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//genesis
// kkit Version 8 flat dumpfile
// Saved on Fri Feb 1 12:54:24 2002
include kkit {argv 1}
FASTDT = 0.0001
SIMDT = 0.005
CONTROLDT = 10
PLOTDT = 10
MAXTIME = 2000
TRANSIENT_TIME = 2
VARIABLE_DT_FLAG = 1
DEFAULT_VOL = 1.6667e-21
VERSION = 8.0
setfield /file/modpath value /home2/bhalla/scripts/modules
kparms
//genesis
initdump -version 3 -ignoreorphans 1
simobjdump table input output alloced step_mode stepsize x y z
simobjdump xtree path script namemode sizescale
simobjdump xcoredraw xmin xmax ymin ymax
simobjdump xtext editable
simobjdump xgraph xmin xmax ymin ymax overlay
simobjdump xplot pixflags script fg ysquish do_slope wy
simobjdump group xtree_fg_req xtree_textfg_req plotfield expanded movealone \
link savename file version md5sum mod_save_flag x y z
simobjdump kpool CoTotal CoInit Co n nInit nTotal nMin vol slave_enable notes \
xtree_fg_req xtree_textfg_req x y z
simobjdump kreac kf kb notes xtree_fg_req xtree_textfg_req x y z
simobjdump kenz CoComplexInit CoComplex nComplexInit nComplex vol k1 k2 k3 \
keepconc usecomplex notes xtree_fg_req xtree_textfg_req link x y z
simobjdump stim level1 width1 delay1 level2 width2 delay2 baselevel trig_time \
trig_mode notes xtree_fg_req xtree_textfg_req is_running x y z
simobjdump xtab input output alloced step_mode stepsize notes editfunc \
xtree_fg_req xtree_textfg_req baselevel last_x last_y is_running x y z
simobjdump kchan perm gmax Vm is_active use_nernst notes xtree_fg_req \
xtree_textfg_req x y z
simobjdump proto x y z
simobjdump linkinfo xtree_fg_req xtree_textfg_req uplink downlink x y z
simobjdump uplink xtree_fg_req xtree_textfg_req x y z
simobjdump downlink xtree_fg_req xtree_textfg_req x y z
simobjdump mirror notes xtree_fg_req x y z
simundump kpool /kinetics/Shc*.Sos.Grb2 1 1.6667e-06 0 0 0 0 1 0 6e+05 0 "" \
brown yellow 68 105 0
simundump kenz /kinetics/Shc*.Sos.Grb2/Sos.Ras_GEF 1 0 0 0 0 6e+05 3.3e-07 \
0.08 0.02 0 0 "" red brown "" 65 94 0
simundump group /kinetics/Sos 1 blue black x 0 1 "" defaultfile \
/home2/bhalla/scripts/modules/defaultfile_0.g 0 0 0 74 113 0
simundump kreac /kinetics/Sos/Shc_bind_Sos.Grb2 1 8.333e-07 0.1 "" white blue \
69 107 0
simundump kpool /kinetics/Sos/Sos*.Grb2 1 1.6667e-06 0 0 0 0 1 0 6e+05 0 "" \
orange blue 76 109 0
simundump kreac /kinetics/Sos/Grb2_bind_Sos* 1 4.1667e-08 0.0168 "" white \
blue 75 107 0
simundump kpool /kinetics/Sos/Grb2 1 1 1 0.94164 5.6499e+05 6e+05 6e+05 0 \
6e+05 0 "" orange blue 73 105 0
simundump kpool /kinetics/Sos/Sos.Grb2 1 1.6667e-06 0 0.058356 35014 0 1 0 \
6e+05 0 "" orange blue 70 105 0
simundump kpool /kinetics/Sos/Sos* 1 1.6667e-06 0 0 0 0 1 0 6e+05 0 "" red \
blue 74 109 0
simundump kreac /kinetics/Sos/dephosph_Sos 1 0.001 0 "" white blue 73 107 0
simundump kreac /kinetics/Sos/Grb2_bind_Sos 1 4.1667e-08 0.0168 "" white blue \
71 107 0
simundump kpool /kinetics/Sos/Sos 1 0.1 0.1 0.041645 24987 60000 60000 0 \
6e+05 0 "" red blue 72 109 0
simundump group /kinetics/PKC 0 blue black x 0 0 "" defaultfile \
/home2/bhalla/scripts/modules/defaultfile_0.g 0 0 0 47 80 0
simundump kpool /kinetics/PKC/PKC-Ca 0 0.28282 3.7208e-17 0.075998 45599 \
2.2325e-11 1.6969e+05 0 6e+05 0 "" red black 48 74 0
simundump kreac /kinetics/PKC/PKC-act-by-Ca 0 1e-06 0.5 "" white blue 48 72 0
simundump kreac /kinetics/PKC/PKC-act-by-DAG 0 1.3333e-08 8.6348 "" white \
blue 56 72 0
simundump kreac /kinetics/PKC/PKC-Ca-to-memb 0 1.2705 3.5026 "" white blue 48 \
76 0
simundump kreac /kinetics/PKC/PKC-DAG-to-memb 0 1 0.1 "" white blue 56 76 0
simundump kreac /kinetics/PKC/PKC-act-by-Ca-AA 0 2e-09 0.1 "" white blue 50 \
76 0
simundump kreac /kinetics/PKC/PKC-act-by-DAG-AA 0 2 0.2 "" white blue 54 76 0
simundump kpool /kinetics/PKC/PKC-DAG-AA* 0 0.12061 4.9137e-18 0.030483 18290 \
2.9482e-12 72366 0 6e+05 0 "" cyan blue 54 78 0
simundump kpool /kinetics/PKC/PKC-Ca-AA* 0 0.16962 1.75e-16 0.0055768 3346.1 \
1.05e-10 1.0177e+05 0 6e+05 0 "" orange blue 50 78 0
simundump kpool /kinetics/PKC/PKC-Ca-memb* 0 0.10258 1.3896e-17 0.027567 \
16540 8.3376e-12 61549 0 6e+05 0 "" pink blue 48 78 0
simundump kpool /kinetics/PKC/PKC-DAG-memb* 0 0.023753 9.4352e-21 0.0082104 \
4926.3 5.6611e-15 14252 0 6e+05 0 "" yellow blue 56 78 0
simundump kpool /kinetics/PKC/PKC-basal* 0 0.0432 0.02 0.015833 9499.8 12000 \
25920 0 6e+05 0 "" pink blue 46 78 0
simundump kreac /kinetics/PKC/PKC-basal-act 0 1 50 "" white blue 46 72 0
simundump kpool /kinetics/PKC/PKC-AA* 0 1 1.8133e-17 0.0058092 3485.5 \
1.088e-11 6e+05 0 6e+05 0 "" cyan blue 52 78 0
simundump kreac /kinetics/PKC/PKC-act-by-AA 0 2e-10 0.1 "" white blue 50 72 0
simundump kpool /kinetics/PKC/PKC-Ca-DAG 0 0.0017993 8.4632e-23 0.00082104 \
492.63 5.0779e-17 1079.6 0 6e+05 0 "" white blue 56 74 0
simundump kreac /kinetics/PKC/PKC-n-DAG 0 1e-09 0.1 "" white blue 52 72 0
simundump kpool /kinetics/PKC/PKC-DAG 0 0.08533 0 0.055389 33233 0 51198 0 \
6e+05 0 "" white blue 52 74 0
simundump kreac /kinetics/PKC/PKC-n-DAG-AA 0 3e-08 2 "" white blue 54 72 0
simundump kpool /kinetics/PKC/PKC-DAG-AA 0 0.012093 2.5188e-19 0.0030483 1829 \
1.5113e-13 7255.5 0 6e+05 0 "" white blue 54 74 0
simundump kpool /kinetics/PKC/PKC-cytosolic 0 1.5489 1 0.79165 4.7499e+05 \
6e+05 9.2935e+05 0 6e+05 0 "" white blue 50 70 0
simundump kpool /kinetics/DAG 1 100 11.661 11.661 6.9966e+06 6.9966e+06 6e+07 \
0 6e+05 6 "" green black 54 60 0
simundump kpool /kinetics/Ca 1 1 0.08 0.08 48000 48000 6e+05 0 6e+05 6 "" red \
black 52 60 0
simundump kpool /kinetics/AA 0 6.12 6.12 6.1151 3.669e+06 3.672e+06 3.672e+06 \
0 6e+05 0 "" darkgreen black 50 68 0
simundump kpool /kinetics/PKC-active 0 0.02 2.1222e-16 0.093103 55862 12000 \
56088 0 6e+05 2 "" yellow black 52 80 0
simundump kenz /kinetics/PKC-active/PKC-act-raf 1 0 0.00024472 0 146.83 6e+05 \
5e-07 16 4 0 0 "" red yellow "" 64 88 0
simundump kenz /kinetics/PKC-active/PKC-inact-GAP 1 0 2.0482e-06 0 1.2289 \
6e+05 3.125e-06 100 25 0 0 "" red yellow "" 60 98 0
simundump kenz /kinetics/PKC-active/PKC-act-GEF 1 0 0.0001296 0 77.762 6e+05 \
5e-07 16 4 0 0 "" red yellow "" 68 98 0
simundump group /kinetics/MAPK 0 brown black x 0 0 "" defaultfile \
/home2/bhalla/scripts/modules/defaultfile_0.g 0 0 0 69 88 0
simundump kpool /kinetics/MAPK/craf-1 0 0.2 0.2 0.17523 1.0514e+05 1.2e+05 \
1.2e+05 0 6e+05 0 "" pink brown 63 86 0
simundump kpool /kinetics/MAPK/craf-1* 0 0.2 0 0.011418 6851 0 1.2e+05 0 \
6e+05 0 "" pink brown 65 86 0
simundump kpool /kinetics/MAPK/MAPKK 0 0.18 0.18 0.16222 97335 1.08e+05 \
1.08e+05 0 6e+05 0 "" pink brown 64 82 0
simundump kpool /kinetics/MAPK/MAPK 0 0.36 0.36 0.34219 2.0531e+05 2.16e+05 \
2.16e+05 0 6e+05 0 "" pink brown 67 78 0
simundump kpool /kinetics/MAPK/craf-1** 1 0.2 0 2.951e-05 17.706 0 1.2e+05 0 \
6e+05 0 "" hotpink brown 67 86 0
simundump kpool /kinetics/MAPK/MAPK-tyr 1 0.36 0 0.013943 8365.6 0 2.16e+05 0 \
6e+05 0 "" orange brown 67 76 0
simundump kpool /kinetics/MAPK/MAPKK* 0 0.18 0 0.00037106 222.64 0 1.08e+05 0 \
6e+05 0 "" pink brown 64 78 0
simundump kenz /kinetics/MAPK/MAPKK*/MAPKKtyr 0 0 0.0027426 0 1645.6 6e+05 \
2.7e-05 0.6 0.15 0 0 "" red pink "" 64 77 0
simundump kenz /kinetics/MAPK/MAPKK*/MAPKKthr 1 0 0.00011175 0 67.049 6e+05 \
2.7e-05 0.6 0.15 0 0 "" red pink "" 64 75 0
simundump kpool /kinetics/MAPK/MAPKK-ser 1 0.18 0 0.0077587 4655.2 0 1.08e+05 \
0 6e+05 0 "" pink brown 64 80 0
simundump kpool /kinetics/MAPK/RGR 1 0.0104 0 0.0026971 1618.3 0 6240 0 6e+05 \
0 "" red brown 62 82 0
simundump kenz /kinetics/MAPK/RGR/RGR.1 1 0 0.0027503 0 1650.2 6e+05 5.5e-06 \
0.42 0.105 0 0 "" red red "" 62 81 0
simundump kenz /kinetics/MAPK/RGR/RGR.2 1 0 0.00013154 0 78.921 6e+05 5.5e-06 \
0.42 0.105 0 0 "" red red "" 62 79 0
simundump kpool /kinetics/MAPK/Raf*-GTP-Ras 1 0.0104 0 0.003515 2109 0 6240 0 \
6e+05 0 "" red brown 66 82 0
simundump kenz /kinetics/MAPK/Raf*-GTP-Ras/Raf*-GTP-Ras.1 1 0 0.0035843 0 \
2150.6 6e+05 5.5e-06 0.42 0.105 0 0 "" red red "" 65 81 0
simundump kenz /kinetics/MAPK/Raf*-GTP-Ras/Raf*-GTP-Ras.2 1 0 0.00017142 0 \
102.85 6e+05 5.5e-06 0.42 0.105 0 0 "" red red "" 65 79 0
simundump kpool /kinetics/MAPK* 0 1 0 0.00056809 340.86 0 6e+05 0 6e+05 0 "" \
orange yellow 67 74 0
simundump kenz /kinetics/MAPK*/MAPK*-feedback 1 0 2.5298e-07 0 0.15179 6e+05 \
3.25e-06 40 10 0 0 "" red orange "" 66 84 0
simundump kenz /kinetics/MAPK*/MAPK* 0 0 2.4171e-06 0 1.4503 6e+05 6.5e-06 80 \
20 0 0 "" red orange "" 52 57 0
simundump kreac /kinetics/Ras-act-craf 1 1e-04 0.5 "" white black 68 84 0
simundump kpool /kinetics/PPhosphatase2A 1 0.224 0.224 0.2237 1.3422e+05 \
1.344e+05 1.344e+05 0 6e+05 0 "" hotpink yellow 68 80 0
simundump kenz /kinetics/PPhosphatase2A/craf-deph 1 0 0.00016314 0 97.886 \
6e+05 3.3e-06 25 6 0 0 "" red hotpink "" 64 84 0
simundump kenz /kinetics/PPhosphatase2A/MAPKK-deph 1 0 5.3016e-06 0 3.181 \
6e+05 3.3e-06 25 6 0 0 "" red hotpink "" 68 79 0
simundump kenz /kinetics/PPhosphatase2A/MAPKK-deph-ser 1 0 0.00011085 0 \
66.513 6e+05 3.3e-06 25 6 0 0 "" red hotpink "" 68 81 0
simundump kenz /kinetics/PPhosphatase2A/craf**-deph 1 0 0.25298 0 0.25298 1 \
3.3e-06 25 6 0 0 "" red hotpink "" 66 88 0
simundump group /kinetics/PLA2 0 darkgreen black x 0 1 "" defaultfile \
/home2/bhalla/scripts/modules/defaultfile_0.g 0 0 0 56 58 0
simundump kpool /kinetics/PLA2/PLA2-cytosolic 0 0.4 0.4 0.1091 65459 2.4e+05 \
2.4e+05 0 6e+05 0 "" yellow darkgreen 48 57 0
simundump kreac /kinetics/PLA2/PLA2-Ca-act 0 1.6667e-06 0.1 "" white \
darkgreen 51 62 0
simundump kpool /kinetics/PLA2/PLA2-Ca* 0 1 0 0.08728 52368 0 6e+05 0 6e+05 0 \
"" yellow darkgreen 52 64 0
simundump kenz /kinetics/PLA2/PLA2-Ca*/kenz 0 0 0.13092 0 78552 6e+05 \
2.25e-06 21.6 5.4 0 0 "" red yellow "" 52 66 0
simundump kreac /kinetics/PLA2/PIP2-PLA2-act 0 2e-09 0.5 "" white darkgreen \
47 62 0
simundump kpool /kinetics/PLA2/PIP2-PLA2* 0 1 0 0.00065459 392.75 0 6e+05 0 \
6e+05 0 "" cyan darkgreen 46 64 0
simundump kenz /kinetics/PLA2/PIP2-PLA2*/kenz 0 0 0.00098188 0 589.13 6e+05 \
4.6e-06 44.16 11.04 0 0 "" red cyan "" 46 66 0
simundump kreac /kinetics/PLA2/PIP2-Ca-PLA2-act 0 2e-08 0.1 "" white \
darkgreen 49 62 0
simundump kpool /kinetics/PLA2/PIP2-Ca-PLA2* 0 1 0 0.026184 15710 0 6e+05 0 \
6e+05 0 "" cyan darkgreen 48 64 0
simundump kenz /kinetics/PLA2/PIP2-Ca-PLA2*/kenz 0 0 0.039276 0 23566 6e+05 \
1.5e-05 144 36 0 0 "" red cyan "" 48 66 0
simundump kreac /kinetics/PLA2/DAG-Ca-PLA2-act 0 5e-09 4 "" white darkgreen \
53 62 0
simundump kpool /kinetics/PLA2/DAG-Ca-PLA2* 0 1 0 0.00076333 458 0 6e+05 0 \
6e+05 0 "" pink darkgreen 54 64 0
simundump kenz /kinetics/PLA2/DAG-Ca-PLA2*/kenz 0 0 0.001145 0 687 6e+05 \
2.5e-05 240 60 0 0 "" red pink "" 54 66 0
simundump kpool /kinetics/PLA2/APC 0 30 30 30 1.8e+07 1.8e+07 1.8e+07 0 6e+05 \
5 "" yellow darkgreen 50 64 0
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"Based on fb29.g, cleaned up the dangling phosph_PLC-gamma" \
"enzyme activity on PDGFR."
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addmsg /kinetics/PLA2/PLA2-Ca-act /kinetics/PLA2/PLA2-cytosolic REAC A B
addmsg /kinetics/PLA2/PIP2-PLA2-act /kinetics/PLA2/PLA2-cytosolic REAC A B
addmsg /kinetics/PLA2/PIP2-PLA2* /kinetics/PLA2/PLA2-cytosolic CONSERVE n nInit
addmsg /kinetics/PLA2/PIP2-Ca-PLA2* /kinetics/PLA2/PLA2-cytosolic CONSERVE n nInit
addmsg /kinetics/PLA2/DAG-Ca-PLA2* /kinetics/PLA2/PLA2-cytosolic CONSERVE n nInit
addmsg /kinetics/PLA2/PLA2-Ca* /kinetics/PLA2/PLA2-cytosolic CONSERVE n nInit
addmsg /kinetics/PLA2/PLA2*-Ca /kinetics/PLA2/PLA2-cytosolic CONSERVE n nInit
addmsg /kinetics/MAPK*/MAPK* /kinetics/PLA2/PLA2-cytosolic CONSERVE nComplex nComplexInit
addmsg /kinetics/PLA2/PLA2*-Ca/kenz /kinetics/PLA2/PLA2-cytosolic CONSERVE nComplex nComplexInit
addmsg /kinetics/PLA2/PLA2-Ca*/kenz /kinetics/PLA2/PLA2-cytosolic CONSERVE nComplex nComplexInit
addmsg /kinetics/PLA2/DAG-Ca-PLA2*/kenz /kinetics/PLA2/PLA2-cytosolic CONSERVE nComplex nComplexInit
addmsg /kinetics/PLA2/PIP2-Ca-PLA2*/kenz /kinetics/PLA2/PLA2-cytosolic CONSERVE nComplex nComplexInit
addmsg /kinetics/PLA2/PIP2-PLA2*/kenz /kinetics/PLA2/PLA2-cytosolic CONSERVE nComplex nComplexInit
addmsg /kinetics/MAPK*/MAPK* /kinetics/PLA2/PLA2-cytosolic REAC sA B
addmsg /kinetics/PLA2/PLA2* /kinetics/PLA2/PLA2-cytosolic CONSERVE n nInit
addmsg /kinetics/PLA2/dephosphorylate-PLA2* /kinetics/PLA2/PLA2-cytosolic REAC B A
addmsg /kinetics/PLA2/PLA2-cytosolic /kinetics/PLA2/PLA2-Ca-act SUBSTRATE n
addmsg /kinetics/Ca /kinetics/PLA2/PLA2-Ca-act SUBSTRATE n
addmsg /kinetics/PLA2/PLA2-Ca* /kinetics/PLA2/PLA2-Ca-act PRODUCT n
addmsg /kinetics/PLA2/PLA2-Ca-act /kinetics/PLA2/PLA2-Ca* REAC B A
addmsg /kinetics/PLA2/PLA2-Ca*/kenz /kinetics/PLA2/PLA2-Ca* REAC eA B
addmsg /kinetics/PLA2/PIP2-Ca-PLA2-act /kinetics/PLA2/PLA2-Ca* REAC A B
addmsg /kinetics/PLA2/DAG-Ca-PLA2-act /kinetics/PLA2/PLA2-Ca* REAC A B
addmsg /kinetics/PLA2/PLA2-Ca* /kinetics/PLA2/PLA2-Ca*/kenz ENZYME n
addmsg /kinetics/PLA2/APC /kinetics/PLA2/PLA2-Ca*/kenz SUBSTRATE n
addmsg /kinetics/temp-PIP2 /kinetics/PLA2/PIP2-PLA2-act SUBSTRATE n
addmsg /kinetics/PLA2/PLA2-cytosolic /kinetics/PLA2/PIP2-PLA2-act SUBSTRATE n
addmsg /kinetics/PLA2/PIP2-PLA2* /kinetics/PLA2/PIP2-PLA2-act PRODUCT n
addmsg /kinetics/PLA2/PIP2-PLA2-act /kinetics/PLA2/PIP2-PLA2* REAC B A
addmsg /kinetics/PLA2/PIP2-PLA2*/kenz /kinetics/PLA2/PIP2-PLA2* REAC eA B
addmsg /kinetics/PLA2/PIP2-PLA2* /kinetics/PLA2/PIP2-PLA2*/kenz ENZYME n
addmsg /kinetics/PLA2/APC /kinetics/PLA2/PIP2-PLA2*/kenz SUBSTRATE n
addmsg /kinetics/temp-PIP2 /kinetics/PLA2/PIP2-Ca-PLA2-act SUBSTRATE n
addmsg /kinetics/PLA2/PLA2-Ca* /kinetics/PLA2/PIP2-Ca-PLA2-act SUBSTRATE n
addmsg /kinetics/PLA2/PIP2-Ca-PLA2* /kinetics/PLA2/PIP2-Ca-PLA2-act PRODUCT n
addmsg /kinetics/PLA2/PIP2-Ca-PLA2-act /kinetics/PLA2/PIP2-Ca-PLA2* REAC B A
addmsg /kinetics/PLA2/PIP2-Ca-PLA2*/kenz /kinetics/PLA2/PIP2-Ca-PLA2* REAC eA B
addmsg /kinetics/PLA2/PIP2-Ca-PLA2* /kinetics/PLA2/PIP2-Ca-PLA2*/kenz ENZYME n
addmsg /kinetics/PLA2/APC /kinetics/PLA2/PIP2-Ca-PLA2*/kenz SUBSTRATE n
addmsg /kinetics/DAG /kinetics/PLA2/DAG-Ca-PLA2-act SUBSTRATE n
addmsg /kinetics/PLA2/PLA2-Ca* /kinetics/PLA2/DAG-Ca-PLA2-act SUBSTRATE n
addmsg /kinetics/PLA2/DAG-Ca-PLA2* /kinetics/PLA2/DAG-Ca-PLA2-act PRODUCT n
addmsg /kinetics/PLA2/DAG-Ca-PLA2-act /kinetics/PLA2/DAG-Ca-PLA2* REAC B A
addmsg /kinetics/PLA2/DAG-Ca-PLA2*/kenz /kinetics/PLA2/DAG-Ca-PLA2* REAC eA B
addmsg /kinetics/PLA2/DAG-Ca-PLA2* /kinetics/PLA2/DAG-Ca-PLA2*/kenz ENZYME n
addmsg /kinetics/PLA2/APC /kinetics/PLA2/DAG-Ca-PLA2*/kenz SUBSTRATE n
addmsg /kinetics/PLA2/PLA2-Ca*/kenz /kinetics/PLA2/APC REAC sA B
addmsg /kinetics/PLA2/PIP2-PLA2*/kenz /kinetics/PLA2/APC REAC sA B
addmsg /kinetics/PLA2/PIP2-Ca-PLA2*/kenz /kinetics/PLA2/APC REAC sA B
addmsg /kinetics/PLA2/DAG-Ca-PLA2*/kenz /kinetics/PLA2/APC REAC sA B
addmsg /kinetics/PLA2/PLA2*-Ca/kenz /kinetics/PLA2/APC REAC sA B
addmsg /kinetics/PLA2/Degrade-AA /kinetics/PLA2/APC REAC B A
addmsg /kinetics/AA /kinetics/PLA2/Degrade-AA SUBSTRATE n
addmsg /kinetics/PLA2/APC /kinetics/PLA2/Degrade-AA PRODUCT n
addmsg /kinetics/PLA2/PLA2*-Ca/kenz /kinetics/PLA2/PLA2*-Ca REAC eA B
addmsg /kinetics/PLA2/PLA2*-Ca-act /kinetics/PLA2/PLA2*-Ca REAC B A
addmsg /kinetics/PLA2/PLA2*-Ca /kinetics/PLA2/PLA2*-Ca/kenz ENZYME n
addmsg /kinetics/PLA2/APC /kinetics/PLA2/PLA2*-Ca/kenz SUBSTRATE n
addmsg /kinetics/MAPK*/MAPK* /kinetics/PLA2/PLA2* MM_PRD pA
addmsg /kinetics/PLA2/PLA2*-Ca-act /kinetics/PLA2/PLA2* REAC A B
addmsg /kinetics/PLA2/dephosphorylate-PLA2* /kinetics/PLA2/PLA2* REAC A B
addmsg /kinetics/PLA2/PLA2* /kinetics/PLA2/PLA2*-Ca-act SUBSTRATE n
addmsg /kinetics/PLA2/PLA2*-Ca /kinetics/PLA2/PLA2*-Ca-act PRODUCT n
addmsg /kinetics/Ca /kinetics/PLA2/PLA2*-Ca-act SUBSTRATE n
addmsg /kinetics/PLA2/PLA2* /kinetics/PLA2/dephosphorylate-PLA2* SUBSTRATE n
addmsg /kinetics/PLA2/PLA2-cytosolic /kinetics/PLA2/dephosphorylate-PLA2* PRODUCT n
addmsg /kinetics/PLA2/PIP2-PLA2-act /kinetics/temp-PIP2 REAC A B
addmsg /kinetics/PLA2/PIP2-Ca-PLA2-act /kinetics/temp-PIP2 REAC A B
addmsg /kinetics/Ras/GEF* /kinetics/Ras/dephosph-GEF SUBSTRATE n
addmsg /kinetics/Ras/inact-GEF /kinetics/Ras/dephosph-GEF PRODUCT n
addmsg /kinetics/PKC-active/PKC-act-GEF /kinetics/Ras/inact-GEF REAC sA B
addmsg /kinetics/Ras/dephosph-GEF /kinetics/Ras/inact-GEF REAC B A
addmsg /kinetics/PKC-active/PKC-act-GEF /kinetics/Ras/GEF* MM_PRD pA
addmsg /kinetics/Ras/dephosph-GEF /kinetics/Ras/GEF* REAC A B
addmsg /kinetics/Ras/GEF*/GEF*-act-ras /kinetics/Ras/GEF* REAC eA B
addmsg /kinetics/Ras/GEF* /kinetics/Ras/GEF*/GEF*-act-ras ENZYME n
addmsg /kinetics/Ras/GDP-Ras /kinetics/Ras/GEF*/GEF*-act-ras SUBSTRATE n
addmsg /kinetics/Ras/GAP/GAP-inact-ras /kinetics/Ras/GTP-Ras REAC sA B
addmsg /kinetics/Ras/Ras-intrinsic-GTPase /kinetics/Ras/GTP-Ras REAC A B
addmsg /kinetics/Ras/GEF*/GEF*-act-ras /kinetics/Ras/GTP-Ras MM_PRD pA
addmsg /kinetics/Ras-act-craf /kinetics/Ras/GTP-Ras REAC A B
addmsg /kinetics/Shc*.Sos.Grb2/Sos.Ras_GEF /kinetics/Ras/GTP-Ras MM_PRD pA
addmsg /kinetics/Ras-act-unphosph-raf /kinetics/Ras/GTP-Ras REAC A B
addmsg /kinetics/Ras/GAP/GAP-inact-ras /kinetics/Ras/GDP-Ras MM_PRD pA
addmsg /kinetics/Ras/Ras-intrinsic-GTPase /kinetics/Ras/GDP-Ras REAC B A
addmsg /kinetics/Ras/GEF*/GEF*-act-ras /kinetics/Ras/GDP-Ras REAC sA B
addmsg /kinetics/Shc*.Sos.Grb2/Sos.Ras_GEF /kinetics/Ras/GDP-Ras REAC sA B
addmsg /kinetics/Ras/GTP-Ras /kinetics/Ras/Ras-intrinsic-GTPase SUBSTRATE n
addmsg /kinetics/Ras/GDP-Ras /kinetics/Ras/Ras-intrinsic-GTPase PRODUCT n
addmsg /kinetics/Ras/GAP* /kinetics/Ras/dephosph-GAP SUBSTRATE n
addmsg /kinetics/Ras/GAP /kinetics/Ras/dephosph-GAP PRODUCT n
addmsg /kinetics/PKC-active/PKC-inact-GAP /kinetics/Ras/GAP* MM_PRD pA
addmsg /kinetics/Ras/dephosph-GAP /kinetics/Ras/GAP* REAC A B
addmsg /kinetics/Ras/GAP/GAP-inact-ras /kinetics/Ras/GAP REAC eA B
addmsg /kinetics/PKC-active/PKC-inact-GAP /kinetics/Ras/GAP REAC sA B
addmsg /kinetics/Ras/dephosph-GAP /kinetics/Ras/GAP REAC B A
addmsg /kinetics/Ras/GAP /kinetics/Ras/GAP/GAP-inact-ras ENZYME n
addmsg /kinetics/Ras/GTP-Ras /kinetics/Ras/GAP/GAP-inact-ras SUBSTRATE n
addmsg /kinetics/MAPK/craf-1 /kinetics/Ras-act-unphosph-raf SUBSTRATE n
addmsg /kinetics/MAPK/RGR /kinetics/Ras-act-unphosph-raf PRODUCT n
addmsg /kinetics/Ras/GTP-Ras /kinetics/Ras-act-unphosph-raf SUBSTRATE n
addmsg /kinetics/PDGFR/act_PDGFR /kinetics/PDGFR/PDGFR REAC A B
addmsg /kinetics/PDGFR/PDGFR /kinetics/PDGFR/act_PDGFR SUBSTRATE n
addmsg /kinetics/PDGFR/PDGF /kinetics/PDGFR/act_PDGFR SUBSTRATE n
addmsg /kinetics/PDGFR/L.PDGFR /kinetics/PDGFR/act_PDGFR PRODUCT n
addmsg /kinetics/PDGFR/act_PDGFR /kinetics/PDGFR/L.PDGFR REAC B A
addmsg /kinetics/PDGFR/L.PDGFR/phosph_Shc /kinetics/PDGFR/L.PDGFR REAC eA B
addmsg /kinetics/PDGFR/Internalize /kinetics/PDGFR/L.PDGFR REAC A B
addmsg /kinetics/PDGFR/L.PDGFR /kinetics/PDGFR/L.PDGFR/phosph_Shc ENZYME n
addmsg /kinetics/PDGFR/SHC /kinetics/PDGFR/L.PDGFR/phosph_Shc SUBSTRATE n
addmsg /kinetics/PDGFR/act_PDGFR /kinetics/PDGFR/PDGF REAC A B
addmsg /kinetics/PDGFR/dephosph_Shc /kinetics/PDGFR/SHC REAC B A
addmsg /kinetics/PDGFR/L.PDGFR/phosph_Shc /kinetics/PDGFR/SHC REAC sA B
addmsg /kinetics/PDGFR/dephosph_Shc /kinetics/PDGFR/SHC* REAC A B
addmsg /kinetics/Sos/Shc_bind_Sos.Grb2 /kinetics/PDGFR/SHC* REAC A B
addmsg /kinetics/PDGFR/L.PDGFR/phosph_Shc /kinetics/PDGFR/SHC* MM_PRD pA
addmsg /kinetics/PDGFR/SHC* /kinetics/PDGFR/dephosph_Shc SUBSTRATE n
addmsg /kinetics/PDGFR/SHC /kinetics/PDGFR/dephosph_Shc PRODUCT n
addmsg /kinetics/PDGFR/Internalize /kinetics/PDGFR/Internal_L.PDGFR REAC B A
addmsg /kinetics/PDGFR/L.PDGFR /kinetics/PDGFR/Internalize SUBSTRATE n
addmsg /kinetics/PDGFR/Internal_L.PDGFR /kinetics/PDGFR/Internalize PRODUCT n
addmsg /kinetics/MKP-2/MKP2-tyr-deph /kinetics/MKP-2 REAC eA B
addmsg /kinetics/MKP-2/MKP2-thr-deph /kinetics/MKP-2 REAC eA B
addmsg /kinetics/MKP-2 /kinetics/MKP-2/MKP2-tyr-deph ENZYME n
addmsg /kinetics/MAPK/MAPK-tyr /kinetics/MKP-2/MKP2-tyr-deph SUBSTRATE n
addmsg /kinetics/MKP-2 /kinetics/MKP-2/MKP2-thr-deph ENZYME n
addmsg /kinetics/MAPK* /kinetics/MKP-2/MKP2-thr-deph SUBSTRATE n
addmsg /kinetics/MAPK* /graphs/conc1/MAPK*.Co PLOT Co *MAPK*.Co *orange
addmsg /kinetics/PKC-active /graphs/conc1/PKC-active.Co PLOT Co *PKC-active.Co *yellow
addmsg /kinetics/PDGFR/PDGFR /graphs/conc2/PDGFR.Co PLOT Co *PDGFR.Co *red
addmsg /kinetics/PDGFR/PDGF /graphs/conc2/PDGF.Co PLOT Co *PDGF.Co *red
enddump
// End of dump
call /kinetics/Shc*.Sos.Grb2/notes LOAD \
"This three-way complex is one of the main GEFs for activating Ras."
call /kinetics/Shc*.Sos.Grb2/Sos.Ras_GEF/notes LOAD \
"Rates from Orita et al JBC 268(34):25542-25546"
call /kinetics/Sos/notes LOAD \
"This represents the mSos protein and the Grb2 adapter protein" \
"involved in Ras activation. This module provides for input from" \
"RTKs as well as feedback inhibition from MAPK, although the" \
"latter is not implemented in this specific model."
call /kinetics/Sos/Shc_bind_Sos.Grb2/notes LOAD \
"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."
call /kinetics/Sos/Sos*.Grb2/notes LOAD \
"Inactive complex of Sos* with Grb2 due to phosphorylation of the Sos." \
"See Porfiri and McCormick 1996 JBC 271(10):5871."
call /kinetics/Sos/Grb2_bind_Sos*/notes LOAD \
"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."
call /kinetics/Sos/Grb2/notes LOAD \
"There is probably a lot of it in the cell: it is also known" \
"as Ash (abundant src homology protein). Also " \
"Waters et al JBC 271:30 18224 1996 say that only a small" \
"fraction of cellular Grb is precipitated out when SoS is" \
"precipitated. As most of the Sos seems to be associated" \
"with Grb2, it would seem like there is a lot of the latter." \
"Say 1 uM. This would comfortably saturate the SoS."
call /kinetics/Sos/Sos.Grb2/notes LOAD \
"For simplicity I treat the activation of Sos as involving a" \
"single complex comprising Sos, Grb2 and Shc*. This is" \
"reasonably documented:" \
"Sasaoka et al 1994 JBC 269(51):32621-5" \
"Chook et al JBC 1996 271(48):30472" \
""
call /kinetics/Sos/Sos*/notes LOAD \
"Phosphorylated form of SoS. Nominally this is an inactivation step" \
"mediated by MAPK, see Profiri and McCormick 1996 JBC 271(10):5871." \
"I have not put this inactivation in this pathway so this molecule " \
"currently only represents a potential interaction point."
call /kinetics/Sos/dephosph_Sos/notes LOAD \
"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"
call /kinetics/Sos/Grb2_bind_Sos/notes LOAD \
"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."
call /kinetics/Sos/Sos/notes LOAD \
"I have tried using low (0.02 uM) initial concs, but these" \
"give a very flat response to EGF stim although the overall" \
"activation of Ras is not too bad. I am reverting to 0.1 " \
"because we expect a sharp initial response, followed by" \
"a decline." \
""
call /kinetics/PKC/notes LOAD \
"Protein Kinase C. This module represents a weighted average of" \
"the alpha, beta and gamma isoforms. It takes inputs from" \
"Ca, DAG (Diacyl Glycerol) and AA (arachidonic acid)." \
"Regulation parameters are largely from Schaechter and Benowitz" \
"1993 J Neurosci 13(10):4361 who use synaptosomes from" \
"mammalian brain and in one paper look at all three inputs." \
"Shinomura et al 1991 PNAS 88:5149-5153 is also a useful source" \
"of data and helps to tighten the DAG inputs. " \
"General reviews include Azzi et al 1992 Eur J Bioch 208:541" \
"and Nishizuka 1988, Nature 334:661" \
"Concentration info from Kikkawa et al 1982 JBC 257(22):13341" \
"The process of parameterization is described in detail" \
"in several places. See Supplementary notes to " \
"Bhalla and Iyengar 1999 Science 284:92-96, available at the site" \
"http://www.ncbs.res.in/~bhalla/ltploop/pkc_example.html" \
"The parameterization is also described in a book chapter:" \
"Bhalla, 2000: Simulations of Biochemical Signaling in" \
"Computational Neuroscience: Realistic Modeling for Experimentalists." \
"Ed. E. De Schutter. CRC Press." \
""
call /kinetics/PKC/PKC-Ca/notes LOAD \
"This intermediate is strongly indicated by the synergistic" \
"activation of PKC by combinations of DAG and Ca, as well" \
"as AA and Ca. PKC by definition also has a direct Ca-activation," \
"to which this also contributes."
call /kinetics/PKC/PKC-act-by-Ca/notes LOAD \
"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." \
"" \
""
call /kinetics/PKC/PKC-act-by-DAG/notes LOAD \
"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."
call /kinetics/PKC/PKC-Ca-to-memb/notes LOAD \
"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."
call /kinetics/PKC/PKC-DAG-to-memb/notes LOAD \
"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."
call /kinetics/PKC/PKC-act-by-Ca-AA/notes LOAD \
"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"
call /kinetics/PKC/PKC-act-by-DAG-AA/notes LOAD \
"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"
call /kinetics/PKC/PKC-DAG-AA*/notes LOAD \
"Membrane translocated form of PKC-DAG-AA complex."
call /kinetics/PKC/PKC-Ca-AA*/notes LOAD \
"Membrane bound and active complex of PKC, Ca and AA."
call /kinetics/PKC/PKC-Ca-memb*/notes LOAD \
"This is the direct Ca-stimulated activity of PKC."
call /kinetics/PKC/PKC-DAG-memb*/notes LOAD \
"Active, membrane attached form of Ca.DAG.PKC complex."
call /kinetics/PKC/PKC-basal*/notes LOAD \
"This is the basal PKC activity which contributes about" \
"2% to the maximum."
call /kinetics/PKC/PKC-basal-act/notes LOAD \
"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."
call /kinetics/PKC/PKC-AA*/notes LOAD \
"This is the membrane-bound and active form of the PKC-AA complex." \
""
call /kinetics/PKC/PKC-act-by-AA/notes LOAD \
"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."
call /kinetics/PKC/PKC-Ca-DAG/notes LOAD \
"This is the active PKC form involving Ca and DAG." \
"It has to translocate to the membrane."
call /kinetics/PKC/PKC-n-DAG/notes LOAD \
"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."
call /kinetics/PKC/PKC-DAG/notes LOAD \
"This is a DAG-bound intermediate used in synergistic activation" \
"of PKC by DAG and AA."
call /kinetics/PKC/PKC-n-DAG-AA/notes LOAD \
"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."
call /kinetics/PKC/PKC-DAG-AA/notes LOAD \
"Complex of PKC, DAG and AA giving rise to synergistic" \
"activation of PKC by DAG and AA at resting Ca." \
""
call /kinetics/PKC/PKC-cytosolic/notes LOAD \
"Marquez et al J. Immun 149,2560(92) est 1e6/cell for chromaffin cells" \
"" \
"Kikkawa et al 1982 JBC 257(22):13341 have PKC levels in brain at " \
"about 1 uM." \
"" \
"The cytosolic form is the inactive PKC. This is really a composite" \
"of three isoforms: alpha, beta and gamma which have slightly" \
"different properties and respond to different combinations of" \
"Ca, AA and DAG."
call /kinetics/DAG/notes LOAD \
"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." \
"" \
"" \
""
call /kinetics/Ca/notes LOAD \
"This calcium pool is treated as being buffered to a" \
"steady 0.08 uM, which is the resting level. "
call /kinetics/AA/notes LOAD \
"Arachidonic Acid. This messenger diffuses through membranes" \
"as well as cytosolically, has been suggested as a possible" \
"retrograde messenger at synapses. "
call /kinetics/PKC-active/notes LOAD \
"This is the total active PKC. It is the sum of the respective" \
"activities of " \
"PKC-basal*" \
"PKC-Ca-memb*" \
"PKC-DAG-memb*" \
"PKC-Ca-AA*" \
"PKC-DAG-AA*" \
"PKC-AA*" \
"I treat PKC here in a two-state manner: Either it is in an active" \
"state (any one of the above list) or it is inactive. No matter what " \
"combination of stimuli activate the PKC, I treat it as having the same" \
"activity. The scaling comes in through the relative amounts of PKC" \
"which bind to the respecive stimuli." \
"The justification for this is the mode of action of PKC, which like" \
"most Ser/Thr kinases has a kinase domain normally bound to and blocked" \
"by a regulatory domain. I assume that all the activators simply free" \
"up the kinase domain." \
"A more general model would incorporate a different enzyme activity for" \
"each combination of activating inputs, as well as for each substrate." \
"The current model seems to be a decent and much simpler approximation" \
"for the available data." \
"One caveat of this way of representing PKC is that the summation" \
"procedure assumes that PKC does not saturate with its substrates. " \
"If this assumption fails, then the contributing PKC complexes would" \
"experience changes in availability which would affect their " \
"balance. Given the relatively low percentage of PKC usually activated," \
"and its high throughput as an enzyme, this is a safe assumption under" \
"physiological conditions." \
""
call /kinetics/PKC-active/PKC-act-raf/notes LOAD \
"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" \
"" \
""
call /kinetics/PKC-active/PKC-inact-GAP/notes LOAD \
"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."
call /kinetics/PKC-active/PKC-act-GEF/notes LOAD \
"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." \
""
call /kinetics/MAPK/notes LOAD \
"The Mitogen Activated Protein Kinase (MAPK) cascade model " \
"here includes both the MAPK cascade and" \
"its regulation by two forms of MKP. MKP-1 is induced upon MAPK" \
"activation, whereas MKP-2 is treated as a steady level of" \
"protein. The phosphatase Protein phosphatase 2 A (PP2A) " \
"is also included in this model to balance the activity of" \
"the kinases."
call /kinetics/MAPK/craf-1/notes LOAD \
"Strom et al 1990 Oncogene 5 pp 345-51 report high general expression" \
"in all tissues." \
"Huang and Ferrell 1996 PNAS 93(19):10078 use a value of 3 nM for oocytes." \
"Here we stick with a much higher expression based on the Strom report." \
""
call /kinetics/MAPK/craf-1*/notes LOAD \
"Singly phosphorylated form of c-raf-1. This is the form that gets" \
"best activated by GTP.Ras."
call /kinetics/MAPK/MAPKK/notes LOAD \
"Conc is from Seger et al JBC 267:20 pp14373 (1992)" \
"mwt is 45/46 Kd" \
"We assume that phosphorylation on both ser and thr is needed for" \
"activiation. See Kyriakis et al Nature 358 417 1992" \
"Init conc of total is 0.18" \
""
call /kinetics/MAPK/MAPK/notes LOAD \
"Mol wt is 42 KDa." \
"conc is from Sanghera et al JBC 265 pp 52 (1990)" \
"They estimate MAPK is 1e-4x total protein, and protein is 15% of cell wt," \
"so MAPK is 1.5e-5g/ml = 0.36uM." \
"Lets use this." \
"Note though that Huang and Ferrell 1996 PNAS 93(19):10078" \
"report 1.2 uM in oocytes." \
"Also note that brain concs may be high." \
"Ortiz et al 1995 J. Neurosci 15(2):1285-1297 report " \
"0.3 ng/ug protein in Cingulate Gyrus and 1.2 ng/ug protein" \
"in nucleus accumbens. In hippocampus 270 ng/mg protein for ERK1 and" \
"820 ng/mg protein for ERK 2. " \
"If 15% of cell weight is protein, that means that about 300 * 0.15 ng/ul" \
"is ERK 1. ie, 45e-9g/1e-6 litre = 45 mg/litre or about 1 uM. " \
"For non-neuronal tissues a lower value may be better."
call /kinetics/MAPK/craf-1**/notes LOAD \
"Negative feedback by MAPK* by hyperphosphorylating craf-1* gives" \
"rise to this pool." \
"Ueki et al JBC 269(22):15756-15761, 1994" \
""
call /kinetics/MAPK/MAPK-tyr/notes LOAD \
"Haystead et al FEBS Lett. 306(1) pp 17-22 show that phosphorylation" \
"is strictly sequential, first tyr185 then thr183."
call /kinetics/MAPK/MAPKK*/notes LOAD \
"MAPKK phosphorylates MAPK on both the tyr and thr residues, first" \
"tyr then thr. Refs: Seger et al JBC267:20 pp 14373 1992" \
"The MAPKK itself is phosphorylated on ser as well as thr residues." \
"Let us assume that the ser goes first, and that the sequential phosphorylation" \
"is needed. See Kyriakis et al Nature 358 417-421 1992"
call /kinetics/MAPK/MAPKK*/MAPKKtyr/notes LOAD \
"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."
call /kinetics/MAPK/MAPKK*/MAPKKthr/notes LOAD \
"Rate consts same as for MAPKKtyr."
call /kinetics/MAPK/MAPKK-ser/notes LOAD \
"Intermediately phophorylated, assumed inactive, form of MAPKK"
call /kinetics/MAPK/RGR/notes LOAD \
"Shorthand name for Raf.GTP.Ras. This refers to the complex between" \
"GTP.Ras and the unphosphorylated Raf. I treat this as having the " \
"same enzyme activity as the Raf*.GTP.Ras form."
call /kinetics/MAPK/RGR/RGR.1/notes LOAD \
"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." \
""
call /kinetics/MAPK/RGR/RGR.2/notes LOAD \
"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" \
""
call /kinetics/MAPK/Raf*-GTP-Ras/notes LOAD \
"This is the main activated form of craf. It requires binding to ras for" \
"activation, but the presence of the phosphorylation increases this" \
"binding. See Leevers 1994 Nature 369:411-414 and" \
"Hallberg et al 1994 JBC 269(6):3913-3916"
call /kinetics/MAPK/Raf*-GTP-Ras/Raf*-GTP-Ras.1/notes LOAD \
"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." \
"" \
""
call /kinetics/MAPK/Raf*-GTP-Ras/Raf*-GTP-Ras.2/notes LOAD \
"Same kinetics as other c-raf activated forms. See " \
"Force et al PNAS 91 1270-1274 1994." \
""
call /kinetics/MAPK*/notes LOAD \
"This molecule is phosphorylated on both the tyr and thr residues and" \
"is active: Seger et al 1992 JBC 267(20):14373" \
"The rate consts are from two sources: Combine Sanghera et al" \
"JBC 265(1) :52-57 with Nemenoff et al JBC 93 pp 1960 to get" \
" k3 = 10, k2 = 40, k1 = 3.25e-6"
call /kinetics/MAPK*/MAPK*-feedback/notes LOAD \
"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."
call /kinetics/MAPK*/MAPK*/notes LOAD \
"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." \
""