: kf*Ras_slash_GEF_star_-kb*Ras_slash_inact_minus_GEF

352843
type: LocalParameter
units: 146944
value: 0.0

352841
type: LocalParameter
units: 146944
value: 1.0E-13

148345
type: SpeciesReference
stoichiometry: 1.0
species: 542431

542431
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.1
initial amount: NaN
in compartment: 541094

148333
type: SpeciesReference
stoichiometry: 1.0
species: 542451

542451
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

543731
type: Reaction
kinetic law: 148527
product: 148515
reactant: 148503
reactant: 148491
notes: From Heidaran et al JBC268(13):9287 Fig 5. Kd is ~0.5 nM
fast: false
reversible: true

148527
type: KineticLaw
local parameters: 352859
local parameters: 352857
notes: kf*PDGFR_slash_PDGFR*PDGFR_slash_PDGF-kb*PDGFR_slash_L_dot_PDGFR

352859
type: LocalParameter
units: 146944
value: 1.0E-13

352857
type: LocalParameter
units: 146981
value: 1.99998E-10

148515
type: SpeciesReference
stoichiometry: 1.0
species: 542611

542611
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

148503
type: SpeciesReference
stoichiometry: 1.0
species: 542911

542911
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: 541094

148491
type: SpeciesReference
stoichiometry: 1.0
species: 542591

542591
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.108333333333333
initial amount: NaN
in compartment: 541094

544171
type: Reaction
kinetic law: 149570
product: 149558
product: 149546
reactant: 149533
fast: false
reversible: false

149570
type: KineticLaw
local parameters: 352913
notes: k3*MAPK_slash_nuc_MAPK_star__slash_act_transcription_slash_act_transcription_cplx

352913
type: LocalParameter
units: 146944
value: 1.6E-16

149558
type: SpeciesReference
stoichiometry: 1.0
species: 541871

541871
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541111

149546
type: SpeciesReference
stoichiometry: 1.0
species: 541911

149533
type: SpeciesReference
stoichiometry: 1.0
species: 541891

541891
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541111

544251
type: Reaction
kinetic law: 149763
product: 149751
product: 149739
reactant: 149727
fast: false
reversible: false

149763
type: KineticLaw
local parameters: 352919
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

352919
type: LocalParameter
units: 146944
value: 1.05E-13

149751
type: SpeciesReference
stoichiometry: 1.0
species: 541931

149739
type: SpeciesReference
stoichiometry: 1.0
species: 541691

149727
type: SpeciesReference
stoichiometry: 1.0
species: 541971

544411
type: Reaction
kinetic law: 150153
product: 150141
product: 150129
reactant: 150117
fast: false
reversible: false

150153
type: KineticLaw
local parameters: 352940
notes: k3*MAPK_star__slash_MKP_minus_1_minus_phosph2_slash_MKP_minus_1_minus_phosph2_cplx

352940
type: LocalParameter
units: 146944
value: 1.0E-12

150141
type: SpeciesReference
stoichiometry: 1.0
species: 541991

541991
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

150129
type: SpeciesReference
stoichiometry: 1.0
species: 541851

541851
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

150117
type: SpeciesReference
stoichiometry: 1.0
species: 542071

542071
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

541531
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

541516
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

544631
type: Reaction
kinetic law: 150683
product: 150671
reactant: 150659
reactant: 150647
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

150683
type: KineticLaw
local parameters: 352971
local parameters: 352969
notes: k1*PLA2_slash_APC*PLA2_slash_PLA2_minus_Ca_star_-k2*PLA2_slash_PLA2_minus_Ca_star__slash_kenz_slash_kenz_cplx

352971
type: LocalParameter
units: 146944
value: 2.16E-11

352969
type: LocalParameter
units: 146981
value: 1.35E-12

150671
type: SpeciesReference
stoichiometry: 1.0
species: 542231

150659
type: SpeciesReference
stoichiometry: 1.0
species: 542211

150647
type: SpeciesReference
stoichiometry: 1.0
species: 542871

543171
type: Reaction
kinetic law: 147364
product: 147352
reactant: 147340
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

147364
type: KineticLaw
local parameters: 352654
local parameters: 352652
notes: kf*PKC_slash_PKC_minus_Ca-kb*PKC_slash_PKC_minus_Ca_minus_memb_star_

352654
type: LocalParameter
units: 146944
value: 3.5026E-12

352652
type: LocalParameter
units: 146944
value: 1.2705E-12

147352
type: SpeciesReference
stoichiometry: 1.0
species: 541331

147340
type: SpeciesReference
stoichiometry: 1.0
species: 541271

544451
type: Reaction
kinetic law: 150249
modifier: 150237
product: 150225
reactant: 150213
notes: See MKP1-tyr-deph
fast: false
reversible: false

150249
type: KineticLaw
local parameters: 352947
local parameters: 352945
notes: kcat*MKP_minus_1*MAPK_star_/(Km+MAPK_star_)

352947
type: LocalParameter
units: 146908
value: 0.0666666666666667

352945
type: LocalParameter
units: 146944
value: 1.0E-12

150225
type: SpeciesReference
stoichiometry: 1.0
species: 541671

150213
type: SpeciesReference
stoichiometry: 1.0
species: 541991

543111
type: Reaction
kinetic law: 147232
product: 147220
reactant: 147208
reactant: 147196
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

147232
type: KineticLaw
local parameters: 352642
local parameters: 352640
notes: kf*Sos_slash_Grb2*Sos_slash_Sos-kb*Sos_slash_Sos_dot_Grb2

352642
type: LocalParameter
units: 146944
value: 1.68E-14

352640
type: LocalParameter
units: 146981
value: 2.50002E-14

147220
type: SpeciesReference
stoichiometry: 1.0
species: 541211

541211
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

147208
type: SpeciesReference
stoichiometry: 1.0
species: 541251

147196
type: SpeciesReference
stoichiometry: 1.0
species: 541191

543511
type: Reaction
kinetic law: 148040
product: 148028
reactant: 148016
reactant: 148004
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

148040
type: KineticLaw
local parameters: 352816
local parameters: 352815
notes: kf*MAPK_slash_craf_minus_1_star_*Ras_slash_GTP_minus_Ras-kb*MAPK_slash_Raf_star__minus_GTP_minus_Ras

352816
type: LocalParameter
units: 146944
value: 5.0E-13

352815
type: LocalParameter
units: 146981
value: 6.0E-11

148028
type: SpeciesReference
stoichiometry: 1.0
species: 541931

148016
type: SpeciesReference
stoichiometry: 1.0
species: 542491

148004
type: SpeciesReference
stoichiometry: 1.0
species: 541591

541591
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

543571
type: Reaction
kinetic law: 148185
product: 148173
reactant: 148161
reactant: 148149
notes: Synergistic activation of PLA2 by Ca and PIP2. Again from Leslie and Channon 1990 BBA 1045:261
fast: false
reversible: true

148185
type: KineticLaw
local parameters: 352827
local parameters: 352825
notes: kf*temp_minus_PIP2*PLA2_slash_PLA2_minus_Ca_star_-kb*PLA2_slash_PIP2_minus_Ca_minus_PLA2_star_

352827
type: LocalParameter
units: 146944
value: 1.0E-13

352825
type: LocalParameter
units: 146981
value: 1.2E-14

148173
type: SpeciesReference
stoichiometry: 1.0
species: 542291

542291
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

148161
type: SpeciesReference
stoichiometry: 1.0
species: 542211

148149
type: SpeciesReference
stoichiometry: 1.0
species: 542891

542891
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: 541094

543831
type: Reaction
kinetic law: 148745
product: 148732
reactant: 148720
reactant: 148707
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

148745
type: KineticLaw
local parameters: 352876
local parameters: 352874
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

352876
type: LocalParameter
units: 146944
value: 1.6E-11

352874
type: LocalParameter
units: 146981
value: 3.0E-13

148732
type: SpeciesReference
stoichiometry: 1.0
species: 541516

148720
type: SpeciesReference
stoichiometry: 1.0
species: 542931

542931
type: Species
constant: false
boundary condition: true
has only substance units: false
initial concentration: 0.02
initial amount: NaN
in compartment: 541094

148707
type: SpeciesReference
stoichiometry: 1.0
species: 541571

543911
type: Reaction
kinetic law: 148939
product: 148926
reactant: 148914
reactant: 148902
notes: Rate constants are generic PKC rates. See Chen SJ, Klann E, Gower MC, Powell CM, Sessoms JS, Sweatt JD. (1993) Biochemistry 32(4):1032-9. 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

148939
type: KineticLaw
local parameters: 352886
local parameters: 352884
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

352886
type: LocalParameter
units: 146944
value: 1.6E-11

352884
type: LocalParameter
units: 146981
value: 3.0E-13

148926
type: SpeciesReference
stoichiometry: 1.0
species: 541551

541551
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

148914
type: SpeciesReference
stoichiometry: 1.0
species: 542931

148902
type: SpeciesReference
stoichiometry: 1.0
species: 542431

544931
type: Reaction
kinetic law: 151409
product: 151397
product: 151385
reactant: 151373
fast: false
reversible: false

151409
type: KineticLaw
local parameters: 353008
notes: k3*PDGFR_slash_L_dot_PDGFR_slash_phosph_Shc_slash_phosph_Shc_cplx

353008
type: LocalParameter
units: 146944
value: 5.0E-14

151397
type: SpeciesReference
stoichiometry: 1.0
species: 542611

151385
type: SpeciesReference
stoichiometry: 1.0
species: 542691

151373
type: SpeciesReference
stoichiometry: 1.0
species: 542631

542631
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

541171
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

541311
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 1.75E-16
initial amount: NaN
in compartment: 541094

543311
type: Reaction
kinetic law: 147667
product: 147654
reactant: 147641
reactant: 147629
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

147667
type: KineticLaw
local parameters: 352682
local parameters: 352680
notes: kf*PKC_slash_PKC_minus_DAG*AA-kb*PKC_slash_PKC_minus_DAG_minus_AA

352682
type: LocalParameter
units: 146944
value: 2.0E-12

352680
type: LocalParameter
units: 146981
value: 1.8E-14

147654
type: SpeciesReference
stoichiometry: 1.0
species: 541451

541451
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 2.51883333333333E-19
initial amount: NaN
in compartment: 541094

147641
type: SpeciesReference
stoichiometry: 1.0
species: 541491

147629
type: SpeciesReference
stoichiometry: 1.0
species: 541431

541771
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

542151
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

544231
type: Reaction
kinetic law: 149715
product: 149703
reactant: 149691
reactant: 149679
notes: Same kinetics as other c-raf activated forms. See Force et al PNAS 91 1270-1274 1994.
fast: false
reversible: true

149715
type: KineticLaw
local parameters: 352918
local parameters: 352917
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

352918
type: LocalParameter
units: 146944
value: 4.2E-13

352917
type: LocalParameter
units: 146981
value: 3.3E-12

149703
type: SpeciesReference
stoichiometry: 1.0
species: 541971

149691
type: SpeciesReference
stoichiometry: 1.0
species: 541931

149679
type: SpeciesReference
stoichiometry: 1.0
species: 541751

542651
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

544991
type: Reaction
kinetic law: 151553
product: 151541
reactant: 151529
reactant: 151517
notes: See MKP2-tyr-deph
fast: false
reversible: true

151553
type: KineticLaw
local parameters: 353016
local parameters: 353014
notes: k1*MAPK_star_*MKP_minus_2-k2*MKP_minus_2_slash_MKP2_minus_thr_minus_deph_slash_MKP2_minus_thr_minus_deph_cplx

353016
type: LocalParameter
units: 146944
value: 4.0E-12

353014
type: LocalParameter
units: 146981
value: 7.5E-11

151541
type: SpeciesReference
stoichiometry: 1.0
species: 542771

542771
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

151529
type: SpeciesReference
stoichiometry: 1.0
species: 542731

151517
type: SpeciesReference
stoichiometry: 1.0
species: 541991

543491
type: Reaction
kinetic law: 147992
product: 147979
reactant: 147967
notes: This is just a basal rate of MKP-1 transcription scaled to give reasonable basal levels of the MKP-1.
fast: false
reversible: true

147992
type: KineticLaw
local parameters: 352813
local parameters: 352812
notes: kf*MAPK_slash_Nucleotides-kb*MAPK_slash_MKP1_minus_RNA

352813
type: LocalParameter
units: 146944
value: 0.0

352812
type: LocalParameter
units: 146944
value: 1.0E-18

147979
type: SpeciesReference
stoichiometry: 1.0
species: 541911

147967
type: SpeciesReference
stoichiometry: 1.0
species: 542851

543351
type: Reaction
kinetic law: 147739
product: 147727
reactant: 147715
notes: Rate of turnover of non-phosph form of MKP1 is from Brondello et al Science 286:2514 1999. Tau is about 45 min.
fast: false
reversible: true

147739
type: KineticLaw
local parameters: 352690
local parameters: 352688
notes: kf*MKP_minus_1-kb*MAPK_slash_Ubiquitination

352690
type: LocalParameter
units: 146944
value: 0.0

352688
type: LocalParameter
units: 146944
value: 3.7E-16

147727
type: SpeciesReference
stoichiometry: 1.0
species: 542831

147715
type: SpeciesReference
stoichiometry: 1.0
species: 542072

543751
type: Reaction
kinetic law: 148563
product: 148551
reactant: 148539
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

148563
type: KineticLaw
local parameters: 352863
local parameters: 352861
notes: kf*PDGFR_slash_SHC_star_-kb*PDGFR_slash_SHC

352863
type: LocalParameter
units: 146944
value: 0.0

352861
type: LocalParameter
units: 146944
value: 1.0E-14

148551
type: SpeciesReference
stoichiometry: 1.0
species: 542671

542671
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.5
initial amount: NaN
in compartment: 541094

148539
type: SpeciesReference
stoichiometry: 1.0
species: 542691

543611
type: Reaction
kinetic law: 148284
product: 148271
reactant: 148259
reactant: 148247
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

148284
type: KineticLaw
local parameters: 352835
local parameters: 352833
notes: kf*PLA2_slash_PLA2_star_*Ca-kb*PLA2_slash_PLA2_star__minus_Ca

352835
type: LocalParameter
units: 146944
value: 1.0E-13

352833
type: LocalParameter
units: 146981
value: 6.0E-12

148271
type: SpeciesReference
stoichiometry: 1.0
species: 542371

542371
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

148259
type: SpeciesReference
stoichiometry: 1.0
species: 542811

148247
type: SpeciesReference
stoichiometry: 1.0
species: 542411

542411
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

544271
type: Reaction
kinetic law: 149812
product: 149800
reactant: 149788
reactant: 149775
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

149812
type: KineticLaw
local parameters: 352923
local parameters: 352921
notes: k1*MAPK_slash_craf_minus_1_star_*MAPK_star_-k2*MAPK_star__slash_MAPK_star__minus_feedback_slash_MAPK_star__minus_feedback_cplx

352923
type: LocalParameter
units: 146944
value: 4.0E-11

352921
type: LocalParameter
units: 146981
value: 1.95E-12

149800
type: SpeciesReference
stoichiometry: 1.0
species: 542011

149788
type: SpeciesReference
stoichiometry: 1.0
species: 541991

149775
type: SpeciesReference
stoichiometry: 1.0
species: 541591

544131
type: Reaction
kinetic law: 149473
modifier: 149461
product: 149449
reactant: 149437
notes: 3 Feb 2000. Same rates as MKP1
fast: false
reversible: false

149473
type: KineticLaw
local parameters: 352910
local parameters: 352909
notes: kcat*MAPK_slash_MKP_minus_1_star__star_*MAPK_star_/(Km+MAPK_star_)

352910
type: LocalParameter
units: 146908
value: 0.0666666666666667

352909
type: LocalParameter
units: 146944
value: 1.0E-12

149449
type: SpeciesReference
stoichiometry: 1.0
species: 541671

149437
type: SpeciesReference
stoichiometry: 1.0
species: 541991

541791
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

544731
type: Reaction
kinetic law: 150924
product: 150912
product: 150900
reactant: 150888
fast: false
reversible: false

150924
type: KineticLaw
local parameters: 352983
notes: k3*PLA2_slash_PIP2_minus_Ca_minus_PLA2_star__slash_kenz_slash_kenz_cplx

352983
type: LocalParameter
units: 146944
value: 3.6E-11

150912
type: SpeciesReference
stoichiometry: 1.0
species: 542291

150900
type: SpeciesReference
stoichiometry: 1.0
species: 541491

150888
type: SpeciesReference
stoichiometry: 1.0
species: 542311

542311
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

541291
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 4.91366666666667E-18
initial amount: NaN
in compartment: 541094

544831
type: Reaction
kinetic law: 151165
product: 151153
reactant: 151141
reactant: 151129
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

151165
type: KineticLaw
local parameters: 352996
local parameters: 352994
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

352996
type: LocalParameter
units: 146944
value: 8.0E-14

352994
type: LocalParameter
units: 146981
value: 1.98E-13

151153
type: SpeciesReference
stoichiometry: 1.0
species: 542471

542471
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

151141
type: SpeciesReference
stoichiometry: 1.0
species: 542451

151129
type: SpeciesReference
stoichiometry: 1.0
species: 542511

543131
type: Reaction
kinetic law: 147280
product: 147268
reactant: 147256
reactant: 147244
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

147280
type: KineticLaw
local parameters: 352646
local parameters: 352644
notes: kf*PKC_slash_PKC_minus_cytosolic*Ca-kb*PKC_slash_PKC_minus_Ca

352646
type: LocalParameter
units: 146944
value: 5.0E-13

352644
type: LocalParameter
units: 146981
value: 6.0E-13

147268
type: SpeciesReference
stoichiometry: 1.0
species: 541271

147256
type: SpeciesReference
stoichiometry: 1.0
species: 542811

147244
type: SpeciesReference
stoichiometry: 1.0
species: 541471

541471
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 1.0
initial amount: NaN
in compartment: 541094

543671
type: Reaction
kinetic law: 148393
product: 148381
reactant: 148369
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

148393
type: KineticLaw
local parameters: 352847
local parameters: 352845
notes: kf*Ras_slash_GTP_minus_Ras-kb*Ras_slash_GDP_minus_Ras

352847
type: LocalParameter
units: 146944
value: 0.0

352845
type: LocalParameter
units: 146944
value: 1.0E-16

148381
type: SpeciesReference
stoichiometry: 1.0
species: 542511

148369
type: SpeciesReference
stoichiometry: 1.0
species: 542491

543931
type: Reaction
kinetic law: 148988
product: 148976
product: 148964
reactant: 148951
fast: false
reversible: false

148988
type: KineticLaw
local parameters: 352888
notes: k3*PKC_minus_active_slash_PKC_minus_act_minus_GEF_slash_PKC_minus_act_minus_GEF_cplx

352888
type: LocalParameter
units: 146944
value: 4.0E-12

148976
type: SpeciesReference
stoichiometry: 1.0
species: 542931

148964
type: SpeciesReference
stoichiometry: 1.0
species: 542451

148951
type: SpeciesReference
stoichiometry: 1.0
species: 541551

543771
type: Reaction
kinetic law: 148599
product: 148587
reactant: 148575
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

148599
type: KineticLaw
local parameters: 352867
local parameters: 352865
notes: kf*PDGFR_slash_L_dot_PDGFR-kb*PDGFR_slash_Internal_L_dot_PDGFR

352867
type: LocalParameter
units: 146944
value: 6.6E-16

352865
type: LocalParameter
units: 146944
value: 1.0E-15

148587
type: SpeciesReference
stoichiometry: 1.0
species: 542711

148575
type: SpeciesReference
stoichiometry: 1.0
species: 542611

541811
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

542131
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

544291
type: Reaction
kinetic law: 149862
product: 149850
product: 149837
reactant: 149824
fast: false
reversible: false

149862
type: KineticLaw
local parameters: 352925
notes: k3*MAPK_star__slash_MAPK_star__minus_feedback_slash_MAPK_star__minus_feedback_cplx

352925
type: LocalParameter
units: 146944
value: 1.0E-11

149850
type: SpeciesReference
stoichiometry: 1.0
species: 541991

149837
type: SpeciesReference
stoichiometry: 1.0
species: 541651

541651
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

149824
type: SpeciesReference
stoichiometry: 1.0
species: 542011

543411
type: Reaction
kinetic law: 147847
product: 147835
reactant: 147823
notes: 24 Apr 2K: Based on 12 Feb 2K: Scaled up 10x so kf=0.01, kb=0 13 Apr 2001: MKP1* Goes down too fast, equil amount too small. Note that tau for turnover is 150 min. Doesn\'t make sense to have this tau be so much less. Go for 1e-4
fast: false
reversible: true

147847
type: KineticLaw
local parameters: 352797
local parameters: 352796
notes: kf*MAPK_slash_MKP_minus_1_minus_ser359_star_-kb*MKP_minus_1

352797
type: LocalParameter
units: 146944
value: 0.0

352796
type: LocalParameter
units: 146944
value: 1.0E-16

147835
type: SpeciesReference
stoichiometry: 1.0
species: 542072

147823
type: SpeciesReference
stoichiometry: 1.0
species: 541831

544671
type: Reaction
kinetic law: 150779
product: 150767
reactant: 150755
reactant: 150743
notes: Based on Leslie and Channon 1990 BBA 1045:261.
fast: false
reversible: true

150779
type: KineticLaw
local parameters: 352976
local parameters: 352974
notes: k1*PLA2_slash_APC*PLA2_slash_PIP2_minus_PLA2_star_-k2*PLA2_slash_PIP2_minus_PLA2_star__slash_kenz_slash_kenz_cplx

352976
type: LocalParameter
units: 146944
value: 4.416E-11

352974
type: LocalParameter
units: 146981
value: 2.76E-12

150767
type: SpeciesReference
stoichiometry: 1.0
species: 542271

150755
type: SpeciesReference
stoichiometry: 1.0
species: 542251

150743
type: SpeciesReference
stoichiometry: 1.0
species: 542871

544031
type: Reaction
kinetic law: 149230
product: 149218
reactant: 149205
reactant: 149193
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

149230
type: KineticLaw
local parameters: 352901
local parameters: 352899
notes: k1*MAPK_slash_MAPKK*MAPK_slash_RGR-k2*MAPK_slash_RGR_slash_RGR_dot_1_slash_RGR_dot_1_cplx

352901
type: LocalParameter
units: 146944
value: 4.2E-13

352899
type: LocalParameter
units: 146981
value: 3.3E-12

149218
type: SpeciesReference
stoichiometry: 1.0
species: 541791

149205
type: SpeciesReference
stoichiometry: 1.0
species: 541771

149193
type: SpeciesReference
stoichiometry: 1.0
species: 541611

541391
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 1.81333333333333E-17
initial amount: NaN
in compartment: 541094

543711
type: Reaction
kinetic law: 148479
product: 148467
reactant: 148455
reactant: 148442
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

148479
type: KineticLaw
local parameters: 352855
local parameters: 352853
notes: kf*MAPK_slash_craf_minus_1*Ras_slash_GTP_minus_Ras-kb*MAPK_slash_RGR

352855
type: LocalParameter
units: 146944
value: 1.0E-12

352853
type: LocalParameter
units: 146981
value: 6.0E-12

148467
type: SpeciesReference
stoichiometry: 1.0
species: 541771

148455
type: SpeciesReference
stoichiometry: 1.0
species: 542491

148442
type: SpeciesReference
stoichiometry: 1.0
species: 541571

542951
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

544071
type: Reaction
kinetic law: 149328
product: 149315
reactant: 149303
reactant: 149291
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

149328
type: KineticLaw
local parameters: 352905
local parameters: 352904
notes: k1*MAPK_slash_MAPKK_minus_ser*MAPK_slash_RGR-k2*MAPK_slash_RGR_slash_RGR_dot_2_slash_RGR_dot_2_cplx

352905
type: LocalParameter
units: 146944
value: 4.2E-13

352904
type: LocalParameter
units: 146981
value: 3.3E-12

149315
type: SpeciesReference
stoichiometry: 1.0
species: 541811

149303
type: SpeciesReference
stoichiometry: 1.0
species: 541771

149291
type: SpeciesReference
stoichiometry: 1.0
species: 541751

544371
type: Reaction
kinetic law: 150056
product: 150043
product: 150030
reactant: 150018
fast: false
reversible: false

150056
type: KineticLaw
local parameters: 352935
notes: k3*MAPK_star__slash_MKP_minus_1_minus_phosph_slash_MKP_minus_1_minus_phosph_cplx

352935
type: LocalParameter
units: 146944
value: 1.0E-12

150043
type: SpeciesReference
stoichiometry: 1.0
species: 541991

150030
type: SpeciesReference
stoichiometry: 1.0
species: 541831

150018
type: SpeciesReference
stoichiometry: 1.0
species: 542051

543191
type: Reaction
kinetic law: 147400
product: 147388
reactant: 147376
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

147400
type: KineticLaw
local parameters: 352658
local parameters: 352656
notes: kf*PKC_slash_PKC_minus_Ca_minus_DAG-kb*PKC_slash_PKC_minus_DAG_minus_memb_star_

352658
type: LocalParameter
units: 146944
value: 1.0E-13

352656
type: LocalParameter
units: 146944
value: 1.0E-12

147388
type: SpeciesReference
stoichiometry: 1.0
species: 541351

147376
type: SpeciesReference
stoichiometry: 1.0
species: 541411

541093
type: Compartment
constant: true
size: 1.0E-18
spatial dimensions: 3.0

544591
type: Reaction
kinetic law: 150585
product: 150573
reactant: 150561
reactant: 150549
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

352966
type: LocalParameter
units: 146944
value: 2.5E-11

352964
type: LocalParameter
units: 146981
value: 1.98E-12

150573
type: SpeciesReference
stoichiometry: 1.0
species: 542171

150561
type: SpeciesReference
stoichiometry: 1.0
species: 542091

150549
type: SpeciesReference
stoichiometry: 1.0
species: 541651

544851
type: Reaction
kinetic law: 151214
product: 151202
product: 151189
reactant: 151177
fast: false
reversible: false

151214
type: KineticLaw
local parameters: 352998
notes: k3*Ras_slash_GEF_star__slash_GEF_star__minus_act_minus_ras_slash_GEF_star__minus_act_minus_ras_cplx

352998
type: LocalParameter
units: 146944
value: 2.0E-14

151202
type: SpeciesReference
stoichiometry: 1.0
species: 542451

151189
type: SpeciesReference
stoichiometry: 1.0
species: 542491

151177
type: SpeciesReference
stoichiometry: 1.0
species: 542471

544711
type: Reaction
kinetic law: 150876
product: 150864
reactant: 150852
reactant: 150839
notes: Based on AA generation by different stimuli according to Leslie and Channon 1990 BBA 1045:261
fast: false
reversible: true

150876
type: KineticLaw
local parameters: 352981
local parameters: 352979
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

352981
type: LocalParameter
units: 146944
value: 1.44E-10

352979
type: LocalParameter
units: 146981
value: 9.0E-12

150864
type: SpeciesReference
stoichiometry: 1.0
species: 542311

150852
type: SpeciesReference
stoichiometry: 1.0
species: 542291

150839
type: SpeciesReference
stoichiometry: 1.0
species: 542871

545011
type: Reaction
kinetic law: 151602
product: 151590
product: 151577
reactant: 151565
fast: false
reversible: false

151602
type: KineticLaw
local parameters: 353018
notes: k3*MKP_minus_2_slash_MKP2_minus_thr_minus_deph_slash_MKP2_minus_thr_minus_deph_cplx

353018
type: LocalParameter
units: 146944
value: 1.0E-12

151590
type: SpeciesReference
stoichiometry: 1.0
species: 542731

151577
type: SpeciesReference
stoichiometry: 1.0
species: 541671

151565
type: SpeciesReference
stoichiometry: 1.0
species: 542771

147042
type: SBMLUnit
exponent: 1.0
scale: -6
multipler: 1.0
kind: MOLE

542971
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

544311
type: Reaction
kinetic law: 149910
product: 149898
reactant: 149886
reactant: 149874
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

149910
type: KineticLaw
local parameters: 352928
local parameters: 352926
notes: k1*PLA2_slash_PLA2_minus_cytosolic*MAPK_star_-k2*MAPK_star__slash_MAPK_star__slash_MAPK_star__cplx

352928
type: LocalParameter
units: 146944
value: 8.0E-11

352926
type: LocalParameter
units: 146981
value: 3.9E-12

149898
type: SpeciesReference
stoichiometry: 1.0
species: 542031

149886
type: SpeciesReference
stoichiometry: 1.0
species: 541991

149874
type: SpeciesReference
stoichiometry: 1.0
species: 542191

542191
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.4
initial amount: NaN
in compartment: 541094

543271
type: Reaction
kinetic law: 147569
product: 147557
reactant: 147545
reactant: 147533
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

147569
type: KineticLaw
local parameters: 352674
local parameters: 352672
notes: kf*AA*PKC_slash_PKC_minus_cytosolic-kb*PKC_slash_PKC_minus_AA_star_

352674
type: LocalParameter
units: 146944
value: 1.0E-13

352672
type: LocalParameter
units: 146981
value: 1.2E-16

147557
type: SpeciesReference
stoichiometry: 1.0
species: 541391

147545
type: SpeciesReference
stoichiometry: 1.0
species: 541471

147533
type: SpeciesReference
stoichiometry: 1.0
species: 541491

544771
type: Reaction
kinetic law: 151020
product: 151008
product: 150996
reactant: 150984
fast: false
reversible: false

151020
type: KineticLaw
local parameters: 352988
notes: k3*PLA2_slash_DAG_minus_Ca_minus_PLA2_star__slash_kenz_slash_kenz_cplx

352988
type: LocalParameter
units: 146944
value: 6.0E-11

151008
type: SpeciesReference
stoichiometry: 1.0
species: 542331

542331
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

150996
type: SpeciesReference
stoichiometry: 1.0
species: 541491

150984
type: SpeciesReference
stoichiometry: 1.0
species: 542351

542351
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

544051
type: Reaction
kinetic law: 149278
product: 149266
product: 149254
reactant: 149242
fast: false
reversible: false

149278
type: KineticLaw
local parameters: 352903
notes: k3*MAPK_slash_RGR_slash_RGR_dot_1_slash_RGR_dot_1_cplx

352903
type: LocalParameter
units: 146944
value: 1.05E-13

149266
type: SpeciesReference
stoichiometry: 1.0
species: 541771

149254
type: SpeciesReference
stoichiometry: 1.0
species: 541751

149242
type: SpeciesReference
stoichiometry: 1.0
species: 541791

544511
type: Reaction
kinetic law: 150393
product: 150381
reactant: 150369
reactant: 150357
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

352956
type: LocalParameter
units: 146944
value: 2.5E-11

352954
type: LocalParameter
units: 146981
value: 1.98E-12

150381
type: SpeciesReference
stoichiometry: 1.0
species: 542131

150369
type: SpeciesReference
stoichiometry: 1.0
species: 542091

150357
type: SpeciesReference
stoichiometry: 1.0
species: 541691

544091
type: Reaction
kinetic law: 149377
product: 149365
product: 149352
reactant: 149340
fast: false
reversible: false

149377
type: KineticLaw
local parameters: 352906
notes: k3*MAPK_slash_RGR_slash_RGR_dot_2_slash_RGR_dot_2_cplx

352906
type: LocalParameter
units: 146944
value: 1.05E-13

149365
type: SpeciesReference
stoichiometry: 1.0
species: 541771

149352
type: SpeciesReference
stoichiometry: 1.0
species: 541691

149340
type: SpeciesReference
stoichiometry: 1.0
species: 541811

542391
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
in compartment: 541094

544471
type: Reaction
kinetic law: 150297
product: 150285
reactant: 150273
reactant: 150261
notes: See parent PPhosphatase2A for parms
fast: false
reversible: true

352951
type: LocalParameter
units: 146944
value: 2.5E-11

352949
type: LocalParameter
units: 146981
value: 1.98E-12

150285
type: SpeciesReference
stoichiometry: 1.0
species: 542111

150273
type: SpeciesReference
stoichiometry: 1.0
species: 542091

150261
type: SpeciesReference
stoichiometry: 1.0
species: 541591

544331
type: Reaction
kinetic law: 149958
product: 149946
product: 149934
reactant: 149922
fast: false
reversible: false

149958
type: KineticLaw
local parameters: 352930
notes: k3*MAPK_star__slash_MAPK_star__slash_MAPK_star__cplx

352930
type: LocalParameter
units: 146944
value: 2.0E-11

149946
type: SpeciesReference
stoichiometry: 1.0
species: 541991

149934
type: SpeciesReference
stoichiometry: 1.0
species: 542411

149922
type: SpeciesReference
stoichiometry: 1.0
species: 542031

543591
type: Reaction
kinetic law: 148235
product: 148223
reactant: 148210
reactant: 148197
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

148235
type: KineticLaw
local parameters: 352831
local parameters: 352829
notes: kf*DAG*PLA2_slash_PLA2_minus_Ca_star_-kb*PLA2_slash_DAG_minus_Ca_minus_PLA2_star_

352831
type: LocalParameter
units: 146944
value: 4.0E-12

352829
type: LocalParameter
units: 146981
value: 3.0E-15

148223
type: SpeciesReference
stoichiometry: 1.0
species: 542331

148210
type: SpeciesReference
stoichiometry: 1.0
species: 542211

148197
type: SpeciesReference
stoichiometry: 1.0
species: 542791

543451
type: Reaction
kinetic law: 147919
product: 147907
reactant: 147895
notes: A nuclear translocation step. This lumps in all sorts of processes into a single set of rates constrained by time courses. Furuno et al J Immunol 166:4416-4421 (2001): In within 6 min, out within 7. The outgoing path is dephosphorylated MAPK so this reac will be one-way. Kf=0.01, Kb=0.005. The reaction is 2nd order in MAPK*, to represent dimerization of transcription factors.
fast: false
reversible: true

147919
type: KineticLaw
local parameters: 352805
local parameters: 352804
notes: kf*MAPK_star_^2-kb*MAPK_slash_nuc_MAPK_star_

352805
type: LocalParameter
units: 146944
value: 1.0E-15

352804
type: LocalParameter
units: 146981
value: 1.00002E-14

147907
type: SpeciesReference
stoichiometry: 1.0
species: 541871

147895
type: SpeciesReference
stoichiometry: 2.0
species: 541991

544691
type: Reaction
kinetic law: 150827
product: 150815
product: 150803
reactant: 150791
fast: false
reversible: false

150827
type: KineticLaw
local parameters: 352978
notes: k3*PLA2_slash_PIP2_minus_PLA2_star__slash_kenz_slash_kenz_cplx

352978
type: LocalParameter
units: 146944
value: 1.104E-11

150815
type: SpeciesReference
stoichiometry: 1.0
species: 542251

150803
type: SpeciesReference
stoichiometry: 1.0
species: 541491

150791
type: SpeciesReference
stoichiometry: 1.0
species: 542271

544551
type: Reaction
kinetic law: 150489
product: 150477
reactant: 150465
reactant: 150453
notes: See parent PPhostphatase2A description for rate details
fast: false
reversible: true

352961
type: LocalParameter
units: 146944
value: 2.5E-11

352959
type: LocalParameter
units: 146981
value: 1.98E-12

150477
type: SpeciesReference
stoichiometry: 1.0
species: 542151

150465
type: SpeciesReference
stoichiometry: 1.0
species: 542091

150453
type: SpeciesReference
stoichiometry: 1.0
species: 541751

544951
type: Reaction
kinetic law: 151457
product: 151445
reactant: 151433
reactant: 151421
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

151457
type: KineticLaw
local parameters: 353011
local parameters: 353009
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

353011
type: LocalParameter
units: 146944
value: 4.0E-12

353009
type: LocalParameter
units: 146981
value: 7.5E-11

151445
type: SpeciesReference
stoichiometry: 1.0
species: 542751

151433
type: SpeciesReference
stoichiometry: 1.0
species: 542731

151421
type: SpeciesReference
stoichiometry: 1.0
species: 541671

544811
type: Reaction
kinetic law: 151117
product: 151104
product: 151092
reactant: 151080
fast: false
reversible: false

151117
type: KineticLaw
local parameters: 352993
notes: k3*PLA2_slash_PLA2_star__minus_Ca_slash_kenz_slash_kenz_cplx

352993
type: LocalParameter
units: 146944
value: 1.2E-10

151104
type: SpeciesReference
stoichiometry: 1.0
species: 542371

151092
type: SpeciesReference
stoichiometry: 1.0
species: 541491

151080
type: SpeciesReference
stoichiometry: 1.0
species: 542391

543851
type: Reaction
kinetic law: 148793
product: 148781
product: 148769
reactant: 148757
fast: false
reversible: false

148793
type: KineticLaw
local parameters: 352878
notes: k3*PKC_minus_active_slash_PKC_minus_act_minus_raf_slash_PKC_minus_act_minus_raf_cplx

352878
type: LocalParameter
units: 146944
value: 4.0E-12

148781
type: SpeciesReference
stoichiometry: 1.0
species: 542931

148769
type: SpeciesReference
stoichiometry: 1.0
species: 541591

148757
type: SpeciesReference
stoichiometry: 1.0
species: 541516

544111
type: Reaction
kinetic law: 149425
modifier: 149413
product: 149401
reactant: 149389
notes: 3 Feb 2000. Same rates as MKP-1.
fast: false
reversible: false

149425
type: KineticLaw
local parameters: 352908
local parameters: 352907
notes: kcat*MAPK_slash_MKP_minus_1_star__star_*MAPK_slash_MAPK_minus_tyr/(Km+MAPK_slash_MAPK_minus_tyr)

352908
type: LocalParameter
units: 146908
value: 0.0666666666666667

352907
type: LocalParameter
units: 146944
value: 1.0E-12

149401
type: SpeciesReference
stoichiometry: 1.0
species: 541631

149389
type: SpeciesReference
stoichiometry: 1.0
species: 541671

544751
type: Reaction
kinetic law: 150972
product: 150960
reactant: 150948
reactant: 150936
notes: Based on Leslie and Channon 1990 BBA 1045:261.
fast: false
reversible: true

150972
type: KineticLaw
local parameters: 352986
local parameters: 352984
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

352986
type: LocalParameter
units: 146944
value: 2.4E-10

352984
type: LocalParameter
units: 146981
value: 1.5E-11

150960
type: SpeciesReference
stoichiometry: 1.0
species: 542351

150948
type: SpeciesReference
stoichiometry: 1.0
species: 542331

150936
type: SpeciesReference
stoichiometry: 1.0
species: 542871

543291
type: Reaction
kinetic law: 147617
product: 147605
reactant: 147593
reactant: 147581
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

147617
type: KineticLaw
local parameters: 352678
local parameters: 352676
notes: kf*PKC_slash_PKC_minus_cytosolic*DAG-kb*PKC_slash_PKC_minus_DAG

352678
type: LocalParameter
units: 146944
value: 1.0E-13

352676
type: LocalParameter
units: 146981
value: 6.0E-16

147605
type: SpeciesReference
stoichiometry: 1.0
species: 541431

147593
type: SpeciesReference
stoichiometry: 1.0
species: 542791

147581
type: SpeciesReference
stoichiometry: 1.0
species: 541471

543371
type: Reaction
kinetic law: 147775
product: 147763
reactant: 147751
notes: Rate of turnover of phosph form of MKP1 is from Brondello et al Science 286:2514 1999. Tau is about 150 min though it is not a clean exponential falloff.
fast: false
reversible: true

147775
type: KineticLaw
local parameters: 352694
local parameters: 352692
notes: kf*MAPK_slash_MKP_minus_1_star__star_-kb*MAPK_slash_Ubiquitination

352694
type: LocalParameter
units: 146944
value: 0.0

352692
type: LocalParameter
units: 146944
value: 1.0E-16

147763
type: SpeciesReference
stoichiometry: 1.0
species: 542831

147751
type: SpeciesReference
stoichiometry: 1.0
species: 541851

543231
type: Reaction
kinetic law: 147484
product: 147472
reactant: 147460
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

147484
type: KineticLaw
local parameters: 352666
local parameters: 352664
notes: kf*PKC_slash_PKC_minus_DAG_minus_AA-kb*PKC_slash_PKC_minus_DAG_minus_AA_star_

352666
type: LocalParameter
units: 146944
value: 2.0E-13

352664
type: LocalParameter
units: 146944
value: 2.0E-12

147472
type: SpeciesReference
stoichiometry: 1.0
species: 541291

147460
type: SpeciesReference
stoichiometry: 1.0
species: 541451

543631
type: Reaction
kinetic law: 148321
product: 148309
reactant: 148296
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

148321
type: KineticLaw
local parameters: 352839
local parameters: 352837
notes: kf*PLA2_slash_PLA2_star_-kb*PLA2_slash_PLA2_minus_cytosolic

352839
type: LocalParameter
units: 146944
value: 0.0

352837
type: LocalParameter
units: 146944
value: 1.7E-13

148309
type: SpeciesReference
stoichiometry: 1.0
species: 542191

148296
type: SpeciesReference
stoichiometry: 1.0
species: 542411

543691
type: Reaction
kinetic law: 148430
product: 148418
reactant: 148405
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

148430
type: KineticLaw
local parameters: 352851
local parameters: 352849
notes: kf*Ras_slash_GAP_star_-kb*Ras_slash_GAP

352851
type: LocalParameter
units: 146944
value: 0.0

352849
type: LocalParameter
units: 146944
value: 1.0E-13

148418
type: SpeciesReference
stoichiometry: 1.0
species: 542551

148405
type: SpeciesReference
stoichiometry: 1.0
species: 542531

544151
type: Reaction
kinetic law: 149521
product: 149509
reactant: 149497
reactant: 149485
notes: This is a \'black box\' representation of a lot of steps. Constraint provided by determining rate of formation of MKP-1.
fast: false
reversible: true

149521
type: KineticLaw
local parameters: 352912
local parameters: 352911
notes: k1*MAPK_slash_Nucleotides*MAPK_slash_nuc_MAPK_star_-k2*MAPK_slash_nuc_MAPK_star__slash_act_transcription_slash_act_transcription_cplx

352912
type: LocalParameter
units: 146944
value: 6.4E-16

352911
type: LocalParameter
units: 146981
value: 1.999992E-16

149509
type: SpeciesReference
stoichiometry: 1.0
species: 541891

149497
type: SpeciesReference
stoichiometry: 1.0
species: 541871

149485
type: SpeciesReference
stoichiometry: 1.0
species: 542851

544011
type: Reaction
kinetic law: 149181
product: 149169
product: 149157
reactant: 149145
fast: false
reversible: false

149181
type: KineticLaw
local parameters: 352898
notes: k3*MAPK_slash_MAPKK_star__slash_MAPKKthr_slash_MAPKKthr_cplx

352898
type: LocalParameter
units: 146944
value: 1.5E-13

149169
type: SpeciesReference
stoichiometry: 1.0
species: 541691

149157
type: SpeciesReference
stoichiometry: 1.0
species: 541991

149145
type: SpeciesReference
stoichiometry: 1.0
species: 541731

543051
type: Reaction
kinetic law: 147094
product: 147081
reactant: 147068
reactant: 147055
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

147094
type: KineticLaw
local parameters: 352630
local parameters: 352628
notes: kf*Sos_slash_Sos_dot_Grb2*PDGFR_slash_SHC_star_-kb*Shc_star__dot_Sos_dot_Grb2

352630
type: LocalParameter
units: 146944
value: 1.0E-13

352628
type: LocalParameter
units: 146981
value: 4.9998E-13

147081
type: SpeciesReference
stoichiometry: 1.0
species: 541131

147068
type: SpeciesReference
stoichiometry: 1.0
species: 542691

147055
type: SpeciesReference
stoichiometry: 1.0
species: 541211

544531
type: Reaction
kinetic law: 150441
product: 150429
product: 150417
reactant: 150405
fast: false
reversible: false

352958
type: LocalParameter
units: 146944
value: 6.0E-12

150429
type: SpeciesReference
stoichiometry: 1.0
species: 542091

150417
type: SpeciesReference
stoichiometry: 1.0
species: 541751

150405
type: SpeciesReference
stoichiometry: 1.0
species: 542131

544611
type: Reaction
kinetic law: 150635
product: 150622
product: 150610
reactant: 150598
fast: false
reversible: false

352968
type: LocalParameter
units: 146944
value: 6.0E-12

150622
type: SpeciesReference
stoichiometry: 1.0
species: 542091

150610
type: SpeciesReference
stoichiometry: 1.0
species: 541591

150598
type: SpeciesReference
stoichiometry: 1.0
species: 542171

543431
type: Reaction
kinetic law: 147883
product: 147871
reactant: 147859
notes: 24 Apr 2K, based on 12 Feb 2K: Scaled up 10x to kf=0.01, kb=0 13 Apr 2001. Slowing down to 0.0001 to match turnover rates.
fast: false
reversible: true

147883
type: KineticLaw
local parameters: 352802
local parameters: 352800
notes: kf*MAPK_slash_MKP_minus_1_star__star_-kb*MAPK_slash_MKP_minus_1_minus_ser359_star_

352802
type: LocalParameter
units: 146944
value: 0.0

352800
type: LocalParameter
units: 146944
value: 1.0E-16

147871
type: SpeciesReference
stoichiometry: 1.0
species: 541831

147859
type: SpeciesReference
stoichiometry: 1.0
species: 541851

544351
type: Reaction
kinetic law: 150006
product: 149994
reactant: 149982
reactant: 149970
notes: 3 Feb 2000. See Brondello et al Science 286:2514 1999. Rates assumed standard MAPK rates based on Sanghera et al JBC 265(1):53-57 1990. The Vmax is scaled down 10 fold to match the time-course of phosph by MAPK, from the Brondello paper.
fast: false
reversible: true

150006
type: KineticLaw
local parameters: 352933
local parameters: 352931
notes: k1*MKP_minus_1*MAPK_star_-k2*MAPK_star__slash_MKP_minus_1_minus_phosph_slash_MKP_minus_1_minus_phosph_cplx

352933
type: LocalParameter
units: 146944
value: 4.0E-12

352931
type: LocalParameter
units: 146981
value: 1.95E-13

149994
type: SpeciesReference
stoichiometry: 1.0
species: 542051

149982
type: SpeciesReference
stoichiometry: 1.0
species: 541991

149970
type: SpeciesReference
stoichiometry: 1.0
species: 542072

544431
type: Reaction
kinetic law: 150201
modifier: 150189
product: 150177
reactant: 150165
notes: The original kinetics from Bhalla and Iyengar Science 1999 have now been modified to obey the k2 = 4 * k3 rule, while keeping kcat and Km fixed. The main constraining data point is the time course of MAPK dephosphorylation, which this model satisfies. See Charles et al 1993 PNAS 90:5292-5296 and Charles et al Oncogene 7:187-190 Effective Km : 67 nM kcat = 1.43 umol/min/mg
fast: false
reversible: false

150201
type: KineticLaw
local parameters: 352943
local parameters: 352941
notes: kcat*MKP_minus_1*MAPK_slash_MAPK_minus_tyr/(Km+MAPK_slash_MAPK_minus_tyr)

352943
type: LocalParameter
units: 146908
value: 0.0666666666666667

352941
type: LocalParameter
units: 146944
value: 1.0E-12

150177
type: SpeciesReference
stoichiometry: 1.0
species: 541631

150165
type: SpeciesReference
stoichiometry: 1.0
species: 541671

543551
type: Reaction
kinetic law: 148137
product: 148125
reactant: 148113
reactant: 148101
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

148137
type: KineticLaw
local parameters: 352823
local parameters: 352822
notes: kf*temp_minus_PIP2*PLA2_slash_PLA2_minus_cytosolic-kb*PLA2_slash_PIP2_minus_PLA2_star_

352823
type: LocalParameter
units: 146944
value: 5.0E-13

352822
type: LocalParameter
units: 146981
value: 1.2E-15

148125
type: SpeciesReference
stoichiometry: 1.0
species: 542251

148113
type: SpeciesReference
stoichiometry: 1.0
species: 542191

148101
type: SpeciesReference
stoichiometry: 1.0
species: 542891

544571
type: Reaction
kinetic law: 150537
product: 150525
product: 150513
reactant: 150501
fast: false
reversible: false

352963
type: LocalParameter
units: 146944
value: 6.0E-12

150525
type: SpeciesReference
stoichiometry: 1.0
species: 542091

150513
type: SpeciesReference
stoichiometry: 1.0
species: 541611

150501
type: SpeciesReference
stoichiometry: 1.0
species: 542151

544911
type: Reaction
kinetic law: 151361
product: 151349
reactant: 151337
reactant: 151324
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

151361
type: KineticLaw
local parameters: 353006
local parameters: 353004
notes: k1*PDGFR_slash_SHC*PDGFR_slash_L_dot_PDGFR-k2*PDGFR_slash_L_dot_PDGFR_slash_phosph_Shc_slash_phosph_Shc_cplx

353006
type: LocalParameter
units: 146944
value: 2.0E-13

353004
type: LocalParameter
units: 146981
value: 3.0E-13

151349
type: SpeciesReference
stoichiometry: 1.0
species: 542631

151337
type: SpeciesReference
stoichiometry: 1.0
species: 542611

151324
type: SpeciesReference
stoichiometry: 1.0
species: 542671

543871
type: Reaction
kinetic law: 148841
product: 148829
reactant: 148817
reactant: 148805
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

148841
type: KineticLaw
local parameters: 352881
local parameters: 352879
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

352881
type: LocalParameter
units: 146944
value: 1.0E-10

352879
type: LocalParameter
units: 146981
value: 1.875E-12

148829
type: SpeciesReference
stoichiometry: 1.0
species: 541531

148817
type: SpeciesReference
stoichiometry: 1.0
species: 542931

148805
type: SpeciesReference
stoichiometry: 1.0
species: 542551

541371
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.02
initial amount: NaN
in compartment: 541094

544391
type: Reaction
kinetic law: 150104
product: 150092
reactant: 150080
reactant: 150068
notes: 3 Feb 2000. See Brondello et al Science 286:2514 1999. Rates assumed standard MAPK rates based on Sanghera et al JBC 265(1):53-57 1990. The Vmax is scaled down by 10 fold to match the time-courses from the Brondello experiment.
fast: false
reversible: true

150104
type: KineticLaw
local parameters: 352938
local parameters: 352936
notes: k1*MAPK_slash_MKP_minus_1_minus_ser359_star_*MAPK_star_-k2*MAPK_star__slash_MKP_minus_1_minus_phosph2_slash_MKP_minus_1_minus_phosph2_cplx

352938
type: LocalParameter
units: 146944
value: 4.0E-12

352936
type: LocalParameter
units: 146981
value: 1.95E-13

150092
type: SpeciesReference
stoichiometry: 1.0
species: 542071

150080
type: SpeciesReference
stoichiometry: 1.0
species: 541991

150068
type: SpeciesReference
stoichiometry: 1.0
species: 541831

543211
type: Reaction
kinetic law: 147448
product: 147436
reactant: 147424
reactant: 147412
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

147448
type: KineticLaw
local parameters: 352662
local parameters: 352660
notes: kf*PKC_slash_PKC_minus_Ca*AA-kb*PKC_slash_PKC_minus_Ca_minus_AA_star_

352662
type: LocalParameter
units: 146944
value: 1.0E-13

352660
type: LocalParameter
units: 146981
value: 1.2E-15

147436
type: SpeciesReference
stoichiometry: 1.0
species: 541311

147424
type: SpeciesReference
stoichiometry: 1.0
species: 541491

147412
type: SpeciesReference
stoichiometry: 1.0
species: 541271

543251
type: Reaction
kinetic law: 147520
product: 147508
reactant: 147496
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

147520
type: KineticLaw
local parameters: 352670
local parameters: 352668
notes: kf*PKC_slash_PKC_minus_cytosolic-kb*PKC_slash_PKC_minus_basal_star_

352670
type: LocalParameter
units: 146944
value: 5.0E-11

352668
type: LocalParameter
units: 146944
value: 1.0E-12

147508
type: SpeciesReference
stoichiometry: 1.0
species: 541371

147496
type: SpeciesReference
stoichiometry: 1.0
species: 541471

543791
type: Reaction
kinetic law: 148647
product: 148635
reactant: 148623
reactant: 148611
notes: Rates from Orita et al JBC 268(34):25542-25546
fast: false
reversible: true

148647
type: KineticLaw
local parameters: 352871
local parameters: 352869
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

352871
type: LocalParameter
units: 146944
value: 8.0E-14

352869
type: LocalParameter
units: 146981
value: 1.98E-13

148635
type: SpeciesReference
stoichiometry: 1.0
species: 541151

148623
type: SpeciesReference
stoichiometry: 1.0
species: 541131

148611
type: SpeciesReference
stoichiometry: 1.0
species: 542511

543891
type: Reaction
kinetic law: 148890
product: 148878
product: 148865
reactant: 148853
fast: false
reversible: false

148890
type: KineticLaw
local parameters: 352883
notes: k3*PKC_minus_active_slash_PKC_minus_inact_minus_GAP_slash_PKC_minus_inact_minus_GAP_cplx

352883
type: LocalParameter
units: 146944
value: 2.5E-11

148878
type: SpeciesReference
stoichiometry: 1.0
species: 542931

148865
type: SpeciesReference
stoichiometry: 1.0
species: 542531

148853
type: SpeciesReference
stoichiometry: 1.0
species: 541531

543071
type: Reaction
kinetic law: 147147
product: 147134
reactant: 147121
reactant: 147107
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

147147
type: KineticLaw
local parameters: 352634
local parameters: 352632
notes: kf*Sos_slash_Sos_star_*Sos_slash_Grb2-kb*Sos_slash_Sos_star__dot_Grb2

352634
type: LocalParameter
units: 146944
value: 1.68E-14

352632
type: LocalParameter
units: 146981
value: 2.50002E-14

147134
type: SpeciesReference
stoichiometry: 1.0
species: 541171

147121
type: SpeciesReference
stoichiometry: 1.0
species: 541191

147107
type: SpeciesReference
stoichiometry: 1.0
species: 541231

543531
type: Reaction
kinetic law: 148089
product: 148077
reactant: 148065
reactant: 148052
notes: Direct activation of PLA2 by Ca. From Leslie and Channon BBA 1045 (1990) 261-270 fig6 pp267.
fast: false
reversible: true

148089
type: KineticLaw
local parameters: 352820
local parameters: 352818
notes: kf*PLA2_slash_PLA2_minus_cytosolic*Ca-kb*PLA2_slash_PLA2_minus_Ca_star_

352820
type: LocalParameter
units: 146944
value: 1.0E-13

352818
type: LocalParameter
units: 146981
value: 1.00002E-12

148077
type: SpeciesReference
stoichiometry: 1.0
species: 542211

148065
type: SpeciesReference
stoichiometry: 1.0
species: 542811

148052
type: SpeciesReference
stoichiometry: 1.0
species: 542191

544791
type: Reaction
kinetic law: 151068
product: 151056
reactant: 151044
reactant: 151032
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

151068
type: KineticLaw
local parameters: 352991
local parameters: 352989
notes: k1*PLA2_slash_APC*PLA2_slash_PLA2_star__minus_Ca-k2*PLA2_slash_PLA2_star__minus_Ca_slash_kenz_slash_kenz_cplx

352991
type: LocalParameter
units: 146944
value: 4.8E-10

352989
type: LocalParameter
units: 146981
value: 3.0E-11

151056
type: SpeciesReference
stoichiometry: 1.0
species: 542391

151044
type: SpeciesReference
stoichiometry: 1.0
species: 542371

151032
type: SpeciesReference
stoichiometry: 1.0
species: 542871