193545
stoichiometry: 1.0
species: 918705
type: SpeciesReference

190737
stoichiometry: 1.0
species: 917845
type: SpeciesReference

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

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

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

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

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

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

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

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

192224
stoichiometry: 1.0
species: 918305
type: SpeciesReference

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

193824
stoichiometry: 1.0
species: 918885
type: SpeciesReference

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

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

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

191836
stoichiometry: 1.0
species: 919245
type: SpeciesReference

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

190457
stoichiometry: 1.0
species: 917765
type: SpeciesReference

190506
stoichiometry: 1.0
species: 917785
type: SpeciesReference

193437
stoichiometry: 1.0
species: 918025
type: SpeciesReference

190615
stoichiometry: 1.0
species: 917945
type: SpeciesReference

191438
stoichiometry: 1.0
species: 918925
type: SpeciesReference

192566
stoichiometry: 1.0
species: 918225
type: SpeciesReference

193243
stoichiometry: 1.0
species: 918025
type: SpeciesReference

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

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

194128
stoichiometry: 1.0
species: 919085
type: SpeciesReference

193594
stoichiometry: 1.0
species: 918765
type: SpeciesReference

191523
stoichiometry: 1.0
species: 919225
type: SpeciesReference

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

190725
stoichiometry: 1.0
species: 918025
type: SpeciesReference

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

192285
stoichiometry: 1.0
species: 918305
type: SpeciesReference

193811
stoichiometry: 1.0
species: 918945
type: SpeciesReference

191848
stoichiometry: 1.0
species: 918065
type: SpeciesReference

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

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

192212
stoichiometry: 1.0
species: 918145
type: SpeciesReference

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

191595
stoichiometry: 1.0
species: 918985
type: SpeciesReference

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

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

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

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

190518
stoichiometry: 1.0
species: 917745
type: SpeciesReference

192530
stoichiometry: 1.0
species: 918405
type: SpeciesReference

193449
stoichiometry: 1.0
species: 918665
type: SpeciesReference

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

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

192406
stoichiometry: 1.0
species: 918145
type: SpeciesReference

191535
stoichiometry: 1.0
species: 918985
type: SpeciesReference

194116
stoichiometry: 1.0
species: 918205
type: SpeciesReference

193255
stoichiometry: 1.0
species: 918585
type: SpeciesReference

192578
stoichiometry: 1.0
species: 918365
type: SpeciesReference

190640
stoichiometry: 1.0
species: 917805
type: SpeciesReference

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

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

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

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

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

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

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

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

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

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

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

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

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

193643
stoichiometry: 1.0
species: 918745
type: SpeciesReference

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

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

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

193521
stoichiometry: 1.0
species: 918725
type: SpeciesReference

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

190469
stoichiometry: 1.0
species: 917785
type: SpeciesReference

193860
stoichiometry: 1.0
species: 919025
type: SpeciesReference

191643
stoichiometry: 1.0
species: 917665
type: SpeciesReference

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

193909
stoichiometry: 1.0
species: 919005
type: SpeciesReference

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

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

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

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

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

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

190652
stoichiometry: 1.0
species: 917865
type: SpeciesReference

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

193570
stoichiometry: 1.0
species: 919185
type: SpeciesReference

192480
stoichiometry: 1.0
species: 918365
type: SpeciesReference

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

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

190980
stoichiometry: 1.0
species: 918125
type: SpeciesReference

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

191101
stoichiometry: 1.0
species: 918625
type: SpeciesReference

192818
stoichiometry: 1.0
species: 918505
type: SpeciesReference

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

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

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

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

192942
stoichiometry: 1.0
species: 918525
type: SpeciesReference

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

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

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

192904
stoichiometry: 1.0
species: 918485
type: SpeciesReference

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

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

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

190494
stoichiometry: 1.0
species: 917725
type: SpeciesReference

191571
stoichiometry: 1.0
species: 919025
type: SpeciesReference

193631
stoichiometry: 1.0
species: 918025
type: SpeciesReference

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

190931
stoichiometry: 1.0
species: 917965
type: SpeciesReference

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

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

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

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

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

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

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

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

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

190591
stoichiometry: 1.0
species: 919145
type: SpeciesReference

191631
stoichiometry: 1.0
species: 918885
type: SpeciesReference

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

920385
kinetic law: 192929
product: 192916
reactant: 192904
reactant: 192892
notes: See: Kyriakis et al Nature 358 pp 417-421 1992 Ahn et al Curr Op Cell Biol 4:992-999 1992 for this pathway. See parent PPhosphatase2A for parms.
fast: false
reversible: true
type: Reaction

192019
stoichiometry: 1.0
species: 918165
type: SpeciesReference

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

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

919345
kinetic law: 190531
product: 190518
reactant: 190506
reactant: 190494
notes: As there are 2 SH3 domains, this reaction could be 2nd order. I have a Kd of 22 uM from peptide binding (Lemmon et al JBC 269:50 pg 31653). However, Chook et al JBC 271:48 pg30472 say it is 0.4uM with purified proteins, so we believe them. They say it is 1:1 binding. Porfiri and McCormick JBC 271 also have related data. After comparing with the time-course of 1 min and the efficacy of activation of Ras, settle on Kd of 0.672 which is close to the Chook et al value.
fast: false
reversible: true
type: Reaction

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

193533
stoichiometry: 1.0
species: 918025
type: SpeciesReference

191559
stoichiometry: 1.0
species: 919045
type: SpeciesReference

193582
stoichiometry: 1.0
species: 918745
type: SpeciesReference

190992
stoichiometry: 1.0
species: 918865
type: SpeciesReference

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

193231
stoichiometry: 1.0
species: 918605
type: SpeciesReference

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

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

192554
stoichiometry: 1.0
species: 918405
type: SpeciesReference

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

192916
stoichiometry: 1.0
species: 918525
type: SpeciesReference

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

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

190603
stoichiometry: 1.0
species: 917805
type: SpeciesReference

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

192954
stoichiometry: 1.0
species: 918285
type: SpeciesReference

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

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

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

191752
stoichiometry: 1.0
species: 918045
type: SpeciesReference

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

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

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

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

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

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

192164
stoichiometry: 1.0
species: 918265
type: SpeciesReference

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

191969
stoichiometry: 1.0
species: 918085
type: SpeciesReference

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

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

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

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

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

193111
stoichiometry: 1.0
species: 918545
type: SpeciesReference

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

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

919845
kinetic law: 191619
product: 191607
reactant: 191595
notes: Original model derived from EGFR model. See Helin and Beguinot JBC 266:13 1991 pg 8363-8368. In Fig 3 they have internalization tau about 10 min, equil at about 20% EGF available. So kf = 4x kb, and 1/(kf + kb) = 600 sec so kb = 1/3K = 3.3e-4, and kf = 1.33e-3. This doesn\'t take into account the unbound receptor, so we need to push the kf up a bit, to 0.002 26 apr 2001: Keq too low for the PDGF model. Now Kf=0.001,Kb=0.00066 The previously calculated internalization equilibrium led to very high internalization which shifted the effective dependence of the receptor on PDGF so it looked like the receptor binding was higher affinity than experimentally determined. Used two constraining factors: 1. Time course of SHC phosphorylation/dephosphorylation which is fast on, but 10-20 minutes off. 2. Conc dependence of MAPK on PDGF has a halfmax around 3ng/ml. See Brondello et al 1997 JBC 272(2):1368-1376 and Brondello et al 1999 Science 286:2514-1517.
fast: false
reversible: true
type: Reaction

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

191174
stoichiometry: 1.0
species: 919145
type: SpeciesReference

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

192855
stoichiometry: 1.0
species: 918105
type: SpeciesReference

920265
kinetic law: 192638
product: 192626
reactant: 192614
reactant: 192602
notes: Ueki et al JBC 269(22):15756-15761 show the presence of this step, but not the rate consts, which are derived from Sanghera et al JBC 265(1):52-57, 1990, see the deriv in the MAPK* notes.
fast: false
reversible: true
type: Reaction

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

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

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

193015
stoichiometry: 1.0
species: 918526
type: SpeciesReference

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

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

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

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

193291
stoichiometry: 1.0
species: 918625
type: SpeciesReference

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

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

193619
stoichiometry: 1.0
species: 918765
type: SpeciesReference

190761
stoichiometry: 1.0
species: 917985
type: SpeciesReference

192990
stoichiometry: 1.0
species: 918285
type: SpeciesReference

193667
stoichiometry: 1.0
species: 918885
type: SpeciesReference

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

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

192674
stoichiometry: 1.0
species: 918425
type: SpeciesReference

190689
stoichiometry: 1.0
species: 917885
type: SpeciesReference

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

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

192806
stoichiometry: 1.0
species: 918485
type: SpeciesReference

191740
stoichiometry: 1.0
species: 919245
type: SpeciesReference

191235
stoichiometry: 1.0
species: 919185
type: SpeciesReference

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

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

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

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

191462
stoichiometry: 1.0
species: 918105
type: SpeciesReference

920025
kinetic law: 192055
product: 192043
reactant: 192031
reactant: 192019
notes: The actual MAPKK is 2 forms from Seger et al JBC 267:20 14373(1992) Vmax = 150nmol/min/mg From Haystead et al FEBS 306(1):17-22 we get Km=46.6nM for at least one of the phosphs. Putting these together: k3=0.15/sec, ratio of 4 to get k2=0.6. k1=0.75/46.6nM=2.7e-5 In terms of Michaelis-Menten rates, Km = 0.046, Vmax = 0.15, ratio = 4.
fast: false
reversible: true
type: Reaction

191401
stoichiometry: 1.0
species: 918885
type: SpeciesReference

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

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

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

191186
stoichiometry: 1.0
species: 918585
type: SpeciesReference

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

920745
kinetic law: 193799
product: 193787
reactant: 193775
reactant: 193763
notes: From Eccleston et al JBC 268(36)pp27012-19 get Kd < 2uM, kcat - 10/sec From Martin et al Cell 63 843-849 1990 get Kd ~ 250 nM, kcat = 20/min I will go with the Eccleston figures as there are good error bars (10%). The two sets of values are reasonably close. k1 = 1.666e-3/sec, k2 = 1000/sec, k3 = 10/sec (note k3 is rate-limiting) This is one of the rare cases where we have direct info on the k3 being rate-limiting. Hence the ratio I use for the k2:k3 rates is 100 rather than the usual 4.
fast: false
reversible: true
type: Reaction

193984
stoichiometry: 1.0
species: 919105
type: SpeciesReference

190677
stoichiometry: 1.0
species: 917945
type: SpeciesReference

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

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

193195
stoichiometry: 1.0
species: 918585
type: SpeciesReference

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

190773
stoichiometry: 1.0
species: 917825
type: SpeciesReference

192868
stoichiometry: 1.0
species: 918485
type: SpeciesReference

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

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

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

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

193003
stoichiometry: 1.0
species: 918485
type: SpeciesReference

190883
stoichiometry: 1.0
species: 918005
type: SpeciesReference

190798
stoichiometry: 1.0
species: 918005
type: SpeciesReference

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

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

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

192710
stoichiometry: 1.0
species: 918425
type: SpeciesReference

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

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

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

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

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

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

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

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

194104
stoichiometry: 1.0
species: 919125
type: SpeciesReference

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

192188
stoichiometry: 1.0
species: 918225
type: SpeciesReference

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

191776
stoichiometry: 1.0
species: 918045
type: SpeciesReference

191223
stoichiometry: 1.0
species: 918025
type: SpeciesReference

192518
stoichiometry: 1.0
species: 918365
type: SpeciesReference

192067
stoichiometry: 1.0
species: 918245
type: SpeciesReference

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

193087
stoichiometry: 1.0
species: 918185
type: SpeciesReference

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

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

192260
stoichiometry: 1.0
species: 918325
type: SpeciesReference

191199
stoichiometry: 1.0
species: 918705
type: SpeciesReference

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

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

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

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

193039
stoichiometry: 1.0
species: 918526
type: SpeciesReference

193972
stoichiometry: 1.0
species: 919085
type: SpeciesReference

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

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

193183
stoichiometry: 1.0
species: 919185
type: SpeciesReference

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

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

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

190713
stoichiometry: 1.0
species: 917805
type: SpeciesReference

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

192273
stoichiometry: 1.0
species: 918285
type: SpeciesReference

919745
kinetic law: 191414
product: 191401
reactant: 191388
notes: This is extremely slow (kf = 1e-4), but it is significant as so little GAP actually gets complexed with it that the total GTP turnover rises only by 2-3 X (see Gibbs et al, JBC 265(33) 20437-20422) and Eccleston et al JBC 268(36) 27012-27019 There is no back reaction as we assume this to be a regular irreversible Michaelis-Menten zeroth order hydrolysis.
fast: false
reversible: true
type: Reaction

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

191138
stoichiometry: 1.0
species: 918585
type: SpeciesReference

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

192892
stoichiometry: 1.0
species: 918225
type: SpeciesReference

193328
stoichiometry: 1.0
species: 918645
type: SpeciesReference

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

193303
stoichiometry: 1.0
species: 918645
type: SpeciesReference

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

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

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

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

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

193099
stoichiometry: 1.0
species: 918485
type: SpeciesReference

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

191426
stoichiometry: 1.0
species: 918905
type: SpeciesReference

192176
stoichiometry: 1.0
species: 918425
type: SpeciesReference

192698
stoichiometry: 1.0
species: 918565
type: SpeciesReference

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

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

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

191764
local parameters: 115408
local parameters: 115407
notes: k1*MAPK_slash_craf_minus_1*PKC_minus_active-k2*PKC_minus_active_slash_PKC_minus_act_minus_raf_slash_PKC_minus_act_minus_raf_cplx
type: KineticLaw

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

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

192079
stoichiometry: 1.0
species: 918205
type: SpeciesReference

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

193836
stoichiometry: 1.0
species: 918925
type: SpeciesReference

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

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

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

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

193679
stoichiometry: 1.0
species: 918825
type: SpeciesReference

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

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

190409
stoichiometry: 1.0
species: 917765
type: SpeciesReference

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

191362
stoichiometry: 1.0
species: 918805
type: SpeciesReference

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

191126
stoichiometry: 1.0
species: 919205
type: SpeciesReference

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

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

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

192505
stoichiometry: 1.0
species: 918285
type: SpeciesReference

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

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

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

191077
stoichiometry: 1.0
species: 919205
type: SpeciesReference

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

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

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

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

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

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

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

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

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

193691
stoichiometry: 1.0
species: 918845
type: SpeciesReference

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

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

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

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

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

190555
stoichiometry: 1.0
species: 919165
type: SpeciesReference

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

193739
stoichiometry: 1.0
species: 918825
type: SpeciesReference

115380
units: 190250
value: 0.0
type: LocalParameter

115296
units: 190250
value: 0.0
type: LocalParameter

191957
local parameters: 115414
local parameters: 115413
notes: k1*Ras_slash_inact_minus_GEF*PKC_minus_active-k2*PKC_minus_active_slash_PKC_minus_act_minus_GEF_slash_PKC_minus_act_minus_GEF_cplx
type: KineticLaw

193147
stoichiometry: 1.0
species: 918125
type: SpeciesReference

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

191788
stoichiometry: 1.0
species: 918125
type: SpeciesReference

191896
stoichiometry: 1.0
species: 919245
type: SpeciesReference

193922
stoichiometry: 1.0
species: 919045
type: SpeciesReference

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

191310
stoichiometry: 1.0
species: 918785
type: SpeciesReference

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

192031
stoichiometry: 1.0
species: 918225
type: SpeciesReference

192127
stoichiometry: 1.0
species: 918225
type: SpeciesReference

192722
stoichiometry: 1.0
species: 918465
type: SpeciesReference

192382
stoichiometry: 1.0
species: 918305
type: SpeciesReference

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

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

190895
stoichiometry: 1.0
species: 919145
type: SpeciesReference

193340
stoichiometry: 1.0
species: 918025
type: SpeciesReference

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

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

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

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

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

192418
stoichiometry: 1.0
species: 918365
type: SpeciesReference

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

192794
stoichiometry: 1.0
species: 918125
type: SpeciesReference

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

191945
stoichiometry: 1.0
species: 918085
type: SpeciesReference

193135
stoichiometry: 1.0
species: 918545
type: SpeciesReference

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

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

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

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

190543
stoichiometry: 1.0
species: 918005
type: SpeciesReference

193727
stoichiometry: 1.0
species: 918865
type: SpeciesReference

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

193063
stoichiometry: 1.0
species: 918485
type: SpeciesReference

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

190810
stoichiometry: 1.0
species: 917905
type: SpeciesReference

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

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

192370
stoichiometry: 1.0
species: 918225
type: SpeciesReference

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

194056
stoichiometry: 1.0
species: 918425
type: SpeciesReference

193935
stoichiometry: 1.0
species: 918985
type: SpeciesReference

192139
stoichiometry: 1.0
species: 918265
type: SpeciesReference

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

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

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

115372
units: 190250
value: 0.0
type: LocalParameter

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

191995
stoichiometry: 1.0
species: 919245
type: SpeciesReference

193787
stoichiometry: 1.0
species: 918945
type: SpeciesReference

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

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

190847
stoichiometry: 1.0
species: 918005
type: SpeciesReference

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

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

192456
stoichiometry: 1.0
species: 918385
type: SpeciesReference

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

192843
stoichiometry: 1.0
species: 918505
type: SpeciesReference

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

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

192758
stoichiometry: 1.0
species: 918785
type: SpeciesReference

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

194080
stoichiometry: 1.0
species: 919125
type: SpeciesReference

191053
stoichiometry: 1.0
species: 918585
type: SpeciesReference

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

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

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

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

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

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

115384
units: 190250
value: 0.0
type: LocalParameter

191004
stoichiometry: 1.0
species: 918365
type: SpeciesReference

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

194020
stoichiometry: 1.0
species: 918165
type: SpeciesReference

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

193872
stoichiometry: 1.0
species: 918985
type: SpeciesReference

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

193485
stoichiometry: 1.0
species: 918705
type: SpeciesReference

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

193715
stoichiometry: 1.0
species: 918845
type: SpeciesReference

193051
stoichiometry: 1.0
species: 918145
type: SpeciesReference

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

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

191872
stoichiometry: 1.0
species: 918065
type: SpeciesReference

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

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

192770
stoichiometry: 1.0
species: 918425
type: SpeciesReference

190835
stoichiometry: 1.0
species: 918025
type: SpeciesReference

919305
kinetic law: 190445
product: 190433
reactant: 190421
reactant: 190409
notes: Same rates as Grb2_bind_Sos: Porfiri and McCormick JBC 271:10 pp 5871 1996 show that the binding is not affected by the phosphorylation.
fast: false
reversible: true
type: Reaction

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

193799
local parameters: 115486
local parameters: 115485
notes: k1*Ras_slash_GTP_minus_Ras*Ras_slash_GAP-k2*Ras_slash_GAP_slash_GAP_minus_inact_minus_ras_slash_GAP_minus_inact_minus_ras_cplx
type: KineticLaw

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

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

191323
stoichiometry: 1.0
species: 918565
type: SpeciesReference

919325
kinetic law: 190482
product: 190469
reactant: 190457
notes: The best clue I have to these rates is from the time courses of the EGF activation, which is around 1 to 5 min. The dephosph would be expected to be of the same order, perhaps a bit longer. Lets use 0.002 which is about 8 min. Sep 17: The transient activation curve matches better with kf = 0.001
fast: false
reversible: true
type: Reaction

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

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

191150
stoichiometry: 1.0
species: 918665
type: SpeciesReference

192468
stoichiometry: 1.0
species: 918285
type: SpeciesReference

192746
stoichiometry: 1.0
species: 918465
type: SpeciesReference

191041
stoichiometry: 1.0
species: 919165
type: SpeciesReference

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

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

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

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

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

191029
stoichiometry: 1.0
species: 918565
type: SpeciesReference

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

191932
stoichiometry: 1.0
species: 919245
type: SpeciesReference

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

193884
stoichiometry: 1.0
species: 919005
type: SpeciesReference

194032
stoichiometry: 1.0
species: 919085
type: SpeciesReference

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

192091
stoichiometry: 1.0
species: 918225
type: SpeciesReference

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

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

193959
stoichiometry: 1.0
species: 918205
type: SpeciesReference

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

115396
units: 190250
value: 0.0
type: LocalParameter

191982
stoichiometry: 1.0
species: 918825
type: SpeciesReference

191920
stoichiometry: 1.0
species: 918805
type: SpeciesReference

192043
stoichiometry: 1.0
species: 918245
type: SpeciesReference

192115
stoichiometry: 1.0
species: 918205
type: SpeciesReference

193207
stoichiometry: 1.0
species: 918605
type: SpeciesReference

193159
stoichiometry: 1.0
species: 918485
type: SpeciesReference

191607
stoichiometry: 1.0
species: 919065
type: SpeciesReference

191884
stoichiometry: 1.0
species: 918905
type: SpeciesReference

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

193497
stoichiometry: 1.0
species: 918725
type: SpeciesReference

190567
stoichiometry: 1.0
species: 917805
type: SpeciesReference

193703
local parameters: 115483
local parameters: 115482
notes: k1*Ras_slash_GDP_minus_Ras*Ras_slash_GEF_star_-k2*Ras_slash_GEF_star__slash_GEF_star__minus_act_minus_ras_slash_GEF_star__minus_act_minus_ras_cplx
type: KineticLaw

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

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

193279
stoichiometry: 1.0
species: 919185
type: SpeciesReference

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

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

193377
stoichiometry: 1.0
species: 919185
type: SpeciesReference

191475
stoichiometry: 1.0
species: 918865
type: SpeciesReference

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

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

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

190421
stoichiometry: 1.0
species: 917725
type: SpeciesReference

193401
stoichiometry: 1.0
species: 918685
type: SpeciesReference

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

191261
stoichiometry: 1.0
species: 918785
type: SpeciesReference

192431
stoichiometry: 1.0
species: 918385
type: SpeciesReference

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

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

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

191824
stoichiometry: 1.0
species: 918925
type: SpeciesReference

191655
stoichiometry: 1.0
species: 917685
type: SpeciesReference

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

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

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

191704
stoichiometry: 1.0
species: 917665
type: SpeciesReference

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

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

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

190955
stoichiometry: 1.0
species: 917985
type: SpeciesReference

193763
stoichiometry: 1.0
species: 918865
type: SpeciesReference

190385
stoichiometry: 1.0
species: 917665
type: SpeciesReference

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

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

192650
stoichiometry: 1.0
species: 918445
type: SpeciesReference

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

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

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

191349
stoichiometry: 1.0
species: 918825
type: SpeciesReference

191860
local parameters: 115411
local parameters: 115410
notes: k1*Ras_slash_GAP*PKC_minus_active-k2*PKC_minus_active_slash_PKC_minus_inact_minus_GAP_slash_PKC_minus_inact_minus_GAP_cplx
type: KineticLaw

191679
stoichiometry: 1.0
species: 917685
type: SpeciesReference

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

191273
stoichiometry: 1.0
species: 919165
type: SpeciesReference

193473
stoichiometry: 1.0
species: 919185
type: SpeciesReference

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

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

191487
stoichiometry: 1.0
species: 918305
type: SpeciesReference

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

193389
stoichiometry: 1.0
species: 918665
type: SpeciesReference

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

192602
stoichiometry: 1.0
species: 918125
type: SpeciesReference

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

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

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

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

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

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

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

191388
stoichiometry: 1.0
species: 918865
type: SpeciesReference

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

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

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

192358
stoichiometry: 1.0
species: 918345
type: SpeciesReference

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

191667
local parameters: 115404
local parameters: 115402
notes: k1*Ras_slash_GDP_minus_Ras*Shc_star__dot_Sos_dot_Grb2-k2*Shc_star__dot_Sos_dot_Grb2_slash_Sos_dot_Ras_GEF_slash_Sos_dot_Ras_GEF_cplx
type: KineticLaw

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

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

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

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

192662
stoichiometry: 1.0
species: 918185
type: SpeciesReference

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

190859
stoichiometry: 1.0
species: 917925
type: SpeciesReference

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

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

190943
stoichiometry: 1.0
species: 918025
type: SpeciesReference

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

193775
stoichiometry: 1.0
species: 918925
type: SpeciesReference

191511
stoichiometry: 1.0
species: 918965
type: SpeciesReference

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

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

190360
stoichiometry: 1.0
species: 917745
type: SpeciesReference

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

194068
stoichiometry: 1.0
species: 919085
type: SpeciesReference

191691
stoichiometry: 1.0
species: 918865
type: SpeciesReference

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

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

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

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

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

920185
kinetic law: 192444
product: 192431
reactant: 192418
reactant: 192406
notes: Kinetics are the same as for the craf-1* activity, ie., k1=1.1e-6, k2=.42, k3 =0.105 These are based on Force et al PNAS USA 91 1270-1274 1994. They report Km for MAPKK of 0.8 uM. and a Vmax of ~500 fm/min/ug. These parms cannot reach the observed 4X stimulation of MAPK. So we increase the affinity, ie, raise k1 5x to 5.5e-6 which is equivalent to 5-fold reduction in Km to about 0.16. This is, of course, dependent on the amount of MAPKK present.
fast: false
reversible: true
type: Reaction

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

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

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

191285
stoichiometry: 1.0
species: 918745
type: SpeciesReference

193425
stoichiometry: 1.0
species: 918685
type: SpeciesReference

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

919565
kinetic law: 191016
product: 191004
reactant: 190992
reactant: 190980
notes: Assume binding is fast and limited only by available Ras*. So kf = kb/[craf-1] If kb is 1/sec, then kf = 1/0.2 uM = 1/(0.2 * 6e5) = 8.3e-6 Later: Raise it by 10 X to about 1e-4, giving a Kf of 60 for Kb of 0.5 and a tau of approx 2 sec. Based on: Hallberg et al JBC 269:6 3913-3916 1994, 3% of cellular Raf is complexed with Ras. This step needed to memb-anchor and activate Raf: Leevers et al Nature 369 411-414. Also see Koide et al 1993 PNAS USA 90(18):8683-8686
fast: false
reversible: true
type: Reaction

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

919285
kinetic law: 190397
product: 190385
reactant: 190372
reactant: 190360
notes: Sasaoka et al JBC 269:51 pp 32621 1994, table on pg 32623 indicates that this pathway accounts for about 50% of the GEF activation. (88% - 39%). Error is large, about 20%. Fig 1 is most useful in constraining rates. Chook et al JBC 271:48 pp 30472, 1996 say that the Kd is 0.2 uM for Shc binding to EGFR. The Kd for Grb direct binding is 0.7, so we\'ll ignore it.
fast: false
reversible: true
type: Reaction

115364
units: 190250
value: 0.0
type: LocalParameter

192236
stoichiometry: 1.0
species: 918325
type: SpeciesReference

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

920465
kinetic law: 193123
product: 193111
reactant: 193099
reactant: 193087
notes: Ueki et al JBC 269(22) pp 15756-15761 1994 show hyperphosphorylation of craf, so this is there to dephosphorylate it. Identity of phosphatase is assumed to be PP2A.
fast: false
reversible: true
type: Reaction

191728
stoichiometry: 1.0
species: 918105
type: SpeciesReference

191800
stoichiometry: 1.0
species: 919245
type: SpeciesReference

192322
stoichiometry: 1.0
species: 918305
type: SpeciesReference

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

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

193352
stoichiometry: 1.0
species: 918625
type: SpeciesReference

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

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

192614
stoichiometry: 1.0
species: 918425
type: SpeciesReference

920785
kinetic law: 193897
product: 193884
reactant: 193872
reactant: 193860
notes: Rates from Okada et al JBC 270:35 pp 20737 1995 Km = 0.70 to 0.85 uM, Vmax = 4.4 to 5.0 pmol/min. Unfortunately the amount of enzyme is not known, the prep is only partially purified. Tau phosph is max within 30 sec, falls back within 20 min. Ref: Sasaoka et al JBC 269:51 32621 1994. Use k3 = 0.1 based on this tau. 27 Apr 2001: Lowered k3 to 0.05 to fix conc-effect of SHC phosph by PDGF. This gives results for downstream effects in agreement with other papers, e.g., the Brondello papers.
fast: false
reversible: true
type: Reaction

192309
stoichiometry: 1.0
species: 918285
type: SpeciesReference

190372
stoichiometry: 1.0
species: 919045
type: SpeciesReference

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

190433
stoichiometry: 1.0
species: 917705
type: SpeciesReference

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

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

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

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

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

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

115376
units: 190250
value: 0.0
type: LocalParameter

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

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

190907
stoichiometry: 1.0
species: 917965
type: SpeciesReference

192966
stoichiometry: 1.0
species: 918485
type: SpeciesReference

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

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

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

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

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

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

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

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

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

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

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

192626
stoichiometry: 1.0
species: 918445
type: SpeciesReference

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

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

191089
stoichiometry: 1.0
species: 918565
type: SpeciesReference

194008
stoichiometry: 1.0
species: 919105
type: SpeciesReference

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

192334
stoichiometry: 1.0
species: 918345
type: SpeciesReference