//genesis // kkit Version 11 flat dumpfile // Saved on Fri Dec 8 13:51:22 2006 include kkit {argv 1} FASTDT = 1e-05 SIMDT = 0.001 CONTROLDT = 10 PLOTDT = 1 MAXTIME = 2000 TRANSIENT_TIME = 2 VARIABLE_DT_FLAG = 1 DEFAULT_VOL = 1.257e-16 VERSION = 11.0 setfield /file/modpath value /home2/bhalla/scripts/modules kparms //genesis initdump -version 3 -ignoreorphans 1 simobjdump doqcsinfo filename accessname accesstype transcriber developer \ citation species tissue cellcompartment methodology sources \ model_implementation model_validation x y z 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 geometry size dim shape outside xtree_fg_req xtree_textfg_req x y \ z simobjdump kpool DiffConst CoInit Co n nInit mwt nMin vol slave_enable \ geomname 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 transport input output alloced step_mode stepsize dt delay clock \ kf xtree_fg_req xtree_textfg_req x y z simobjdump proto x y z simundump geometry /kinetics/dendgeom 0 1.5e-18 3 cylinder "" white black 8 \ -2 0 simundump group /kinetics/PKC 0 blue black x 0 0 "" defaultfile defaultfile.g \ 0 0 0 -3.0493 8.2163 0 simundump kpool /kinetics/PKC/PKC-Ca 0 -1e-12 3.7208e-17 3.7208e-17 \ 2.8062e-12 2.8062e-12 0 0 75420 0 /kinetics/dendgeom red black -4.0752 \ 1.5108 0 simundump kreac /kinetics/PKC/PKC-act-by-Ca 0 7.9555e-06 0.5 "" white blue \ -4.0752 -0.12295 0 simundump kreac /kinetics/PKC/PKC-act-by-DAG 0 1.0607e-07 8.6348 "" white \ blue -2.0612 0.69395 0 simundump kreac /kinetics/PKC/PKC-Ca-to-memb 0 1.2705 3.5026 "" white blue \ -3.7974 4.2533 0 simundump kreac /kinetics/PKC/PKC-DAG-to-memb 0 1 0.1 "" white blue -2.6168 \ 2.7362 0 simundump kpool /kinetics/PKC/PKC-Ca-memb* 0 -1e-12 1.3896e-17 1.3896e-17 \ 1.048e-12 1.048e-12 0 0 75420 0 /kinetics/dendgeom pink blue -2.7788 6.529 \ 0 simundump kpool /kinetics/PKC/PKC-DAG-memb* 0 -1e-12 9.4352e-21 9.4352e-21 \ 7.116e-16 7.116e-16 0 0 75420 0 /kinetics/dendgeom yellow blue -1.8297 \ 5.5078 0 simundump kpool /kinetics/PKC/PKC-Ca-DAG 0 -1e-12 8.4631e-23 8.4631e-23 \ 6.3829e-18 6.3829e-18 0 0 75420 0 /kinetics/dendgeom white blue 0.2306 \ 1.8026 0 simundump kreac /kinetics/PKC/PKC-n-DAG 0 7.9555e-09 0.1 "" white blue \ -3.0103 -1.9902 0 simundump kpool /kinetics/PKC/PKC-DAG 0 -1e-12 1.161e-16 1.161e-16 8.7563e-12 \ 8.7563e-12 0 0 75420 0 /kinetics/dendgeom white blue -0.99631 -1.0857 0 simundump kpool /kinetics/PKC/PKC-cytosolic 0 -1e-12 1 1 75420 75420 0 0 \ 75420 0 /kinetics/dendgeom white blue -6.1315 0.59711 0 simundump kpool /kinetics/PKC/PKM-zeta 0 -1e-12 0.01 0.01 754.2 754.2 0 0 \ 75420 0 /kinetics/dendgeom cyan blue -3 11 0 simundump kpool /kinetics/DAG 1 -1e-12 12.2 12.2 9.2012e+05 9.2012e+05 0 0 \ 75420 4 /kinetics/dendgeom green black 4 -3 0 simundump kpool /kinetics/PKC-active 1 -1e-12 0 0.01 754.2 0 0 0 75420 2 \ /kinetics/dendgeom red black 0 9 0 simundump kenz /kinetics/PKC-active/PKC-act-raf 1 0 0 0 0 75420 1.3259e-05 16 \ 4 0 0 "" red yellow "" 6 10 0 simundump kenz /kinetics/PKC-active/PKC-inact-GAP 1 0 0 0 0 0.1257 7.9555e-05 \ 16 4 0 0 "" red yellow "" 4 13 0 simundump kenz /kinetics/PKC-active/PKC-act-GEF 1 0 0 0 0 0.1257 7.9555e-05 \ 16 4 0 0 "" red yellow "" 9 20 0 simundump kpool /kinetics/MAPK* 1 -1e-12 0 0 0 0 0 0 75420 0 \ /kinetics/dendgeom orange yellow 13 1 0 simundump kenz /kinetics/MAPK*/MAPK*-feedback 1 0 0 0 0 75420 2.5856e-05 40 \ 10 0 0 "" red orange "" 10 10 0 simundump group /kinetics/MAPK 0 brown black x 0 0 "" defaultfile \ defaultfile.g 0 0 0 15 11 0 simundump kpool /kinetics/MAPK/craf-1 0 0 0.5 0.5 37710 37710 0 0 75420 0 \ /kinetics/dendgeom pink brown 6 8 0 simundump kpool /kinetics/MAPK/craf-1* 0 0 0 0 0 0 0 0 75420 0 \ /kinetics/dendgeom pink brown 9 8 0 simundump kpool /kinetics/MAPK/MAPKK 0 0 0.5 0.5 37710 37710 0 0 75420 0 \ /kinetics/dendgeom pink brown 6 4 0 simundump kpool /kinetics/MAPK/MAPK 0 -1e-12 3.6 3.6 2.7151e+05 2.7151e+05 0 \ 0 75420 0 /kinetics/dendgeom pink brown 6 1 0 simundump kpool /kinetics/MAPK/craf-1** 1 0 0 0 0 0 0 0 75420 0 \ /kinetics/dendgeom hotpink brown 12 8 0 simundump kpool /kinetics/MAPK/MAPK-tyr 1 -1e-12 0 0 0 0 0 0 75420 0 \ /kinetics/dendgeom orange brown 9 1 0 simundump kpool /kinetics/MAPK/MAPKK* 0 0 0 0 0 0 0 0 75420 0 \ /kinetics/dendgeom pink brown 13 4 0 simundump kenz /kinetics/MAPK/MAPKK*/MAPKKtyr 0 0 0 0 0 75420 0.00042959 1.2 \ 0.3 0 0 "" red pink "" 8 3 0 simundump kenz /kinetics/MAPK/MAPKK*/MAPKKthr 1 0 0 0 0 75420 0.00042959 1.2 \ 0.3 0 0 "" red pink "" 13 3 0 simundump kpool /kinetics/MAPK/MAPKK-ser 1 0 0 0 0 0 0 0 75420 0 \ /kinetics/dendgeom pink brown 9 4 0 simundump kpool /kinetics/MAPK/Raf-GTP-Ras 0 0 0 0 0 0 0 0 75420 0 \ /kinetics/dendgeom 55 brown 5 6 0 simundump kenz /kinetics/MAPK/Raf-GTP-Ras/Raf-GTP-Ras.1 0 0 0 0 0 75420 \ 0.00012501 1.2 0.3 0 0 "" red 55 "" 8 6 0 simundump kenz /kinetics/MAPK/Raf-GTP-Ras/Raf-GTP-Ras.2 0 0 0 0 0 75420 \ 0.00012501 1.2 0.3 0 0 "" red 55 "" 11 6 0 simundump kpool /kinetics/MAPK/Raf*-GTP-Ras 1 0 0 0 0 0 0 0 75420 0 \ /kinetics/dendgeom red brown 5 5 0 simundump kenz /kinetics/MAPK/Raf*-GTP-Ras/Raf*-GTP-Ras.1 1 0 0 0 0 0.1257 \ 0.00012501 1.2 0.3 0 0 "" red red "" 8 5 0 simundump kenz /kinetics/MAPK/Raf*-GTP-Ras/Raf*-GTP-Ras.2 1 0 0 0 0 0.1257 \ 0.00012501 1.2 0.3 0 0 "" red red "" 11 5 0 simundump kpool /kinetics/MKP-1 1 -1e-12 0.02 0.02 1508.4 1508.4 0 0 75420 0 \ /kinetics/dendgeom hotpink black 5 2 0 simundump kenz /kinetics/MKP-1/MKP1-tyr-deph 1 0 0 0 0 75420 3.7883e-05 16 4 \ 0 0 "" red hotpink "" 6 3 0 simundump kenz /kinetics/MKP-1/MKP1-thr-deph 1 0 0 0 0 75420 3.7883e-05 16 4 \ 0 0 "" red hotpink "" 11 3 0 simundump kreac /kinetics/Ras-act-craf 1 0.00013259 0.5 "" white black 3 9 0 simundump kpool /kinetics/PPhosphatase2A 1 -1e-12 1 1 75420 75420 0 0 75420 0 \ /kinetics/dendgeom hotpink yellow 9 9 0 simundump kenz /kinetics/PPhosphatase2A/craf-deph 1 0 0 0 0 75420 2.5406e-05 \ 24 6 0 0 "" red hotpink "" 8 10 0 simundump kenz /kinetics/PPhosphatase2A/MAPKK-deph 1 0 0 0 0 75420 2.5406e-05 \ 24 6 0 0 "" red hotpink "" 11 7 0 simundump kenz /kinetics/PPhosphatase2A/MAPKK-deph-ser 1 0 0 0 0 75420 \ 2.5406e-05 24 6 0 0 "" red hotpink "" 8 7 0 simundump kenz /kinetics/PPhosphatase2A/craf**-deph 1 0 0 0 0 0.1257 \ 2.5406e-05 24 6 0 0 "" red hotpink "" 12 10 0 simundump group /kinetics/Ras 1 blue black x 0 0 "" defaultfile defaultfile.g \ 0 0 0 14.513 16.351 0 simundump kreac /kinetics/Ras/dephosph-GEF 1 1 0 "" white blue 9.0702 17.881 \ 0 simundump kpool /kinetics/Ras/inact-GEF 1 -1e-12 0.1 0.1 7542 7542 0 0 75420 \ 0 /kinetics/dendgeom hotpink blue 12.453 18.352 0 simundump kenz /kinetics/Ras/inact-GEF/basal_GEF_activity 0 0 0 0 0 75420 \ 1.3126e-07 0.08 0.02 0 0 "" red hotpink "" 12 17 0 simundump kpool /kinetics/Ras/GEF* 1 -1e-12 0 0 0 0 0 0 75420 0 \ /kinetics/dendgeom hotpink blue 6.4483 17.246 0 simundump kenz /kinetics/Ras/GEF*/GEF*-act-ras 1 0 0 0 0 75420 2.6253e-06 \ 0.08 0.02 0 0 "" red hotpink "" 7.0855 16.086 0 simundump kpool /kinetics/Ras/GTP-Ras 1 0 0 0 0 0 0 0 75420 0 \ /kinetics/dendgeom orange blue 12.564 13.084 0 simundump kpool /kinetics/Ras/GDP-Ras 1 0 0.5 0.5 37710 37710 0 0 75420 0 \ /kinetics/dendgeom pink blue 6.1309 14.165 0 simundump kreac /kinetics/Ras/Ras-intrinsic-GTPase 1 1e-04 0 "" white blue \ 9.0979 13.5 0 simundump kreac /kinetics/Ras/dephosph-GAP 1 0.1 0 "" white blue 4.0234 \ 15.524 0 simundump kpool /kinetics/Ras/GAP* 1 -1e-12 0 0 0 0 0 0 75420 0 \ /kinetics/dendgeom red blue 1.3498 14.349 0 simundump kpool /kinetics/Ras/GAP 1 -1e-12 0.01 0.01 754.2 754.2 0 0 75420 0 \ /kinetics/dendgeom red blue 6.6549 12.338 0 simundump kenz /kinetics/Ras/GAP/GAP-inact-ras 1 0 0 0 0 75420 0.00065613 40 \ 10 0 0 "" red red "" 9.0121 12.403 0 simundump kreac /kinetics/Ras/CaM-bind-GEF 1 0.0026518 1 "" white blue 2.4861 \ 21.679 0 simundump kpool /kinetics/Ras/CaM-GEF 1 -1e-12 0 0 0 0 0 0 75420 0 \ /kinetics/dendgeom pink blue 5.3451 19.58 0 simundump kenz /kinetics/Ras/CaM-GEF/CaM-GEF-act-ras 1 0 0 0 0 75420 \ 2.6253e-05 0.8 0.2 0 0 "" red pink "" 5.0223 18.657 0 simundump group /kinetics/CaM 1 blue black x 0 0 "" defaultfile defaultfile.g \ 0 0 0 -10 21 0 simundump kpool /kinetics/CaM/CaM 1 -1e-12 20 20 1.5084e+06 1.5084e+06 0 0 \ 75420 0 /kinetics/dendgeom pink blue -13 30 0 simundump kreac /kinetics/CaM/CaM-Ca3-bind-Ca 1 6.1655e-06 10 "" white blue \ -10.4 23.26 0 simundump kpool /kinetics/CaM/CaM-Ca3 1 -1e-12 0 0 0 0 0 0 75420 0 \ /kinetics/dendgeom hotpink blue -6.511 24.397 0 simundump kpool /kinetics/CaM/CaM-Ca4 1 -1e-12 0 0 0 0 0 0 75420 0 \ /kinetics/dendgeom blue blue -2 24 0 simundump kreac /kinetics/CaM/CaM-bind-Ca 1 0.0001125 8.4853 "" white blue \ -10 30 0 simundump kpool /kinetics/CaM/CaM-Ca2 1 -1e-12 0 0 0 0 0 0 75420 0 \ /kinetics/dendgeom pink blue -5.001 27.258 0 simundump kreac /kinetics/CaM/CaM-Ca2-bind-Ca 1 4.7733e-05 10 "" white blue \ -8.842 26.225 0 simundump kreac /kinetics/CaM/CaM-Ca-bind-Ca 1 0.0001125 8.4853 "" white blue \ -4 30 0 simundump kpool /kinetics/CaM/CaM-Ca 1 -1e-12 0 0 0 0 0 0 75420 0 \ /kinetics/dendgeom pink blue -7 31 0 simundump kpool /kinetics/Ca 1 -1e-12 0.08 0.08 6033.6 6033.6 0 0 75420 0 \ /kinetics/dendgeom red black -18 23 0 simundump kreac /kinetics/Ras-act-unphosph-raf 0 0 0 "" white black 4 8 0 simundump group /kinetics/PKM 0 25 black x 0 0 "" PKM defaultfile.g 0 \ 5dc016e940e88c1cc7928f4e096ff523 0 -7 19 0 simundump kpool /kinetics/PKM/Ca_detector 0 -1e-12 1 1 75420 75420 0 0 75420 \ 0 /kinetics/dendgeom 7 25 -11 17 0 simundump kpool /kinetics/PKM/PKM_synthesis 0 -1e-12 0.001 0.001 75.42 75.42 \ 0 0 75420 0 /kinetics/dendgeom 8 25 -11 9 0 simundump kenz /kinetics/PKM/PKM_synthesis/kenz 0 0 0 0 0 75420 3.3148e-07 \ 0.2 0.05 0 0 "" red 8 "" -10 10 0 simundump kpool /kinetics/PKM/AA_pool 0 -1e-12 1 1 75420 75420 0 0 75420 4 \ /kinetics/dendgeom 9 25 -7 12 0 simundump kreac /kinetics/PKM/PKM_degradation 0 0.0005 0 "" white 25 -8 7 0 simundump kpool /kinetics/PKM/degraded_PKM 0 -1e-12 0 0 0 0 0 0 75420 4 \ /kinetics/dendgeom 7 25 -12 5 0 simundump kpool /kinetics/PKM/Ca.detector_complex 0 -1e-12 0 0 0 0 0 0 75420 \ 0 /kinetics/dendgeom 7 25 -12 14 0 simundump kenz /kinetics/PKM/Ca.detector_complex/kenz 0 0 0 0 0 75420 \ 2.6518e-06 0.8 0.2 0 0 "" red 7 "" -12 13 0 simundump kpool /kinetics/PKM/PKM_activator 0 -1e-12 0.2 0.2 15084 15084 0 0 \ 75420 0 /kinetics/dendgeom 6 25 -15 12 0 simundump kreac /kinetics/PKM/turn_off_activator 0 0.001 0 "" white 25 -17 9 \ 0 simundump kreac /kinetics/PKM/trigger_PKM 0 0.00013259 1 "" white 25 -17 16 0 simundump kpool /kinetics/Ca_input 0 0 0.08 0.08 6033.6 6033.6 0 0 75420 4 \ /kinetics/dendgeom 61 black -18 30 0 simundump kreac /kinetics/Ca_diff 0 5 5 "" white black -18 26 0 simundump doqcsinfo /kinetics/doqcsinfo 0 Ajay_Bhalla_2007_PKM.g \ Ajay_Bhalla_2007_PKM network "Upinder S. Bhalla, NCBS" \ "Upinder S. Bhalla, NCBS" "citation here" Rat "Hippcampal CA1" Dendrite \ "Semi-Quantitative match to experiments" "Ajay_Bhalla_PKM ( Under Review )" \ "Exact GENESIS implementation" "Replicates original data " 0 0 0 simundump xgraph /graphs/conc1 0 0 4001 0.00087037 0.10434 0 simundump xgraph /graphs/conc2 0 0 4001 0 0.088747 0 simundump xplot /graphs/conc1/PKC-active.Co 3 524288 \ "delete_plot.w ; edit_plot.D " red 0 0 1 simundump xplot /graphs/conc2/PKC-Ca.Co 3 524288 \ "delete_plot.w ; edit_plot.D " red 0 0 1 simundump xgraph /moregraphs/conc3 0 0 4001 0 1 0 simundump xgraph /moregraphs/conc4 0 0 4001 0 1 0 simundump xcoredraw /edit/draw 0 -20 17 -5 33 simundump xtree /edit/draw/tree 0 \ /kinetics/#[],/kinetics/#[]/#[],/kinetics/#[]/#[]/#[][TYPE!=proto],/kinetics/#[]/#[]/#[][TYPE!=linkinfo]/##[] \ "edit_elm.D ; drag_from_edit.w " auto 0.6 simundump xtext /file/notes 0 1 xtextload /file/notes \ "27 Feb 2006. Updated version of pkm_mapk1.g Set up diffusion constants," \ "or more accurately, decided which molecules should not diffuse." \ "2 March 2006. Based on pkm_mapk2.g, just added Ca_input and" \ "Ca_diff to set up the propagation model with slightly smoother" \ "Ca transients. This matches the PKC-MAPK bis model." \ "Saved as pkm_mapk3.g" \ "13 Mar 2006. Speeded up rates of trigger_PKM 10x from the " \ "pkm_mapk3.g model. Also speeded up Ca_diff rates from tau of 0.25" \ "to tau of 0.1" \ "Saved as pkm_mapk12.g" \ "13 Mar 2006. Same as previous, except the trigger_PKM Kd is" \ "now 1.4142. Saved as" \ "pkm_mapk13.g" \ "17 Marh 2006. Changed Ca trigger for PKM Synthesis to depend on" \ "Ca4.CaM. Also scaled up CaM-GEF-act-ras kcat from 0.02 to 0.4." \ "Saved as pkm_mapk20.g" \ "17 March. Based on pkm_mapk20.g Changed CaM-GEF-act-ras kcat " \ "to 0.2." \ "Saved as pkm_mapk21.g" \ "" \ "19 May 2006. Based on pkm_mapk21.g. Split up initial step of" \ "2Ca binding to CaM into two reactions, in each of which 1 Ca" \ "binds. Improves numerical stability but overall equil should" \ "not change. " \ "Saved as pkm_mapk22.g" \ "" \ "" addmsg /kinetics/PKC/PKC-act-by-Ca /kinetics/PKC/PKC-Ca REAC B A addmsg /kinetics/PKC/PKC-act-by-DAG /kinetics/PKC/PKC-Ca REAC A B addmsg /kinetics/PKC/PKC-Ca-to-memb /kinetics/PKC/PKC-Ca REAC A B addmsg /kinetics/PKC/PKC-cytosolic /kinetics/PKC/PKC-act-by-Ca SUBSTRATE n addmsg /kinetics/Ca /kinetics/PKC/PKC-act-by-Ca SUBSTRATE n addmsg /kinetics/PKC/PKC-Ca /kinetics/PKC/PKC-act-by-Ca PRODUCT n addmsg /kinetics/DAG /kinetics/PKC/PKC-act-by-DAG SUBSTRATE n addmsg /kinetics/PKC/PKC-Ca /kinetics/PKC/PKC-act-by-DAG SUBSTRATE n addmsg /kinetics/PKC/PKC-Ca-DAG /kinetics/PKC/PKC-act-by-DAG PRODUCT n addmsg /kinetics/PKC/PKC-Ca /kinetics/PKC/PKC-Ca-to-memb SUBSTRATE n addmsg /kinetics/PKC/PKC-Ca-memb* /kinetics/PKC/PKC-Ca-to-memb PRODUCT n addmsg /kinetics/PKC/PKC-Ca-DAG /kinetics/PKC/PKC-DAG-to-memb SUBSTRATE n addmsg /kinetics/PKC/PKC-DAG-memb* /kinetics/PKC/PKC-DAG-to-memb PRODUCT n addmsg /kinetics/PKC/PKC-Ca-to-memb /kinetics/PKC/PKC-Ca-memb* REAC B A addmsg /kinetics/PKC/PKC-DAG-to-memb /kinetics/PKC/PKC-DAG-memb* REAC B A addmsg /kinetics/PKC/PKC-act-by-DAG /kinetics/PKC/PKC-Ca-DAG REAC B A addmsg /kinetics/PKC/PKC-DAG-to-memb /kinetics/PKC/PKC-Ca-DAG REAC A B addmsg /kinetics/PKC/PKC-cytosolic /kinetics/PKC/PKC-n-DAG SUBSTRATE n addmsg /kinetics/DAG /kinetics/PKC/PKC-n-DAG SUBSTRATE n addmsg /kinetics/PKC/PKC-DAG /kinetics/PKC/PKC-n-DAG PRODUCT n addmsg /kinetics/PKC/PKC-n-DAG /kinetics/PKC/PKC-DAG REAC B A addmsg /kinetics/PKC/PKC-act-by-Ca /kinetics/PKC/PKC-cytosolic REAC A B addmsg /kinetics/PKC/PKC-n-DAG /kinetics/PKC/PKC-cytosolic REAC A B addmsg /kinetics/PKM/PKM_synthesis/kenz /kinetics/PKC/PKM-zeta MM_PRD pA addmsg /kinetics/PKM/PKM_degradation /kinetics/PKC/PKM-zeta REAC A B addmsg /kinetics/PKC/PKC-act-by-DAG /kinetics/DAG REAC A B addmsg /kinetics/PKC/PKC-n-DAG /kinetics/DAG REAC A B addmsg /kinetics/PKC/PKC-Ca-memb* /kinetics/PKC-active SUMTOTAL n nInit addmsg /kinetics/PKC/PKC-DAG-memb* /kinetics/PKC-active SUMTOTAL n nInit addmsg /kinetics/PKC-active/PKC-act-raf /kinetics/PKC-active REAC eA B addmsg /kinetics/PKC-active/PKC-inact-GAP /kinetics/PKC-active REAC eA B addmsg /kinetics/PKC-active/PKC-act-GEF /kinetics/PKC-active REAC eA B addmsg /kinetics/PKC/PKM-zeta /kinetics/PKC-active SUMTOTAL n nInit addmsg /kinetics/PKC-active /kinetics/PKC-active/PKC-act-raf ENZYME n addmsg /kinetics/MAPK/craf-1 /kinetics/PKC-active/PKC-act-raf SUBSTRATE n addmsg /kinetics/PKC-active /kinetics/PKC-active/PKC-inact-GAP ENZYME n addmsg /kinetics/Ras/GAP /kinetics/PKC-active/PKC-inact-GAP SUBSTRATE n addmsg /kinetics/PKC-active /kinetics/PKC-active/PKC-act-GEF ENZYME n addmsg /kinetics/Ras/inact-GEF /kinetics/PKC-active/PKC-act-GEF SUBSTRATE n addmsg /kinetics/MAPK*/MAPK*-feedback /kinetics/MAPK* REAC eA B addmsg /kinetics/MAPK/MAPKK*/MAPKKthr /kinetics/MAPK* MM_PRD pA addmsg /kinetics/MKP-1/MKP1-thr-deph /kinetics/MAPK* REAC sA B addmsg /kinetics/MAPK* /kinetics/MAPK*/MAPK*-feedback ENZYME n addmsg /kinetics/MAPK/craf-1* /kinetics/MAPK*/MAPK*-feedback SUBSTRATE n addmsg /kinetics/PKC-active/PKC-act-raf /kinetics/MAPK/craf-1 REAC sA B addmsg /kinetics/PPhosphatase2A/craf-deph /kinetics/MAPK/craf-1 MM_PRD pA addmsg /kinetics/Ras-act-unphosph-raf /kinetics/MAPK/craf-1 REAC A B addmsg /kinetics/PKC-active/PKC-act-raf /kinetics/MAPK/craf-1* MM_PRD pA addmsg /kinetics/MAPK*/MAPK*-feedback /kinetics/MAPK/craf-1* REAC sA B addmsg /kinetics/PPhosphatase2A/craf-deph /kinetics/MAPK/craf-1* REAC sA B addmsg /kinetics/PPhosphatase2A/craf**-deph /kinetics/MAPK/craf-1* MM_PRD pA addmsg /kinetics/Ras-act-craf /kinetics/MAPK/craf-1* REAC A B addmsg /kinetics/PPhosphatase2A/MAPKK-deph-ser /kinetics/MAPK/MAPKK MM_PRD pA addmsg /kinetics/MAPK/Raf*-GTP-Ras/Raf*-GTP-Ras.1 /kinetics/MAPK/MAPKK REAC sA B addmsg /kinetics/MAPK/Raf-GTP-Ras/Raf-GTP-Ras.1 /kinetics/MAPK/MAPKK REAC sA B addmsg /kinetics/MAPK/MAPKK*/MAPKKtyr /kinetics/MAPK/MAPK REAC sA B addmsg /kinetics/MKP-1/MKP1-tyr-deph /kinetics/MAPK/MAPK MM_PRD pA addmsg /kinetics/MAPK*/MAPK*-feedback /kinetics/MAPK/craf-1** MM_PRD pA addmsg /kinetics/PPhosphatase2A/craf**-deph /kinetics/MAPK/craf-1** REAC sA B addmsg /kinetics/MAPK/MAPKK*/MAPKKtyr /kinetics/MAPK/MAPK-tyr MM_PRD pA addmsg /kinetics/MAPK/MAPKK*/MAPKKthr /kinetics/MAPK/MAPK-tyr REAC sA B addmsg /kinetics/MKP-1/MKP1-tyr-deph /kinetics/MAPK/MAPK-tyr REAC sA B addmsg /kinetics/MKP-1/MKP1-thr-deph /kinetics/MAPK/MAPK-tyr MM_PRD pA addmsg /kinetics/MAPK/MAPKK*/MAPKKtyr /kinetics/MAPK/MAPKK* REAC eA B addmsg /kinetics/MAPK/MAPKK*/MAPKKthr /kinetics/MAPK/MAPKK* REAC eA B addmsg /kinetics/PPhosphatase2A/MAPKK-deph /kinetics/MAPK/MAPKK* REAC sA B addmsg /kinetics/MAPK/Raf*-GTP-Ras/Raf*-GTP-Ras.2 /kinetics/MAPK/MAPKK* MM_PRD pA addmsg /kinetics/MAPK/Raf-GTP-Ras/Raf-GTP-Ras.2 /kinetics/MAPK/MAPKK* MM_PRD pA addmsg /kinetics/MAPK/MAPKK* /kinetics/MAPK/MAPKK*/MAPKKtyr ENZYME n addmsg /kinetics/MAPK/MAPK /kinetics/MAPK/MAPKK*/MAPKKtyr SUBSTRATE n addmsg /kinetics/MAPK/MAPKK* /kinetics/MAPK/MAPKK*/MAPKKthr ENZYME n addmsg /kinetics/MAPK/MAPK-tyr /kinetics/MAPK/MAPKK*/MAPKKthr SUBSTRATE n addmsg /kinetics/PPhosphatase2A/MAPKK-deph /kinetics/MAPK/MAPKK-ser MM_PRD pA addmsg /kinetics/PPhosphatase2A/MAPKK-deph-ser /kinetics/MAPK/MAPKK-ser REAC sA B addmsg /kinetics/MAPK/Raf*-GTP-Ras/Raf*-GTP-Ras.1 /kinetics/MAPK/MAPKK-ser MM_PRD pA addmsg /kinetics/MAPK/Raf*-GTP-Ras/Raf*-GTP-Ras.2 /kinetics/MAPK/MAPKK-ser REAC sA B addmsg /kinetics/MAPK/Raf-GTP-Ras/Raf-GTP-Ras.1 /kinetics/MAPK/MAPKK-ser MM_PRD pA addmsg /kinetics/MAPK/Raf-GTP-Ras/Raf-GTP-Ras.2 /kinetics/MAPK/MAPKK-ser REAC sA B addmsg /kinetics/Ras-act-unphosph-raf /kinetics/MAPK/Raf-GTP-Ras REAC B A addmsg /kinetics/MAPK/Raf-GTP-Ras/Raf-GTP-Ras.1 /kinetics/MAPK/Raf-GTP-Ras REAC eA B addmsg /kinetics/MAPK/Raf-GTP-Ras/Raf-GTP-Ras.2 /kinetics/MAPK/Raf-GTP-Ras REAC eA B addmsg /kinetics/MAPK/Raf-GTP-Ras /kinetics/MAPK/Raf-GTP-Ras/Raf-GTP-Ras.1 ENZYME n addmsg /kinetics/MAPK/MAPKK /kinetics/MAPK/Raf-GTP-Ras/Raf-GTP-Ras.1 SUBSTRATE n addmsg /kinetics/MAPK/Raf-GTP-Ras /kinetics/MAPK/Raf-GTP-Ras/Raf-GTP-Ras.2 ENZYME n addmsg /kinetics/MAPK/MAPKK-ser /kinetics/MAPK/Raf-GTP-Ras/Raf-GTP-Ras.2 SUBSTRATE n addmsg /kinetics/Ras-act-craf /kinetics/MAPK/Raf*-GTP-Ras REAC B A addmsg /kinetics/MAPK/Raf*-GTP-Ras/Raf*-GTP-Ras.1 /kinetics/MAPK/Raf*-GTP-Ras REAC eA B addmsg /kinetics/MAPK/Raf*-GTP-Ras/Raf*-GTP-Ras.2 /kinetics/MAPK/Raf*-GTP-Ras REAC eA B addmsg /kinetics/MAPK/Raf*-GTP-Ras /kinetics/MAPK/Raf*-GTP-Ras/Raf*-GTP-Ras.1 ENZYME n addmsg /kinetics/MAPK/MAPKK /kinetics/MAPK/Raf*-GTP-Ras/Raf*-GTP-Ras.1 SUBSTRATE n addmsg /kinetics/MAPK/Raf*-GTP-Ras /kinetics/MAPK/Raf*-GTP-Ras/Raf*-GTP-Ras.2 ENZYME n addmsg /kinetics/MAPK/MAPKK-ser /kinetics/MAPK/Raf*-GTP-Ras/Raf*-GTP-Ras.2 SUBSTRATE n addmsg /kinetics/MKP-1/MKP1-tyr-deph /kinetics/MKP-1 REAC eA B addmsg /kinetics/MKP-1/MKP1-thr-deph /kinetics/MKP-1 REAC eA B addmsg /kinetics/MKP-1 /kinetics/MKP-1/MKP1-tyr-deph ENZYME n addmsg /kinetics/MAPK/MAPK-tyr /kinetics/MKP-1/MKP1-tyr-deph SUBSTRATE n addmsg /kinetics/MKP-1 /kinetics/MKP-1/MKP1-thr-deph ENZYME n addmsg /kinetics/MAPK* /kinetics/MKP-1/MKP1-thr-deph SUBSTRATE n addmsg /kinetics/MAPK/craf-1* /kinetics/Ras-act-craf SUBSTRATE n addmsg /kinetics/Ras/GTP-Ras /kinetics/Ras-act-craf SUBSTRATE n addmsg /kinetics/MAPK/Raf*-GTP-Ras /kinetics/Ras-act-craf PRODUCT n addmsg /kinetics/PPhosphatase2A/craf-deph /kinetics/PPhosphatase2A REAC eA B addmsg /kinetics/PPhosphatase2A/MAPKK-deph /kinetics/PPhosphatase2A REAC eA B addmsg /kinetics/PPhosphatase2A/MAPKK-deph-ser /kinetics/PPhosphatase2A REAC eA B addmsg /kinetics/PPhosphatase2A/craf**-deph /kinetics/PPhosphatase2A REAC eA B addmsg /kinetics/PPhosphatase2A /kinetics/PPhosphatase2A/craf-deph ENZYME n addmsg /kinetics/MAPK/craf-1* /kinetics/PPhosphatase2A/craf-deph SUBSTRATE n addmsg /kinetics/PPhosphatase2A /kinetics/PPhosphatase2A/MAPKK-deph ENZYME n addmsg /kinetics/MAPK/MAPKK* /kinetics/PPhosphatase2A/MAPKK-deph SUBSTRATE n addmsg /kinetics/PPhosphatase2A /kinetics/PPhosphatase2A/MAPKK-deph-ser ENZYME n addmsg /kinetics/MAPK/MAPKK-ser /kinetics/PPhosphatase2A/MAPKK-deph-ser SUBSTRATE n addmsg /kinetics/PPhosphatase2A /kinetics/PPhosphatase2A/craf**-deph ENZYME n addmsg /kinetics/MAPK/craf-1** /kinetics/PPhosphatase2A/craf**-deph SUBSTRATE n 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/Ras/CaM-bind-GEF /kinetics/Ras/inact-GEF REAC A B addmsg /kinetics/Ras/inact-GEF/basal_GEF_activity /kinetics/Ras/inact-GEF REAC eA B addmsg /kinetics/Ras/inact-GEF /kinetics/Ras/inact-GEF/basal_GEF_activity ENZYME n addmsg /kinetics/Ras/GDP-Ras /kinetics/Ras/inact-GEF/basal_GEF_activity SUBSTRATE n 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/CaM-GEF/CaM-GEF-act-ras /kinetics/Ras/GTP-Ras MM_PRD pA addmsg /kinetics/Ras-act-craf /kinetics/Ras/GTP-Ras REAC A B addmsg /kinetics/Ras-act-unphosph-raf /kinetics/Ras/GTP-Ras REAC A B addmsg /kinetics/Ras/inact-GEF/basal_GEF_activity /kinetics/Ras/GTP-Ras MM_PRD pA 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/Ras/CaM-GEF/CaM-GEF-act-ras /kinetics/Ras/GDP-Ras REAC sA B addmsg /kinetics/Ras/inact-GEF/basal_GEF_activity /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/Ras/inact-GEF /kinetics/Ras/CaM-bind-GEF SUBSTRATE n addmsg /kinetics/Ras/CaM-GEF /kinetics/Ras/CaM-bind-GEF PRODUCT n addmsg /kinetics/CaM/CaM-Ca4 /kinetics/Ras/CaM-bind-GEF SUBSTRATE n addmsg /kinetics/Ras/CaM-bind-GEF /kinetics/Ras/CaM-GEF REAC B A addmsg /kinetics/Ras/CaM-GEF/CaM-GEF-act-ras /kinetics/Ras/CaM-GEF REAC eA B addmsg /kinetics/Ras/CaM-GEF /kinetics/Ras/CaM-GEF/CaM-GEF-act-ras ENZYME n addmsg /kinetics/Ras/GDP-Ras /kinetics/Ras/CaM-GEF/CaM-GEF-act-ras SUBSTRATE n addmsg /kinetics/CaM/CaM-bind-Ca /kinetics/CaM/CaM REAC A B addmsg /kinetics/CaM/CaM-Ca3 /kinetics/CaM/CaM-Ca3-bind-Ca SUBSTRATE n addmsg /kinetics/Ca /kinetics/CaM/CaM-Ca3-bind-Ca SUBSTRATE n addmsg /kinetics/CaM/CaM-Ca4 /kinetics/CaM/CaM-Ca3-bind-Ca PRODUCT n addmsg /kinetics/CaM/CaM-Ca2-bind-Ca /kinetics/CaM/CaM-Ca3 REAC B A addmsg /kinetics/CaM/CaM-Ca3-bind-Ca /kinetics/CaM/CaM-Ca3 REAC A B addmsg /kinetics/Ras/CaM-bind-GEF /kinetics/CaM/CaM-Ca4 REAC A B addmsg /kinetics/CaM/CaM-Ca3-bind-Ca /kinetics/CaM/CaM-Ca4 REAC B A addmsg /kinetics/PKM/trigger_PKM /kinetics/CaM/CaM-Ca4 REAC A B addmsg /kinetics/CaM/CaM /kinetics/CaM/CaM-bind-Ca SUBSTRATE n addmsg /kinetics/Ca /kinetics/CaM/CaM-bind-Ca SUBSTRATE n addmsg /kinetics/CaM/CaM-Ca /kinetics/CaM/CaM-bind-Ca PRODUCT n addmsg /kinetics/CaM/CaM-Ca2-bind-Ca /kinetics/CaM/CaM-Ca2 REAC A B addmsg /kinetics/CaM/CaM-Ca-bind-Ca /kinetics/CaM/CaM-Ca2 REAC B A addmsg /kinetics/CaM/CaM-Ca2 /kinetics/CaM/CaM-Ca2-bind-Ca SUBSTRATE n addmsg /kinetics/Ca /kinetics/CaM/CaM-Ca2-bind-Ca SUBSTRATE n addmsg /kinetics/CaM/CaM-Ca3 /kinetics/CaM/CaM-Ca2-bind-Ca PRODUCT n addmsg /kinetics/CaM/CaM-Ca /kinetics/CaM/CaM-Ca-bind-Ca SUBSTRATE n addmsg /kinetics/Ca /kinetics/CaM/CaM-Ca-bind-Ca SUBSTRATE n addmsg /kinetics/CaM/CaM-Ca2 /kinetics/CaM/CaM-Ca-bind-Ca PRODUCT n addmsg /kinetics/CaM/CaM-bind-Ca /kinetics/CaM/CaM-Ca REAC B A addmsg /kinetics/CaM/CaM-Ca-bind-Ca /kinetics/CaM/CaM-Ca REAC A B addmsg /kinetics/PKC/PKC-act-by-Ca /kinetics/Ca REAC A B addmsg /kinetics/CaM/CaM-bind-Ca /kinetics/Ca REAC A B addmsg /kinetics/CaM/CaM-Ca2-bind-Ca /kinetics/Ca REAC A B addmsg /kinetics/CaM/CaM-Ca3-bind-Ca /kinetics/Ca REAC A B addmsg /kinetics/Ca_diff /kinetics/Ca REAC B A addmsg /kinetics/CaM/CaM-Ca-bind-Ca /kinetics/Ca REAC A B addmsg /kinetics/MAPK/craf-1 /kinetics/Ras-act-unphosph-raf SUBSTRATE n addmsg /kinetics/MAPK/Raf-GTP-Ras /kinetics/Ras-act-unphosph-raf PRODUCT n addmsg /kinetics/Ras/GTP-Ras /kinetics/Ras-act-unphosph-raf SUBSTRATE n addmsg /kinetics/PKM/trigger_PKM /kinetics/PKM/Ca_detector REAC A B addmsg /kinetics/PKM/PKM_synthesis/kenz /kinetics/PKM/PKM_synthesis REAC eA B addmsg /kinetics/PKM/Ca.detector_complex/kenz /kinetics/PKM/PKM_synthesis MM_PRD pA addmsg /kinetics/PKM/turn_off_activator /kinetics/PKM/PKM_synthesis REAC A B addmsg /kinetics/PKM/PKM_synthesis /kinetics/PKM/PKM_synthesis/kenz ENZYME n addmsg /kinetics/PKM/AA_pool /kinetics/PKM/PKM_synthesis/kenz SUBSTRATE n addmsg /kinetics/PKM/PKM_synthesis/kenz /kinetics/PKM/AA_pool REAC sA B addmsg /kinetics/PKC/PKM-zeta /kinetics/PKM/PKM_degradation SUBSTRATE n addmsg /kinetics/PKM/degraded_PKM /kinetics/PKM/PKM_degradation PRODUCT n addmsg /kinetics/PKM/PKM_degradation /kinetics/PKM/degraded_PKM REAC B A addmsg /kinetics/PKM/Ca.detector_complex/kenz /kinetics/PKM/Ca.detector_complex REAC eA B addmsg /kinetics/PKM/trigger_PKM /kinetics/PKM/Ca.detector_complex REAC B A addmsg /kinetics/PKM/Ca.detector_complex /kinetics/PKM/Ca.detector_complex/kenz ENZYME n addmsg /kinetics/PKM/PKM_activator /kinetics/PKM/Ca.detector_complex/kenz SUBSTRATE n addmsg /kinetics/PKM/Ca.detector_complex/kenz /kinetics/PKM/PKM_activator REAC sA B addmsg /kinetics/PKM/turn_off_activator /kinetics/PKM/PKM_activator REAC B A addmsg /kinetics/PKM/PKM_synthesis /kinetics/PKM/turn_off_activator SUBSTRATE n addmsg /kinetics/PKM/PKM_activator /kinetics/PKM/turn_off_activator PRODUCT n addmsg /kinetics/PKM/Ca_detector /kinetics/PKM/trigger_PKM SUBSTRATE n addmsg /kinetics/PKM/Ca.detector_complex /kinetics/PKM/trigger_PKM PRODUCT n addmsg /kinetics/CaM/CaM-Ca4 /kinetics/PKM/trigger_PKM SUBSTRATE n addmsg /kinetics/Ca_diff /kinetics/Ca_input REAC A B addmsg /kinetics/Ca_input /kinetics/Ca_diff SUBSTRATE n addmsg /kinetics/Ca /kinetics/Ca_diff PRODUCT n addmsg /kinetics/PKC-active /graphs/conc1/PKC-active.Co PLOT Co *PKC-active.Co *red addmsg /kinetics/PKC/PKC-Ca /graphs/conc2/PKC-Ca.Co PLOT Co *PKC-Ca.Co *red enddump // End of dump call /kinetics/PKC/PKC-act-by-Ca/notes LOAD \ "Need est of rate of assoc of Ca and PKC. Assume it is fast" \ "The original parameter-searched kf of 439.4 has been" \ "scaled by 1/6e8 to account for change of units to n. Kf now 8.16e-7, kb=.6085" \ "Raised kf to 1e-6 to match Ca curve, kb to .5" \ "" call /kinetics/PKC/PKC-act-by-DAG/notes LOAD \ "Need est of rate. Assume it is fast" \ "Obtained from param search" \ "kf raised 10 X : see Shinomura et al PNAS 88 5149-5153 1991." \ "kf changed from 3.865e-7 to 2.0e-7 in line with closer analysis of" \ "Shinomura data." \ "26 June 1996: Corrected DAG data: reduce kf 15x from " \ "2e-7 to 1.333e-8" call /kinetics/PKC/PKC-DAG-to-memb/notes LOAD \ "Raise kb from .087 to 0.1 to match data from Shinomura et al." \ "Lower kf from 1.155 to 1.0 to match data from Shinomura et al." call /kinetics/PKC/PKC-n-DAG/notes LOAD \ "kf raised 10 X based on Shinomura et al PNAS 88 5149-5153 1991" \ "closer analysis of Shinomura et al: kf now 1e-8 (was 1.66e-8)." \ "Further tweak. To get sufficient AA synergy, increase kf to 1.5e-8" \ "26 June 1996: Corrected DAG levels: reduce kf by 15x from" \ "1.5e-8 to 1e-9" call /kinetics/PKC/PKC-DAG/notes LOAD \ "CoInit was .0624" \ "" call /kinetics/PKC/PKC-cytosolic/notes LOAD \ "Marquez et al J. Immun 149,2560(92) est 1e6/cell for chromaffin cells" \ "We will use 1 uM as our initial concen" \ "" call /kinetics/PKC-active/PKC-act-raf/notes LOAD \ "Rate consts from Chen et al Biochem 32, 1032 (1993)" \ "k3 = k2 = 4" \ "k1 = 9e-5" \ "recalculated gives 1.666e-5, which is not very different." \ "Looks like k3 is rate-limiting in this case: there is a huge amount" \ "of craf locked up in the enz complex. Let us assume a 10x" \ "higher Km, ie, lower affinity. k1 drops by 10x." \ "Also changed k2 to 4x k3." \ "Lowerd k1 to 1e-6 to balance 10X DAG sensitivity of PKC" call /kinetics/PKC-active/PKC-inact-GAP/notes LOAD \ "Rate consts copied from PCK-act-raf" \ "This reaction inactivates GAP. The idea is from the " \ "Boguski and McCormick review." call /kinetics/PKC-active/PKC-act-GEF/notes LOAD \ "Rate consts from PKC-act-raf." \ "This reaction activates GEF. It can lead to at least 2X stim of ras, and" \ "a 2X stim of MAPK over and above that obtained via direct phosph of" \ "c-raf. Note that it is a push-pull reaction, and there is also a contribution" \ "through the phosphorylation and inactivation of GAPs." \ "The original PKC-act-raf rate consts are too fast. We lower K1 by 10 X" 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/craf-1/notes LOAD \ "Couldn't find any ref to the actual conc of craf-1 but I" \ "should try Strom et al Oncogene 5 pp 345" \ "In line with the other kinases in the cascade, I estimate the conc to be" \ "0.2 uM. To init we use 0.15, which is close to equil" \ "16 May 2003: Changing to synaptic levels. Increasing 2.5 fold to 0.5 uM." \ "See Mihaly et al 1991 Brain Res 547(2):309-14" \ "and " \ "Morice et al 1999 Eur J Neurosci 11(6):1995-2006" 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" \ "Ortiz et al 1995 J Neurosci 15(2):1285-1297 suggest that levels are" \ "higher in hippocampus than other brain regions, and further elevated " \ "in synapses. Estimate 3x higher levels than before, at 0.5 uM." \ "Similar results from Schipper et al 1999 Neuroscience 93(2):585-595" \ "but again lacking in quantitation." call /kinetics/MAPK/MAPK/notes LOAD \ "conc is from Sanghera et al JBC 265 pp 52 (1990)" \ "A second calculation gives 3.1 uM, from same paper." \ "They est MAPK is 1e-4x total protein, and protein is 15% of cell wt," \ "so MAPK is 1.5e-5g/ml = 0.36uM. which is closer to our first estimate." \ "Lets use this." \ "Updated 16 May 2003." \ "Ortiz et al 1995 J Neurosci 15(2):1285-1297 provide estimates of " \ "ERK2 levels in hippocampus: 1009 ng/mg. This comes to about 3.6uM, which" \ "may still be an underestimate of synaptic levels." 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, scale to get k2=0.6." \ "k1=0.75/46.6nM=2.7e-5" 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/Raf-GTP-Ras/Raf-GTP-Ras.1/notes LOAD \ "Kinetics are the same as for the craf_1* activity, ie., " \ "k1=5.5e-6, k2=0.42, k3 = 0.105" \ "These are basedo n Force et al PNAS USA 91 1270-1274, 1994.," \ "but k1 is scaled up 5x (ie., Km is scaled down 5x to the value used here" \ "and for craf_1* activity: Km = 0.1591)." call /kinetics/MAPK/Raf-GTP-Ras/Raf-GTP-Ras.2/notes LOAD \ "Kinetics are the same as for the craf_1* activity, ie., " \ "k1=5.5e-6, k2=0.42, k3 = 0.105" \ "These are basedo n Force et al PNAS USA 91 1270-1274, 1994.," \ "but k1 is scaled up 5x (ie., Km is scaled down 5x to the value used here" \ "and for craf_1* activity: Km = 0.1591)." 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." \ "These parms cannot reach the observed 4X stim of MAPK. So lets" \ "increase the affinity, ie, raise k1 10X to 1.1e-5" \ "Lets take it back down to where it was." \ "Back up to 5X: 5.5e-6" 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." \ "k1 = 1.1e-6, k2 = .42, k3 = 1.05" \ "raise k1 to 5.5e-6" \ "" call /kinetics/MKP-1/notes LOAD \ "MKP-1 dephosphoryates and inactivates MAPK in vivo: Sun et al Cell 75 " \ "487-493 1993. Levels of MKP-1" \ "are regulated, and rise in 1 hour. " \ "Kinetics from Charles et al PNAS 90:5292-5296 1993. They refer" \ "to Charles et al Oncogene 7 187-190 who show that half-life of MKP1/3CH134" \ "is 40 min. 80% deph of MAPK in 20 min" \ "Sep 17 1997: CoInit now 0.4x to 0.0032. See parm searches" \ "from jun96 on." call /kinetics/MKP-1/MKP1-tyr-deph/notes LOAD \ "The original kinetics have been modified to obey the k2 = 4 * k3 rule," \ "while keeping kcat and Km fixed. As noted in the NOTES, the only constraining" \ "data point is the time course of MAPK dephosphorylation, which this" \ "model satisfies. It would be nice to have more accurate estimates of" \ "rate consts and MKP-1 levels from the literature. " \ "Effective Km : 67 nM" \ "kcat = 1.43 umol/min/mg" call /kinetics/MKP-1/MKP1-thr-deph/notes LOAD \ "See MKP1-tyr-deph" call /kinetics/Ras-act-craf/notes LOAD \ "Assume the binding is fast and limited only by the amount of " \ "Ras* available. So kf=kb/[craf-1]" \ "If kb is 1/sec, then kf = 1/0.2 uM = 1/(0.2 * 6e5) = 8.3e-6" \ "Later: Raise it by 10 X to 4e-5" \ "From Hallberg et al JBC 269:6 3913-3916 1994, 3% of cellular Raf is" \ "complexed with Ras. So we raise kb 4x to 4" \ "This step needed to memb-anchor and activate Raf: Leevers et al Nature" \ "369 411-414" \ "May 16, 2003" \ "Changed Ras and Raf to synaptic levels, an increase of about 2x for each." \ "To maintain the percentage of complexed Raf, reduced the kf by 2.4 fold" \ "to 10." \ "" call /kinetics/PPhosphatase2A/notes LOAD \ "Refs: Pato et al Biochem J 293:35-41(93);" \ "Takai&Mieskes Biochem J 275:233-239" \ "k1=1.46e-4, k2=1000,k3=250. these use" \ "kcat values for calponin. Also, units of kcat may be in min!" \ "revert to Vmax base:" \ "k3=6, k2=25,k1=3.3e-6 or 6,6,1e-6" \ "CoInit assumed 0.1 uM." \ "See NOTES for MAPK_Ras50.g. CoInit now 0.08" \ "Sep 17 1997: Raise CoInt 1.4x to 0.224, see parm" \ "searches from jun 96 on." \ "" call /kinetics/PPhosphatase2A/craf-deph/notes LOAD \ "See parent PPhosphatase2A for parms" \ "" call /kinetics/PPhosphatase2A/MAPKK-deph/notes LOAD \ "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." call /kinetics/PPhosphatase2A/craf**-deph/notes LOAD \ "Ueki et al JBC 269(22) pp 15756-15761 1994 show hyperphosphorylation of" \ "craf, so this is there to dephosphorylate it. Identity of phosphatase is not" \ "known to me, but it may be PP2A like the rest, so I have made it so." call /kinetics/Ras/notes LOAD \ "Ras has now gotten to be a big enough component of the model to" \ "deserve its own group. The main refs are" \ "Boguski and McCormick Nature 366 643-654 '93 Major review" \ "Eccleston et al JBC 268:36 pp 27012-19" \ "Orita et al JBC 268:34 2554246" call /kinetics/Ras/inact-GEF/notes LOAD \ "Assume that SoS is present only at 50 nM." \ "Revised to 100 nM to get equil to experimentally known levels." call /kinetics/Ras/GEF*/notes LOAD \ "phosphorylated and thereby activated form of GEF. See, e.g." \ "Orita et al JBC 268:34 25542-25546 1993, Gulbins et al." \ "It is not clear whether there is major specificity for tyr or ser/thr." call /kinetics/Ras/GEF*/GEF*-act-ras/notes LOAD \ "Kinetics same as GEF-bg-act-ras" \ "" call /kinetics/Ras/GTP-Ras/notes LOAD \ "Only a very small fraction (7% unstim, 15% stim) of ras is GTP-bound." \ "Gibbs et al JBC 265(33) 20437" \ "" call /kinetics/Ras/GDP-Ras/notes LOAD \ "GDP bound form. See Rosen et al Neuron 12 1207-1221 June 1994." \ "the activation loop is based on Boguski and McCormick Nature 366 643-654 93" \ "Assume Ras is present at about the same level as craf-1, 0.2 uM." \ "Hallberg et al JBC 269:6 3913-3916 1994 estimate upto 5-10% of cellular" \ "Raf is assoc with Ras. Given that only 5-10% of Ras is GTP-bound, we" \ "need similar amounts of Ras as Raf." call /kinetics/Ras/Ras-intrinsic-GTPase/notes LOAD \ "This is extremely slow (1e-4), but it is significant as so little GAP actually" \ "gets complexed with it that the total GTP turnover rises only by" \ "2-3 X (see Gibbs et al, JBC 265(33) 20437-20422) and " \ "Eccleston et al JBC 268(36) 27012-27019" \ "kf = 1e-4" \ "" call /kinetics/Ras/dephosph-GAP/notes LOAD \ "Assume a reasonably good rate for dephosphorylating it, 1/sec" call /kinetics/Ras/GAP/notes LOAD \ "GTPase-activating proteins. See Boguski and McCormick." \ "Turn off Ras by helping to hydrolyze bound GTP. " \ "This one is probably NF1, ie., Neurofibromin as it is inhibited by AA and lipids," \ "and expressed in neural cells. p120-GAP is also a possible candidate, but" \ "is less regulated. Both may exist at similar levels." \ "See Eccleston et al JBC 268(36) pp27012-19" \ "Level=.002" \ "16 May 2003: Increased level to 0.0036, in line with other concentration" \ "raises at the synapse." call /kinetics/Ras/GAP/GAP-inact-ras/notes LOAD \ "From Eccleston et al JBC 268(36)pp27012-19 get Kd < 2uM, kcat - 10/sec" \ "From Martin et al Cell 63 843-849 1990 get Kd ~ 250 nM, kcat = 20/min" \ "I will go with the Eccleston figures as there are good error bars (10%). In general" \ "the values are reasonably close." \ "k1 = 1.666e-3/sec, k2 = 1000/sec, k3 = 10/sec (note k3 is rate-limiting)" \ "5 Nov 2002: Changed ratio term to 4 from 100. Now we have" \ "k1=8.25e-5; k2=40, k3=10. k3 is still rate-limiting." call /kinetics/Ras/CaM-bind-GEF/notes LOAD \ "We have no numbers for this. It is probably between" \ "the two extremes represented by the CaMKII phosph states," \ "and I have used guesses based on this." \ "kf=1e-4" \ "kb=1" \ "The reaction is based on Farnsworth et al Nature 376 524-527" \ "1995" call /kinetics/Ras/CaM-GEF/notes LOAD \ "See Farnsworth et al Nature 376 524-527 1995" call /kinetics/Ras/CaM-GEF/CaM-GEF-act-ras/notes LOAD \ "Kinetics same as GEF-bg_act-ras, but as of" \ "March 17, 2006, the kcat is scaled from 0.02 to 0.2 to" \ "have a stronger Ca response for the direct MAPK input." \ "" call /kinetics/CaM/CaM/notes LOAD \ "There is a LOT of this in the cell: upto 1% of total protein mass. (Alberts et al)" \ "Say 25 uM. Meyer et al Science 256 1199-1202 1992 refer to studies saying" \ "it is comparable to CaMK levels. " \ "" call /kinetics/CaM/CaM-Ca3-bind-Ca/notes LOAD \ "Use K3 = 21.5 uM here from Stemmer and Klee table 3." \ "kb/kf =21.5 * 6e5 so kf = 7.75e-7, kb = 10" call /kinetics/CaM/CaM-bind-Ca/notes LOAD \ "Lets use the fast rate consts here. Since the rates are so different, I am not" \ "sure whether the order is relevant. These correspond to the TR2C fragment." \ "We use the Martin et al rates here, plus the Drabicowski binding consts." \ "All are scaled by 3X to cell temp." \ "kf = 2e-10 kb = 72" \ "Stemmer & Klee: K1=.9, K2=1.1. Assume 1.0uM for both. kb/kf=3.6e11." \ "If kb=72, kf = 2e-10 (Exactly the same !)" \ "" \ "19 May 2006. Splitting the old CaM-TR2-bind-Ca reaction into" \ "two steps, each binding 1 Ca. This improves numerical" \ "stability and is conceptually better too." \ "" \ "Overall rates are the same, so each kf and kb is the " \ "square root of the earlier ones. So" \ "kf = 1.125e-4, kb = 8.4853" \ "" call /kinetics/CaM/CaM-Ca2/notes LOAD \ "This is the intermediate where the TR2 end (the high-affinity end) has" \ "bound the Ca but the TR1 end has not." call /kinetics/CaM/CaM-Ca2-bind-Ca/notes LOAD \ "K3 = 21.5, K4 = 2.8. Assuming that the K4 step happens first, we get" \ "kb/kf = 2.8 uM = 1.68e6 so kf =6e-6 assuming kb = 10" \ "" call /kinetics/CaM/CaM-Ca-bind-Ca/notes LOAD \ "Lets use the fast rate consts here. Since the rates are so different, I am not" \ "sure whether the order is relevant. These correspond to the TR2C fragment." \ "We use the Martin et al rates here, plus the Drabicowski binding consts." \ "All are scaled by 3X to cell temp." \ "kf = 2e-10 kb = 72" \ "Stemmer & Klee: K1=.9, K2=1.1. Assume 1.0uM for both. kb/kf=3.6e11." \ "If kb=72, kf = 2e-10 (Exactly the same !)" \ "" \ "19 May 2006. Splitting the old CaM-TR2-bind-Ca reaction into" \ "two steps, each binding 1 Ca. This improves numerical" \ "stability and is conceptually better too." \ "" \ "Overall rates are the same, so each kf and kb is the " \ "square root of the earlier ones. So" \ "kf = 1.125e-4, kb = 8.4853" \ "" call /kinetics/CaM/CaM-Ca/notes LOAD \ "This is the intermediate where the TR2 end (the high-affinity end) has" \ "bound the Ca but the TR1 end has not." call /kinetics/Ras-act-unphosph-raf/notes LOAD \ "18 May 2003. This reaction is here to" \ "provide basal activity for MAPK as well" \ "as the potential for direct EGF stimulus" \ "without PKC activation." \ "Based on model from FB/fb28c.g: the model" \ "used for MKP-1 turnover. The rates there" \ "were constrained by basal activity values." call /kinetics/PKM/AA_pool/notes LOAD \ "Amino acid pool for synthesis." call /kinetics/PKM/PKM_degradation/notes LOAD \ "Time-course of 2 hours." call /kinetics/doqcsinfo/notes LOAD \ " This is a non-bistable model of ERKII signaling that also incorporates PKM synthesis triggered by Ca influx. It is a simplified variant of the model of Ajay SM, Bhalla US. Eur J Neurosci. 2004 Nov;20(10):2671-80." \ "" complete_loading