// DOQCS : http://doqcs.ncbs.res.in/ // Accession Name = MAPK_MKP1_oscillation // Accession Number = 9 // Transcriber = Upinder S. Bhalla, NCBS // Developer = Upinder S. Bhalla, NCBS // Species = Generic mammalian // Tissue = NIH 3T3 Expression // Cell Compartment = Surface - Nucleus // Notes = This model relates to figure 5 in Bhalla US, Iyengar R. Chaos (2001) 11(1):221-226. It includes the model used for figures 2-4 and also has MKP-1 induction by MAPK activity in the synapse. PP2A is set to 0.16 uM and MKP synthesis is varied from 5x to 40 x basal to get a range of interesting behaviours. //genesis // kkit Version 11 flat dumpfile // Saved on Thu Dec 8 14:06:00 2005 include kkit {argv 1} FASTDT = 0.0001 SIMDT = 0.001 CONTROLDT = 10 PLOTDT = 10 MAXTIME = 5000 TRANSIENT_TIME = 2 VARIABLE_DT_FLAG = 0 DEFAULT_VOL = 1.6667e-21 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/geometry 0 1e-15 3 sphere "" white black 38 30 0 simundump geometry /kinetics/geometry[1] 0 1e-15 3 sphere "" white black 38 \ 27 0 simundump group /kinetics/PKC 0 blue black x 0 0 "" defaultfile defaultfile.g \ 0 0 0 14.951 23.216 0 simundump kpool /kinetics/PKC/PKC-Ca 0 0 3.7208e-17 3.7208e-17 2.2325e-11 \ 2.2325e-11 0 0 6e+05 0 /kinetics/geometry[1] red black 13.925 16.511 0 simundump kreac /kinetics/PKC/PKC-act-by-Ca 0 1e-06 0.5 "" white blue 13.925 \ 14.877 0 simundump kreac /kinetics/PKC/PKC-act-by-DAG 0 1.3333e-08 8.6348 "" white \ blue 15.939 15.694 0 simundump kreac /kinetics/PKC/PKC-Ca-to-memb 0 1.2705 3.5026 "" white blue \ 14.203 19.253 0 simundump kreac /kinetics/PKC/PKC-DAG-to-memb 0 1 0.1 "" white blue 15.383 \ 17.736 0 simundump kreac /kinetics/PKC/PKC-act-by-Ca-AA 0 2e-09 0.1 "" white blue \ 17.212 18.816 0 simundump kreac /kinetics/PKC/PKC-act-by-DAG-AA 0 2 0.2 "" white blue 19.249 \ 18.232 0 simundump kpool /kinetics/PKC/PKC-DAG-AA* 0 0 4.9137e-18 4.9137e-18 \ 2.9482e-12 2.9482e-12 0 0 6e+05 0 /kinetics/geometry[1] cyan blue 18.601 \ 20.537 0 simundump kpool /kinetics/PKC/PKC-Ca-AA* 0 0 1.75e-16 1.75e-16 1.05e-10 \ 1.05e-10 0 0 6e+05 0 /kinetics/geometry[1] orange blue 17.397 21.296 0 simundump kpool /kinetics/PKC/PKC-Ca-memb* 0 0 1.3896e-17 1.3896e-17 \ 8.3376e-12 8.3376e-12 0 0 6e+05 0 /kinetics/geometry[1] pink blue 15.221 \ 21.529 0 simundump kpool /kinetics/PKC/PKC-DAG-memb* 0 0 9.4352e-21 9.4352e-21 \ 5.6611e-15 5.6611e-15 0 0 6e+05 0 /kinetics/geometry[1] yellow blue 16.17 \ 20.508 0 simundump kpool /kinetics/PKC/PKC-basal* 0 0 0.02 0.02 12000 12000 0 0 6e+05 \ 0 /kinetics/geometry[1] pink blue 13.253 20.566 0 simundump kreac /kinetics/PKC/PKC-basal-act 0 1 50 "" white blue 13.022 \ 18.057 0 simundump kpool /kinetics/PKC/PKC-AA* 0 0 1.8133e-17 1.8133e-17 1.088e-11 \ 1.088e-11 0 0 6e+05 0 /kinetics/geometry[1] cyan blue 19.782 21.821 0 simundump kreac /kinetics/PKC/PKC-act-by-AA 0 2e-10 0.1 "" white blue 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orange blue 30.564 28.084 0 simundump kpool /kinetics/Ras/GDP-Ras 1 0 0.2 0.2 1.2e+05 1.2e+05 0 0 6e+05 0 \ /kinetics/geometry[1] pink blue 24.131 29.165 0 simundump kreac /kinetics/Ras/Ras-intrinsic-GTPase 1 1e-04 0 "" white blue \ 27.098 28.5 0 simundump kreac /kinetics/Ras/dephosph-GAP 1 0.1 0 "" white blue 22.023 \ 30.524 0 simundump kpool /kinetics/Ras/GAP* 1 0 0 0 0 0 0 0 6e+05 0 \ /kinetics/geometry[1] red blue 19.35 29.349 0 simundump kpool /kinetics/Ras/GAP 1 0 0.002 0.002 1200 1200 0 0 6e+05 0 \ /kinetics/geometry[1] red blue 24.655 27.338 0 simundump kenz /kinetics/Ras/GAP/GAP-inact-ras 1 0 0 0 0 6e+05 0.001666 1000 \ 10 0 0 "" red red "" 27.012 27.403 0 simundump doqcsinfo /kinetics/doqcsinfo 0 db9.g MAPK_MKP1_oscillation network \ "Upinder S. Bhalla, NCBS" "Upinder S. Bhalla, NCBS" "citation here" \ "Generic Mammalian" "NIH 3T3 Expression" "Surface - Nucleus" Qualitative \ "Bhalla US, Iyengar R. Chaos (2001) 11(1):221-226( Peer-reviewed publication )" \ "Exact GENESIS implementation" \ "Approximates original data , Quantitatively predicts new data" 39 33 0 simundump xgraph /graphs/conc1 0 0 10000 0 0.0067487 0 simundump xgraph /graphs/conc2 0 0 10000 0 0.027695 0 simundump xplot /graphs/conc1/GTP-Ras.Co 3 524288 \ "delete_plot.w ; edit_plot.D " orange 0 0 1 simundump xplot /graphs/conc1/Raf-GTP-Ras*.Co 3 524288 \ "delete_plot.w ; edit_plot.D " red 0 0 1 simundump xplot /graphs/conc1/MAPKK*.Co 3 524288 \ "delete_plot.w ; edit_plot.D " pink 0 0 1 simundump xplot /graphs/conc1/MAPK*.Co 3 524288 \ "delete_plot.w ; edit_plot.D " orange 0 0 1 simundump xplot /graphs/conc1/AA.Co 3 524288 \ "delete_plot.w ; edit_plot.D " darkgreen 0 0 1 simundump xplot /graphs/conc1/PKC-active.Co 3 524288 \ "delete_plot.w ; edit_plot.D " yellow 0 0 1 simundump xplot /graphs/conc1/PLA2*-Ca.Co 3 524288 \ "delete_plot.w ; edit_plot.D " orange 0 0 1 simundump xplot /graphs/conc1/PLA2*.Co 3 524288 \ "delete_plot.w ; edit_plot.D " orange 0 0 1 simundump xplot /graphs/conc2/MKP-1.Co 3 524288 \ "delete_plot.w ; edit_plot.D " hotpink 0 0 1 simundump xplot /graphs/conc2/PPhosphatase2A.Co 3 524288 \ "delete_plot.w ; edit_plot.D " hotpink 0 0 1 simundump xplot /graphs/conc2/RGR.Co 3 524288 \ "delete_plot.w ; edit_plot.D " red 0 0 1 simundump xplot /graphs/conc2/EGF.Co 3 524288 \ "delete_plot.w ; edit_plot.D " red 0 0 1 simundump xplot /graphs/conc2/Shc*.Sos.Grb2.Co 3 524288 \ "delete_plot.w ; edit_plot.D " brown 0 0 1 simundump xgraph /moregraphs/conc3 0 0 10000 0 1 0 simundump xgraph /moregraphs/conc4 0 0 10000 0 1 0 simundump xcoredraw /edit/draw 0 6.2 47.2 -2 35.352 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 \ "Based on fb20i.g and fb3.g. Meant" \ "to be first pass at model to explore" \ "diff between native parms and parms" \ "required to get oscillation. Note" \ "that fb15e.g has also achieved " \ "oscillation but with very different" \ "parms." 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-act-by-Ca-AA /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 /kinetics/PKC/PKC-act-by-Ca-AA SUBSTRATE n addmsg /kinetics/AA /kinetics/PKC/PKC-act-by-Ca-AA SUBSTRATE n addmsg /kinetics/PKC/PKC-Ca-AA* /kinetics/PKC/PKC-act-by-Ca-AA PRODUCT n addmsg /kinetics/PKC/PKC-DAG-AA* /kinetics/PKC/PKC-act-by-DAG-AA PRODUCT n addmsg /kinetics/PKC/PKC-DAG-AA /kinetics/PKC/PKC-act-by-DAG-AA SUBSTRATE n addmsg /kinetics/PKC/PKC-act-by-DAG-AA /kinetics/PKC/PKC-DAG-AA* REAC B A addmsg /kinetics/PKC/PKC-act-by-Ca-AA /kinetics/PKC/PKC-Ca-AA* REAC B A 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-basal-act /kinetics/PKC/PKC-basal* REAC B A addmsg /kinetics/PKC/PKC-cytosolic /kinetics/PKC/PKC-basal-act SUBSTRATE n addmsg /kinetics/PKC/PKC-basal* /kinetics/PKC/PKC-basal-act PRODUCT n addmsg /kinetics/PKC/PKC-act-by-AA /kinetics/PKC/PKC-AA* REAC B A addmsg /kinetics/AA /kinetics/PKC/PKC-act-by-AA SUBSTRATE n addmsg /kinetics/PKC/PKC-AA* /kinetics/PKC/PKC-act-by-AA PRODUCT n addmsg /kinetics/PKC/PKC-cytosolic /kinetics/PKC/PKC-act-by-AA SUBSTRATE n 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-n-DAG-AA /kinetics/PKC/PKC-DAG REAC A B addmsg /kinetics/PKC/PKC-DAG /kinetics/PKC/PKC-n-DAG-AA SUBSTRATE n addmsg /kinetics/AA /kinetics/PKC/PKC-n-DAG-AA SUBSTRATE n addmsg /kinetics/PKC/PKC-DAG-AA /kinetics/PKC/PKC-n-DAG-AA PRODUCT n addmsg /kinetics/PKC/PKC-n-DAG-AA /kinetics/PKC/PKC-DAG-AA REAC B A addmsg /kinetics/PKC/PKC-act-by-DAG-AA /kinetics/PKC/PKC-DAG-AA REAC A B addmsg /kinetics/PKC/PKC-act-by-Ca /kinetics/PKC/PKC-cytosolic REAC A B addmsg /kinetics/PKC/PKC-basal-act /kinetics/PKC/PKC-cytosolic REAC A B addmsg /kinetics/PKC/PKC-act-by-AA /kinetics/PKC/PKC-cytosolic REAC A B addmsg /kinetics/PKC/PKC-n-DAG /kinetics/PKC/PKC-cytosolic 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/PLA2/DAG-Ca-PLA2-act /kinetics/DAG REAC A B addmsg /kinetics/PKC/PKC-act-by-Ca /kinetics/Ca REAC A B addmsg /kinetics/PLA2/PLA2-Ca-act /kinetics/Ca REAC A B addmsg /kinetics/PLA2/PLA2*-Ca-act /kinetics/Ca REAC A B addmsg /kinetics/PKC/PKC-act-by-Ca-AA /kinetics/AA REAC A B addmsg /kinetics/PKC/PKC-act-by-AA /kinetics/AA REAC A B addmsg /kinetics/PKC/PKC-n-DAG-AA /kinetics/AA REAC A B addmsg /kinetics/PLA2/PLA2-Ca*/kenz /kinetics/AA MM_PRD pA addmsg /kinetics/PLA2/PIP2-PLA2*/kenz /kinetics/AA MM_PRD pA addmsg /kinetics/PLA2/PIP2-Ca-PLA2*/kenz /kinetics/AA MM_PRD pA addmsg /kinetics/PLA2/DAG-Ca-PLA2*/kenz /kinetics/AA MM_PRD pA addmsg /kinetics/PLA2/PLA2*-Ca/kenz /kinetics/AA MM_PRD pA addmsg /kinetics/PLA2/Degrade-AA /kinetics/AA REAC A B addmsg /kinetics/PKC/PKC-DAG-AA* /kinetics/PKC-active SUMTOTAL n nInit addmsg /kinetics/PKC/PKC-Ca-memb* /kinetics/PKC-active SUMTOTAL n nInit addmsg /kinetics/PKC/PKC-Ca-AA* /kinetics/PKC-active SUMTOTAL n nInit addmsg /kinetics/PKC/PKC-DAG-memb* /kinetics/PKC-active SUMTOTAL n nInit addmsg /kinetics/PKC/PKC-basal* /kinetics/PKC-active SUMTOTAL n nInit addmsg /kinetics/PKC/PKC-AA* /kinetics/PKC-active SUMTOTAL n nInit addmsg /kinetics/PKC-active/PKC-act-raf /kinetics/PKC-active CONSERVE nComplex nComplexInit addmsg /kinetics/PKC-active/PKC-inact-GAP /kinetics/PKC-active REAC eA B addmsg /kinetics/PKC-active/PKC-inact-GAP /kinetics/PKC-active CONSERVE nComplex nComplexInit addmsg /kinetics/PKC-active/PKC-act-GEF /kinetics/PKC-active REAC eA B addmsg /kinetics/PKC-active/PKC-act-GEF /kinetics/PKC-active CONSERVE nComplex nComplexInit addmsg /kinetics/PKC-active/PKC-act-raf /kinetics/PKC-active REAC eA B 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/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/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/RGR/RGR.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/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/MKP-1**/MKP1*-tyr-deph /kinetics/MAPK/MAPK-tyr REAC sA B addmsg /kinetics/MAPK/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/RGR/RGR.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/RGR/RGR.1 /kinetics/MAPK/MAPKK-ser MM_PRD pA addmsg /kinetics/MAPK/RGR/RGR.2 /kinetics/MAPK/MAPKK-ser REAC sA B 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/MAPK/RGR/RGR.1 /kinetics/MAPK/RGR REAC eA B addmsg /kinetics/MAPK/RGR/RGR.2 /kinetics/MAPK/RGR REAC eA B addmsg /kinetics/MAPK/RGR /kinetics/MAPK/RGR/RGR.1 ENZYME n addmsg /kinetics/MAPK/MAPKK /kinetics/MAPK/RGR/RGR.1 SUBSTRATE n addmsg /kinetics/MAPK/RGR /kinetics/MAPK/RGR/RGR.2 ENZYME n addmsg /kinetics/MAPK/MAPKK-ser /kinetics/MAPK/RGR/RGR.2 SUBSTRATE n addmsg /kinetics/MAPK/MKP-1-basal-synth /kinetics/MAPK/MKP-1-gene REAC A B addmsg /kinetics/MAPK/nuc_MAPK*/MKP-1-synthesis /kinetics/MAPK/MKP-1-gene REAC sA B addmsg /kinetics/MAPK/turnover_MKP1** /kinetics/MAPK/Ubiquitination REAC B A addmsg /kinetics/MAPK/turnover_MKP1 /kinetics/MAPK/Ubiquitination REAC B A addmsg /kinetics/MAPK/turnover_MKP1* /kinetics/MAPK/Ubiquitination REAC B A addmsg /kinetics/MKP-1 /kinetics/MAPK/turnover_MKP1 SUBSTRATE n addmsg /kinetics/MAPK/Ubiquitination /kinetics/MAPK/turnover_MKP1 PRODUCT n addmsg /kinetics/MAPK/MKP-1-gene /kinetics/MAPK/MKP-1-basal-synth SUBSTRATE n addmsg /kinetics/MKP-1 /kinetics/MAPK/MKP-1-basal-synth PRODUCT n addmsg /kinetics/MAPK*/MKP-1-phosph /kinetics/MAPK/MKP-1-ser359* MM_PRD pA addmsg /kinetics/MAPK*/MKP-1-phosph2 /kinetics/MAPK/MKP-1-ser359* REAC sA B addmsg /kinetics/MAPK/turnover_MKP1* /kinetics/MAPK/MKP-1-ser359* REAC A B addmsg /kinetics/MAPK/MKP-1*dephosph /kinetics/MAPK/MKP-1-ser359* REAC A B addmsg /kinetics/MAPK/MKP-1**dephosph /kinetics/MAPK/MKP-1-ser359* REAC B A addmsg /kinetics/MAPK/turnover_MKP1** /kinetics/MAPK/MKP-1** REAC A B addmsg /kinetics/MAPK*/MKP-1-phosph2 /kinetics/MAPK/MKP-1** MM_PRD pA addmsg /kinetics/MAPK/MKP-1**dephosph /kinetics/MAPK/MKP-1** REAC A B addmsg /kinetics/MAPK/MKP-1** /kinetics/MAPK/MKP-1**/MKP1*-tyr-deph ENZYME n addmsg /kinetics/MAPK/MAPK-tyr /kinetics/MAPK/MKP-1**/MKP1*-tyr-deph SUBSTRATE n addmsg /kinetics/MAPK/MKP-1** /kinetics/MAPK/MKP-1**/MKP1*-thr-deph ENZYME n addmsg /kinetics/MAPK* /kinetics/MAPK/MKP-1**/MKP1*-thr-deph SUBSTRATE n addmsg /kinetics/MAPK/MKP-1** /kinetics/MAPK/turnover_MKP1** SUBSTRATE n addmsg /kinetics/MAPK/Ubiquitination /kinetics/MAPK/turnover_MKP1** PRODUCT n addmsg /kinetics/MAPK/MKP-1-ser359* /kinetics/MAPK/turnover_MKP1* SUBSTRATE n addmsg /kinetics/MAPK/Ubiquitination /kinetics/MAPK/turnover_MKP1* PRODUCT n addmsg /kinetics/MAPK/MKP-1-ser359* /kinetics/MAPK/MKP-1*dephosph SUBSTRATE n addmsg /kinetics/MKP-1 /kinetics/MAPK/MKP-1*dephosph PRODUCT n addmsg /kinetics/MAPK/MKP-1** /kinetics/MAPK/MKP-1**dephosph SUBSTRATE n addmsg /kinetics/MAPK/MKP-1-ser359* /kinetics/MAPK/MKP-1**dephosph PRODUCT n addmsg /kinetics/MAPK/translocation /kinetics/MAPK/nuc_MAPK* REAC B A addmsg /kinetics/MAPK/nuc_MAPK*/MKP-1-synthesis /kinetics/MAPK/nuc_MAPK* REAC eA B addmsg /kinetics/MAPK/nuc_MAPK* /kinetics/MAPK/nuc_MAPK*/MKP-1-synthesis ENZYME n addmsg /kinetics/MAPK/MKP-1-gene /kinetics/MAPK/nuc_MAPK*/MKP-1-synthesis SUBSTRATE n addmsg /kinetics/MAPK* /kinetics/MAPK/translocation SUBSTRATE n addmsg /kinetics/MAPK/nuc_MAPK* /kinetics/MAPK/translocation PRODUCT 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*/MAPK* /kinetics/MAPK* REAC eA B addmsg /kinetics/MAPK*/MKP-1-phosph /kinetics/MAPK* REAC eA B addmsg /kinetics/MAPK/MKP-1**/MKP1*-thr-deph /kinetics/MAPK* REAC sA B addmsg /kinetics/MAPK*/MKP-1-phosph2 /kinetics/MAPK* REAC eA B addmsg /kinetics/MAPK/translocation /kinetics/MAPK* REAC A B addmsg /kinetics/MAPK* /kinetics/MAPK*/MAPK*-feedback ENZYME n addmsg /kinetics/MAPK/craf-1* /kinetics/MAPK*/MAPK*-feedback SUBSTRATE n addmsg /kinetics/MAPK* /kinetics/MAPK*/MAPK* ENZYME n addmsg /kinetics/PLA2/PLA2-cytosolic /kinetics/MAPK*/MAPK* SUBSTRATE n addmsg /kinetics/MAPK* /kinetics/MAPK*/MKP-1-phosph ENZYME n addmsg /kinetics/MKP-1 /kinetics/MAPK*/MKP-1-phosph SUBSTRATE n addmsg /kinetics/MAPK* /kinetics/MAPK*/MKP-1-phosph2 ENZYME n addmsg /kinetics/MAPK/MKP-1-ser359* /kinetics/MAPK*/MKP-1-phosph2 SUBSTRATE n addmsg /kinetics/MAPK*/MKP-1-phosph /kinetics/MKP-1 REAC sA B addmsg /kinetics/MAPK/turnover_MKP1 /kinetics/MKP-1 REAC A B addmsg /kinetics/MAPK/MKP-1-basal-synth /kinetics/MKP-1 REAC B A addmsg /kinetics/MAPK/MKP-1*dephosph /kinetics/MKP-1 REAC B A addmsg /kinetics/MAPK/nuc_MAPK*/MKP-1-synthesis /kinetics/MKP-1 MM_PRD pA 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/Raf-GTP-Ras* /kinetics/Ras-act-craf PRODUCT 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/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/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/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/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/GTP-Ras /graphs/conc1/GTP-Ras.Co PLOT Co *GTP-Ras.Co *orange addmsg /kinetics/MAPK/Raf-GTP-Ras* /graphs/conc1/Raf-GTP-Ras*.Co PLOT Co *Raf-GTP-Ras*.Co *red addmsg /kinetics/MAPK/MAPKK* /graphs/conc1/MAPKK*.Co PLOT Co *MAPKK*.Co *pink addmsg /kinetics/MAPK* /graphs/conc1/MAPK*.Co PLOT Co *MAPK*.Co *orange addmsg /kinetics/AA /graphs/conc1/AA.Co PLOT Co *AA.Co *darkgreen addmsg /kinetics/PKC-active /graphs/conc1/PKC-active.Co PLOT Co *PKC-active.Co *yellow addmsg /kinetics/PLA2/PLA2*-Ca /graphs/conc1/PLA2*-Ca.Co PLOT Co *PLA2*-Ca.Co *orange addmsg /kinetics/PLA2/PLA2* /graphs/conc1/PLA2*.Co PLOT Co *PLA2*.Co *orange addmsg /kinetics/MKP-1 /graphs/conc2/MKP-1.Co PLOT Co *MKP-1.Co *hotpink addmsg /kinetics/PPhosphatase2A /graphs/conc2/PPhosphatase2A.Co PLOT Co *PPhosphatase2A.Co *hotpink addmsg /kinetics/MAPK/RGR /graphs/conc2/RGR.Co PLOT Co *RGR.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-act-by-Ca-AA/notes LOAD \ "Schaechter and Benowitz We have to increase Kf for conc scaling" \ "Changed kf to 2e-9 on Sept 19, 94. This gives better match." \ "" call /kinetics/PKC/PKC-act-by-DAG-AA/notes LOAD \ "Assume slowish too. Schaechter and Benowitz" call /kinetics/PKC/PKC-basal-act/notes LOAD \ "Initial basal levels were set by kf = 1, kb = 20. In model, though, the" \ "basal levels of PKC activity are higher." call /kinetics/PKC/PKC-act-by-AA/notes LOAD \ "Raise kf from 1.667e-10 to 2e-10 to get better match to data." 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-n-DAG-AA/notes LOAD \ "Reduced kf to 0.66X to match Shinomura et al data." \ "Initial: kf = 3.3333e-9" \ "New: 2e-9" \ "Newer: 2e-8" \ "kb was 0.2" \ "now 2." 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/DAG/notes LOAD \ "Baseline is 11.661 from running combined model to" \ "steady state. See ALL/NOTES for 23 Apr 1998." call /kinetics/PKC-active/notes LOAD \ "Conc of PKC in brain is about 1 uM (?)" 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" \ "Lower k1 to 1e-6 to balance 10X DAG sensitivity of PKC" \ "11 May2K: Double Vmax. rates=1e-6, 32,8" \ "29 May 2k: Vmax * 0.6. Rates=6e-7, 19.2, 4.8" \ "30 May 2k: vmax=5. Rates=6.25e-7,20,5" \ "3 Jun 2k: vmax=4. Rates=5e-7,16,4" 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. 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" \ "eff through phosph and inact of GAPs." \ "" 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" 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 \ "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." 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=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/MAPK/RGR/RGR.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/RGR/RGR.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/MAPK/MKP-1-gene/notes LOAD \ "3 Feb 2000. This represents the formation of MKP-1 when MAPK" \ "is stimulated. Concentration is pretty irrelevant here," \ "set to 1 uM for convenience." call /kinetics/MAPK/turnover_MKP1/notes LOAD \ "3 Feb 2000. Rate of turnover of non-phosph form of MKP1 " \ "is from Brondello et al Science 286:2514 1999. Tau is " \ "about 45 min. " call /kinetics/MAPK/MKP-1-basal-synth/notes LOAD \ "3 Feb 2000. The levels of basal MAPK are so low that we need" \ "to have a basal mechanism for making MKP-1. This is" \ "easy, as the degradation tau is 45 min and basal MKP-1 levels" \ "are 2.4 nM in our model. x * 1 uM = 2.4e-3 * 0.37e-3 = 8.9e-7" \ "May 30 2k. Basal levels shifted up a bit. kf now 1.0e-6" \ "Jun 3 2k: kf now 8e-7" \ "Jun 4 2k: kf = 7e-7" call /kinetics/MAPK/MKP-1**/notes LOAD \ "3 Feb 2000. Same enz activity as MKP-1, but different" \ "degradation rates. Brondello et al Science 286:2514 1999" \ "4 Feb. Actually this form is doubly phosphorylated." \ "" call /kinetics/MAPK/MKP-1**/MKP1*-tyr-deph/notes LOAD \ "3 Feb 2000. Same rates as MKP-1." call /kinetics/MAPK/MKP-1**/MKP1*-thr-deph/notes LOAD \ "3 Feb 2000. Same rates as MKP1" call /kinetics/MAPK/turnover_MKP1**/notes LOAD \ "3 Feb 2000. Rate of turnover of phosph form of MKP1 " \ "is from Brondello et al Science 286:2514 1999. Tau is " \ "about 150 min though it is not a clean exp falloff. " call /kinetics/MAPK/turnover_MKP1*/notes LOAD \ "3 Feb 2000. Rate of turnover of phosph form of MKP1 " \ "is from Brondello et al Science 286:2514 1999. Tau is " \ "about 150 min though it is not a clean exp falloff. " call /kinetics/MAPK/MKP-1*dephosph/notes LOAD \ "24 Apr 2K: Based on 12 Feb 2K: Scaled up 10x so kf=0.01, kb=0" call /kinetics/MAPK/MKP-1**dephosph/notes LOAD \ "24 Apr 2K, based on 12 Feb 2K: Scaled up 10x to kf=0.01, kb=0" call /kinetics/MAPK/nuc_MAPK*/MKP-1-synthesis/notes LOAD \ "5 Feb 2000" \ "This is a crude model of activation of" \ "MKP1 production by MAPK. Time-course poorly constrained:" \ "10 min to > 100 min. Rates are further constrained" \ "by the known degradation rates of MKP-1, also in this model." \ "Peak MKP-1 is about 10 times basal (from Brondello et al" \ "Science 286:2514 1999). Max MAPK ~.25 uM, degradation" \ "45 min. So this enz has to provide 22nM MKP every 45 min." call /kinetics/MAPK/translocation/notes LOAD \ "5 Feb 2000. A nuclear translocation step. The rates" \ "are set up so that not too much MAPK gets siphoned off." \ "24 Apr 2000. Based on 12 Feb model. Rates slowed down x 0.02" \ "to kf=2e-5 kb=1e-4" call /kinetics/MAPK*/notes LOAD \ "This version is phosphorylated on both the tyr and thr residues and" \ "is active: refs" \ "The rate consts are very hard to nail down. Combine Sanghera et al" \ "JBC 265(1) :52-57 with Nemenoff et al JBC 93 pp 1960 to get" \ "k3=10/sec = k2 (from Nemenoff Vmax) and k1 = (k2 + k3)/Km = 1.3e-6" \ "Or: 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, so:" \ "k3 = .5/sec (rate limiting)" \ "k1 = (k2 + k3)/Km = (.5 + 0)/(25*6e5) = 2e-8 (#/cell)^-1" \ "#s from Sanghera et al JBC 265 pp 52 , 1990. " \ "From Nemenoff et al 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 fig 5" call /kinetics/MAPK*/MKP-1-phosph/notes LOAD \ "3 Feb 2000. See Brondello et al Science 286:2514 1999." \ "Rates assumed standard MAPK rates based on Sanghera et" \ "al JBC 265(1):53-57 1990." \ "24 Apr 2K, based on 12 Feb 2K: scaled by 0.1 to 3.25e-7,4,1" call /kinetics/MAPK*/MKP-1-phosph2/notes LOAD \ "3 Feb 2000. See Brondello et al Science 286:2514 1999." \ "Rates assumed standard MAPK rates based on Sanghera et" \ "al JBC 265(1):53-57 1990." \ "24 Apr 2K, based on 12 Feb 2K: Scaled x0.1 to 3.25e-7,4,1" call /kinetics/MKP-1/notes LOAD \ "MKP-1 deph and inact MAPK in vivo: Sun et al Cell 75 " \ "487-493 1993. " \ "Kinetics from Charles et al PNAS 90:5292-5296 1993. They cite" \ "Charles et al Oncogene 7 187-190 for half-life of" \ "MKP1/3CH 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." \ "30 May 2k: CoInit now 0.0027, but not so critical as its prdn" \ "is regulated." 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 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 4e-5" \ "From Hallberg et al JBC 269:6 3913-3916 1994, 3% of cellular Raf is" \ "complexed with Ras. So raise kb 4x to 4e-5" \ "This step needed to memb-anchor and activate Raf:" \ "Leevers et al Nature 369 411-414." \ "" 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/PLA2/notes LOAD \ "Mail source of data: Leslie and Channon BBA 1045 (1990) pp 261-270." \ "Fig 6 is Ca curve. Fig 4a is PIP2 curve. Fig 4b is DAG curve. Also see" \ "Wijkander and Sundler JBC 202 (1991) pp873-880;" \ "Diez and Mong JBC 265(24) p14654;" \ "Leslie JBC 266(17) (1991) pp11366-11371" call /kinetics/PLA2/PLA2-cytosolic/notes LOAD \ "Calculated cytosolic was 20 nm from Wijkander and Sundler" \ "However, Leslie and Channon use about 400 nM. Need to confirm," \ "but this is the value I use here. Another recalc of W&S gives 1uM" call /kinetics/PLA2/PLA2-Ca-act/notes LOAD \ "Leslie and Channon BBA 1045 (1990) 261-270 fig6 pp267." call /kinetics/PLA2/PLA2-Ca*/kenz/notes LOAD \ "10 x raise oct22" \ "12 x oct 24, set k2 = 4 * k3" call /kinetics/PLA2/PIP2-PLA2*/kenz/notes LOAD \ "10 X raise oct 22" \ "12 X further raise oct 24 to allow for correct conc of enzyme" \ "" call /kinetics/PLA2/PIP2-Ca-PLA2*/kenz/notes LOAD \ "10 x raise oct 22" \ "12 x and rescale for k2 = 4 * k3 convention oct 24" \ "Increase further to get the match to expt, which was spoilt due" \ "to large accumulation of PLA2 in the enzyme complexed forms." \ "Lets raise k3, leaving the others at " \ "k1 = 1.5e-5 and k2 = 144 since they are large already." \ "" call /kinetics/PLA2/DAG-Ca-PLA2-act/notes LOAD \ "27 June 1996" \ "Scaled kf down by 0.015" \ "from 3.33e-7 to 5e-9" \ "to fit with revised DAG estimates" \ "and use of mole-fraction to calculate eff on PLA2." call /kinetics/PLA2/DAG-Ca-PLA2*/kenz/notes LOAD \ "10 X raise oct 22" \ "12 X raise oct 24 + conversion to k2 =4 * k3" call /kinetics/PLA2/APC/notes LOAD \ "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." call /kinetics/PLA2/Degrade-AA/notes LOAD \ "I need to check if the AA degradation pathway really leads back to " \ "APC. Anyway, it is a convenient buffered pool to dump it back into." \ "For the purposes of the full model we use a rate of degradation of" \ "0.2/sec" \ "Raised decay to 0.4 : see PLA35.g notes for Feb17 " call /kinetics/PLA2/PLA2*-Ca/notes LOAD \ "Phosphorylated form of PLA2. Still need to hook it up using kinases." \ "PKA: Wightman et al JBC 257 pp6650 1982" \ "PKC: Many refs, eg Gronich et al JBC 263 pp 16645, 1988 but see Lin etal" \ "MAPK: Lin et al, Cell 72 pp 269, 1993. Show 3x with MAPK but not PKC alone" \ "Do not know if there is a Ca requirement for active phosphorylated state." call /kinetics/PLA2/PLA2*-Ca/kenz/notes LOAD \ "This form should be 3 to 6 times as fast as the Ca-only form." \ "I have scaled by 4x which seems to give a 5x rise." \ "10x raise Oct 22" \ "12 x oct 24, changed k2 = 4 * k3" call /kinetics/PLA2/PLA2*-Ca-act/notes LOAD \ "To start off, same kinetics as the PLA2-Ca-act direct pathway." \ "Oops ! Missed out the Ca input to this pathway first time round." \ "Let's raise the forward rate about 3x to 5e-6. This will let us reduce the" \ "rather high rates we have used for the kenz on PLA2*-Ca. In fact, it" \ "may be that the rates are not that different, just that this pathway for" \ "getting the PLA2 to the memb is more efficien...." call /kinetics/temp-PIP2/notes LOAD \ "This isn't explicitly present in the M&L model, but is obviously needed." \ "I assume its conc is fixed at 1uM for now, which is a bit high. PLA2 is stim" \ "7x by PIP2 @ 0.5 uM (Leslie and Channon BBA 1045:261(1990) " \ "Leslie and Channon say PIP2 is present at 0.1 - 0.2mol% range in membs," \ "which comes to 50 nM. Ref is Majerus et al Cell 37 pp 701-703 1984" \ "Lets use a lower level of 30 nM, same ref...." 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" 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)" call /kinetics/doqcsinfo/notes LOAD \ "This model relates to figure 5 in Bhalla US, Iyengar R. Chaos (2001) 11(1):221-226. It includes the model used for figures 2-4 and also has MKP-1 induction by MAPK activity in the synapse. PP2A is set to 0.16 uM and MKP synthesis is varied from 5x to 40 x basal to get a range of interesting behaviours." complete_loading