// DOQCS : http://doqcs.ncbs.res.in/ // Accession Name = MAPK-bistability-fig1c // Accession Number = 35 // Transcriber = Upinder S. Bhalla, NCBS // Developer = Upinder S. Bhalla, NCBS // Species = Generic mammalian // Tissue = NIH 3T3 Expression // Cell Compartment = Surface - Nucleus // Notes = Model for figure 1c in Bhalla US et al. Science (2002) 297(5583):1018-23.
The demo for this figure is available here. This synaptic signaling model is without the MKP-1 feedback, so it is bistable and remains so over long periods. //genesis // kkit Version 11 flat dumpfile // Saved on Thu Dec 8 15:36:33 2005 include kkit {argv 1} FASTDT = 0.0001 SIMDT = 0.005 CONTROLDT = 10 PLOTDT = 10 MAXTIME = 2000 TRANSIENT_TIME = 2 VARIABLE_DT_FLAG = 1 DEFAULT_VOL = 1.6667e-21 VERSION = 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 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Bhalla, NCBS" "Upinder S. Bhalla, NCBS" "citation here" \ "General Mammalian" "NIH 3T3 Expression" "Surface - Nucleus" \ "Quantitative match to experiments, Qualitative" \ "Bhalla US et al. Science (2002) 297(5583):1018-23 ( peer-reviewed publication )." \ "Exact GENESIS implementation" \ "Replicates original data , Approximates original data " 85 117 0 simundump xgraph /graphs/conc1 0 0 8000 0 0.12896 0 simundump xgraph /graphs/conc2 0 0 8000 0 0.00053347 0 simundump xplot /graphs/conc1/MAPK*.Co 3 524288 \ "delete_plot.w ; edit_plot.D " orange 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/conc2/PDGFR.Co 3 524288 \ "delete_plot.w ; edit_plot.D " red 0 0 1 simundump xplot /graphs/conc2/PDGF.Co 3 524288 \ "delete_plot.w ; edit_plot.D " red 0 0 1 simundump xgraph /moregraphs/conc3 0 0 8000 0 1 0 simundump xgraph /moregraphs/conc4 0 0 8000 0 1 0 simundump xcoredraw /edit/draw 0 44 89 55 119 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 fb29.g, cleaned up the dangling phosph_PLC-gamma" \ "enzyme activity on PDGFR." addmsg /kinetics/Sos/Shc_bind_Sos.Grb2 /kinetics/Shc*.Sos.Grb2 REAC B A addmsg /kinetics/Shc*.Sos.Grb2/Sos.Ras_GEF /kinetics/Shc*.Sos.Grb2 REAC eA B addmsg /kinetics/Shc*.Sos.Grb2 /kinetics/Shc*.Sos.Grb2/Sos.Ras_GEF ENZYME n addmsg /kinetics/Ras/GDP-Ras /kinetics/Shc*.Sos.Grb2/Sos.Ras_GEF SUBSTRATE n addmsg /kinetics/Sos/Sos.Grb2 /kinetics/Sos/Shc_bind_Sos.Grb2 SUBSTRATE n addmsg /kinetics/Shc*.Sos.Grb2 /kinetics/Sos/Shc_bind_Sos.Grb2 PRODUCT n addmsg /kinetics/PDGFR/SHC* /kinetics/Sos/Shc_bind_Sos.Grb2 SUBSTRATE n addmsg /kinetics/Sos/Grb2_bind_Sos* /kinetics/Sos/Sos*.Grb2 REAC B A addmsg /kinetics/Sos/Sos* /kinetics/Sos/Grb2_bind_Sos* SUBSTRATE n addmsg /kinetics/Sos/Grb2 /kinetics/Sos/Grb2_bind_Sos* SUBSTRATE n addmsg /kinetics/Sos/Sos*.Grb2 /kinetics/Sos/Grb2_bind_Sos* PRODUCT n addmsg /kinetics/Sos/Grb2_bind_Sos /kinetics/Sos/Grb2 REAC A B addmsg /kinetics/Sos/Grb2_bind_Sos* /kinetics/Sos/Grb2 REAC A B addmsg /kinetics/Sos/Grb2_bind_Sos /kinetics/Sos/Sos.Grb2 REAC B A addmsg /kinetics/Sos/Shc_bind_Sos.Grb2 /kinetics/Sos/Sos.Grb2 REAC A B addmsg /kinetics/Sos/Grb2_bind_Sos* /kinetics/Sos/Sos* REAC A B addmsg /kinetics/Sos/dephosph_Sos /kinetics/Sos/Sos* REAC A B addmsg /kinetics/Sos/Sos* /kinetics/Sos/dephosph_Sos SUBSTRATE n addmsg /kinetics/Sos/Sos /kinetics/Sos/dephosph_Sos PRODUCT n addmsg /kinetics/Sos/Grb2 /kinetics/Sos/Grb2_bind_Sos SUBSTRATE n addmsg /kinetics/Sos/Sos.Grb2 /kinetics/Sos/Grb2_bind_Sos PRODUCT n addmsg /kinetics/Sos/Sos /kinetics/Sos/Grb2_bind_Sos SUBSTRATE n addmsg /kinetics/Sos/Grb2_bind_Sos /kinetics/Sos/Sos REAC A B addmsg /kinetics/Sos/dephosph_Sos /kinetics/Sos/Sos REAC B A 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/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/RGR/RGR.1 /kinetics/MAPK/MAPKK REAC sA B addmsg /kinetics/MAPK/MAPKK*/MAPKKtyr /kinetics/MAPK/MAPK REAC sA B addmsg /kinetics/MKP-2/MKP2-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-2/MKP2-tyr-deph /kinetics/MAPK/MAPK-tyr REAC sA B addmsg /kinetics/MKP-2/MKP2-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/MAPK/RGR/RGR.1 /kinetics/MAPK/RGR REAC eA B addmsg /kinetics/MAPK/RGR/RGR.2 /kinetics/MAPK/RGR REAC eA B addmsg /kinetics/Ras-act-unphosph-raf /kinetics/MAPK/RGR REAC B A 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/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*/MAPK*-feedback /kinetics/MAPK* REAC eA B addmsg /kinetics/MAPK/MAPKK*/MAPKKthr /kinetics/MAPK* MM_PRD pA addmsg /kinetics/MAPK*/MAPK* /kinetics/MAPK* REAC eA B addmsg /kinetics/MKP-2/MKP2-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/MAPK* /kinetics/MAPK*/MAPK* ENZYME n addmsg /kinetics/PLA2/PLA2-cytosolic /kinetics/MAPK*/MAPK* 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/Shc*.Sos.Grb2/Sos.Ras_GEF /kinetics/Ras/GTP-Ras MM_PRD pA addmsg /kinetics/Ras-act-unphosph-raf /kinetics/Ras/GTP-Ras REAC A B addmsg /kinetics/Ras/GAP/GAP-inact-ras /kinetics/Ras/GDP-Ras MM_PRD pA addmsg /kinetics/Ras/Ras-intrinsic-GTPase /kinetics/Ras/GDP-Ras REAC B A addmsg /kinetics/Ras/GEF*/GEF*-act-ras /kinetics/Ras/GDP-Ras REAC sA B addmsg /kinetics/Shc*.Sos.Grb2/Sos.Ras_GEF /kinetics/Ras/GDP-Ras REAC sA B addmsg /kinetics/Ras/GTP-Ras /kinetics/Ras/Ras-intrinsic-GTPase SUBSTRATE n addmsg /kinetics/Ras/GDP-Ras /kinetics/Ras/Ras-intrinsic-GTPase PRODUCT n addmsg /kinetics/Ras/GAP* /kinetics/Ras/dephosph-GAP SUBSTRATE n addmsg /kinetics/Ras/GAP /kinetics/Ras/dephosph-GAP PRODUCT n addmsg /kinetics/PKC-active/PKC-inact-GAP /kinetics/Ras/GAP* MM_PRD pA addmsg /kinetics/Ras/dephosph-GAP /kinetics/Ras/GAP* REAC A B addmsg /kinetics/Ras/GAP/GAP-inact-ras /kinetics/Ras/GAP REAC eA B addmsg /kinetics/PKC-active/PKC-inact-GAP /kinetics/Ras/GAP REAC sA B addmsg /kinetics/Ras/dephosph-GAP /kinetics/Ras/GAP REAC B A addmsg /kinetics/Ras/GAP /kinetics/Ras/GAP/GAP-inact-ras ENZYME n addmsg /kinetics/Ras/GTP-Ras /kinetics/Ras/GAP/GAP-inact-ras SUBSTRATE n addmsg /kinetics/MAPK/craf-1 /kinetics/Ras-act-unphosph-raf SUBSTRATE n addmsg /kinetics/MAPK/RGR /kinetics/Ras-act-unphosph-raf PRODUCT n addmsg /kinetics/Ras/GTP-Ras /kinetics/Ras-act-unphosph-raf SUBSTRATE n addmsg /kinetics/PDGFR/act_PDGFR /kinetics/PDGFR/PDGFR REAC A B addmsg /kinetics/PDGFR/PDGFR /kinetics/PDGFR/act_PDGFR SUBSTRATE n addmsg /kinetics/PDGFR/PDGF /kinetics/PDGFR/act_PDGFR SUBSTRATE n addmsg /kinetics/PDGFR/L.PDGFR /kinetics/PDGFR/act_PDGFR PRODUCT n addmsg /kinetics/PDGFR/act_PDGFR /kinetics/PDGFR/L.PDGFR REAC B A addmsg /kinetics/PDGFR/L.PDGFR/phosph_Shc /kinetics/PDGFR/L.PDGFR REAC eA B addmsg /kinetics/PDGFR/Internalize /kinetics/PDGFR/L.PDGFR REAC A B addmsg /kinetics/PDGFR/L.PDGFR /kinetics/PDGFR/L.PDGFR/phosph_Shc ENZYME n addmsg /kinetics/PDGFR/SHC /kinetics/PDGFR/L.PDGFR/phosph_Shc SUBSTRATE n addmsg /kinetics/PDGFR/act_PDGFR /kinetics/PDGFR/PDGF REAC A B addmsg /kinetics/PDGFR/dephosph_Shc /kinetics/PDGFR/SHC REAC B A addmsg /kinetics/PDGFR/L.PDGFR/phosph_Shc /kinetics/PDGFR/SHC REAC sA B addmsg /kinetics/PDGFR/dephosph_Shc /kinetics/PDGFR/SHC* REAC A B addmsg /kinetics/Sos/Shc_bind_Sos.Grb2 /kinetics/PDGFR/SHC* REAC A B addmsg /kinetics/PDGFR/L.PDGFR/phosph_Shc /kinetics/PDGFR/SHC* MM_PRD pA addmsg /kinetics/PDGFR/SHC* /kinetics/PDGFR/dephosph_Shc SUBSTRATE n addmsg /kinetics/PDGFR/SHC /kinetics/PDGFR/dephosph_Shc PRODUCT n addmsg /kinetics/PDGFR/Internalize /kinetics/PDGFR/Internal_L.PDGFR REAC B A addmsg /kinetics/PDGFR/L.PDGFR /kinetics/PDGFR/Internalize SUBSTRATE n addmsg /kinetics/PDGFR/Internal_L.PDGFR /kinetics/PDGFR/Internalize PRODUCT n addmsg /kinetics/MKP-2/MKP2-tyr-deph /kinetics/MKP-2 REAC eA B addmsg /kinetics/MKP-2/MKP2-thr-deph /kinetics/MKP-2 REAC eA B addmsg /kinetics/MKP-2 /kinetics/MKP-2/MKP2-tyr-deph ENZYME n addmsg /kinetics/MAPK/MAPK-tyr /kinetics/MKP-2/MKP2-tyr-deph SUBSTRATE n addmsg /kinetics/MKP-2 /kinetics/MKP-2/MKP2-thr-deph ENZYME n addmsg /kinetics/MAPK* /kinetics/MKP-2/MKP2-thr-deph SUBSTRATE n addmsg /kinetics/MAPK* /graphs/conc1/MAPK*.Co PLOT Co *MAPK*.Co *orange addmsg /kinetics/PKC-active /graphs/conc1/PKC-active.Co PLOT Co *PKC-active.Co *yellow addmsg /kinetics/PDGFR/PDGFR /graphs/conc2/PDGFR.Co PLOT Co *PDGFR.Co *red addmsg /kinetics/PDGFR/PDGF /graphs/conc2/PDGF.Co PLOT Co *PDGF.Co *red enddump // End of dump call /kinetics/Shc*.Sos.Grb2/notes LOAD \ "This three-way complex is one of the main GEFs for activating Ras." call /kinetics/Shc*.Sos.Grb2/Sos.Ras_GEF/notes LOAD \ "Rates from Orita et al JBC 268(34):25542-25546" call /kinetics/Sos/notes LOAD \ "This represents the mSos protein and the Grb2 adapter protein" \ "involved in Ras activation. This module provides for input from" \ "RTKs as well as feedback inhibition from MAPK, although the" \ "latter is not implemented in this specific model." call /kinetics/Sos/Shc_bind_Sos.Grb2/notes LOAD \ "Sasaoka et al JBC 269:51 pp 32621 1994, table on pg" \ "32623 indicates that this pathway accounts for about " \ "50% of the GEF activation. (88% - 39%). Error is large," \ "about 20%. Fig 1 is most useful in constraining rates." \ "" \ "Chook et al JBC 271:48 pp 30472, 1996 say that the Kd is" \ "0.2 uM for Shc binding to EGFR. The Kd for Grb direct binding" \ "is 0.7, so we'll ignore it." call /kinetics/Sos/Sos*.Grb2/notes LOAD \ "Inactive complex of Sos* with Grb2 due to phosphorylation of the Sos." \ "See Porfiri and McCormick 1996 JBC 271(10):5871." call /kinetics/Sos/Grb2_bind_Sos*/notes LOAD \ "Same rates as Grb2_bind_Sos: Porfiri and McCormick JBC" \ "271:10 pp 5871 1996 show that the binding is not affected" \ "by the phosphorylation." call /kinetics/Sos/Grb2/notes LOAD \ "There is probably a lot of it in the cell: it is also known" \ "as Ash (abundant src homology protein). Also " \ "Waters et al JBC 271:30 18224 1996 say that only a small" \ "fraction of cellular Grb is precipitated out when SoS is" \ "precipitated. As most of the Sos seems to be associated" \ "with Grb2, it would seem like there is a lot of the latter." \ "Say 1 uM. This would comfortably saturate the SoS." call /kinetics/Sos/Sos.Grb2/notes LOAD \ "For simplicity I treat the activation of Sos as involving a" \ "single complex comprising Sos, Grb2 and Shc*. This is" \ "reasonably documented:" \ "Sasaoka et al 1994 JBC 269(51):32621-5" \ "Chook et al JBC 1996 271(48):30472" \ "" call /kinetics/Sos/Sos*/notes LOAD \ "Phosphorylated form of SoS. Nominally this is an inactivation step" \ "mediated by MAPK, see Profiri and McCormick 1996 JBC 271(10):5871." \ "I have not put this inactivation in this pathway so this molecule " \ "currently only represents a potential interaction point." call /kinetics/Sos/dephosph_Sos/notes LOAD \ "The best clue I have to these rates is from the time" \ "courses of the EGF activation, which is around 1 to 5 min." \ "The dephosph would be expected to be of the same order," \ "perhaps a bit longer. Lets use 0.002 which is about 8 min." \ "Sep 17: The transient activation curve matches better with" \ "kf = 0.001" call /kinetics/Sos/Grb2_bind_Sos/notes LOAD \ "As there are 2 SH3 domains, this reaction could be 2nd order." \ "I have a Kd of 22 uM from peptide binding (Lemmon et al " \ "JBC 269:50 pg 31653). However, Chook et al JBC 271:48 pg30472" \ "say it is 0.4uM with purified proteins, so we believe them." \ "They say it is 1:1 binding." \ "Porfiri and McCormick JBC 271 also have related data." \ "After comparing with the time-course of 1 min and the efficacy" \ "of activation of Ras, settle on Kd of 0.672 which is close" \ "to the Chook et al value." call /kinetics/Sos/Sos/notes LOAD \ "I have tried using low (0.02 uM) initial concs, but these" \ "give a very flat response to EGF stim although the overall" \ "activation of Ras is not too bad. I am reverting to 0.1 " \ "because we expect a sharp initial response, followed by" \ "a decline." \ "" call /kinetics/PKC/notes LOAD \ "Protein Kinase C. This module represents a weighted average of" \ "the alpha, beta and gamma isoforms. It takes inputs from" \ "Ca, DAG (Diacyl Glycerol) and AA (arachidonic acid)." \ "Regulation parameters are largely from Schaechter and Benowitz" \ "1993 J Neurosci 13(10):4361 who use synaptosomes from" \ "mammalian brain and in one paper look at all three inputs." \ "Shinomura et al 1991 PNAS 88:5149-5153 is also a useful source" \ "of data and helps to tighten the DAG inputs. " \ "General reviews include Azzi et al 1992 Eur J Bioch 208:541" \ "and Nishizuka 1988, Nature 334:661" \ "Concentration info from Kikkawa et al 1982 JBC 257(22):13341" \ "The process of parameterization is described in detail" \ "in several places. See Supplementary notes to " \ "Bhalla and Iyengar 1999 Science 284:92-96, available at the site" \ "http://www.ncbs.res.in/~bhalla/ltploop/pkc_example.html" \ "The parameterization is also described in a book chapter:" \ "Bhalla, 2000: Simulations of Biochemical Signaling in" \ "Computational Neuroscience: Realistic Modeling for Experimentalists." \ "Ed. E. De Schutter. CRC Press." \ "" call /kinetics/PKC/PKC-Ca/notes LOAD \ "This intermediate is strongly indicated by the synergistic" \ "activation of PKC by combinations of DAG and Ca, as well" \ "as AA and Ca. PKC by definition also has a direct Ca-activation," \ "to which this also contributes." call /kinetics/PKC/PKC-act-by-Ca/notes LOAD \ "This Kd is a straightforward result from the Schaechter and Benowitz" \ "1993 J Neurosci 13(10):4361 curves. The time-course is based on the" \ "known rapid activation of PKC and also the fact that Ca association" \ "with proteins is typically quite fast. My guess is that this tau of" \ "2 sec is quite conservative and the actualy rate may be much faster." \ "The parameter is quite insensitive for most stimuli." \ "" \ "" call /kinetics/PKC/PKC-act-by-DAG/notes LOAD \ "Ca.PKC interaction with DAG is modeled by this reaction." \ "Kf based on Shinomura et al PNAS 88 5149-5153 1991 and" \ "Schaechter and Benowitz 1993 J Neurosci 13(10):4361 and uses" \ "the constraining procedure referred to in the general" \ "notes for PKC." call /kinetics/PKC/PKC-Ca-to-memb/notes LOAD \ "Membrane translocation is a standard step in PKC activation." \ "It also turns out to be necessary to replicate the curves" \ "from Schaechter and Benowitz 1993 J Neurosci 13(10):4361" \ "and Shonomura et al 1991 PNAS 88:5149-5153. These rates" \ "are constrained by matching the curves in the above papers and" \ "by fixing a rather fast (sub-second) tau for PKC activation." call /kinetics/PKC/PKC-DAG-to-memb/notes LOAD \ "membrane translocation step for Ca.DAG.PKC complex." \ "Rates constrained from Shinomura et al 1991 PNAS 88:5149-5153" \ " and Schaechter and Benowitz 1993 J Neurosci 13(10):4361" \ "as derived in the references cited in PKC general notes." call /kinetics/PKC/PKC-act-by-Ca-AA/notes LOAD \ "Ca-dependent AA activation of PKC." \ "Note that this step combines the AA activation and also the " \ "membrane translocation." \ "From Schaechter and Benowitz 1993 J Neurosci 13(10):4361" call /kinetics/PKC/PKC-act-by-DAG-AA/notes LOAD \ "Membrane translocation step for PKC-DAG-AA complex." \ "Rates from matching concentration-effect data in our" \ "two main references:" \ "Schaechter and Benowitz 1993 J Neurosci 13(10):4361 and" \ "Shinomura et al 1988 PNAS 88: 5149-5153" call /kinetics/PKC/PKC-DAG-AA*/notes LOAD \ "Membrane translocated form of PKC-DAG-AA complex." call /kinetics/PKC/PKC-Ca-AA*/notes LOAD \ "Membrane bound and active complex of PKC, Ca and AA." call /kinetics/PKC/PKC-Ca-memb*/notes LOAD \ "This is the direct Ca-stimulated activity of PKC." call /kinetics/PKC/PKC-DAG-memb*/notes LOAD \ "Active, membrane attached form of Ca.DAG.PKC complex." call /kinetics/PKC/PKC-basal*/notes LOAD \ "This is the basal PKC activity which contributes about" \ "2% to the maximum." call /kinetics/PKC/PKC-basal-act/notes LOAD \ "Basal activity of PKC is quite high, about 10% of max." \ "See Schaechter and Benowitz 1993 J Neurosci 13(10):4361 and" \ "Shinomura et al 1991 PNAS 88:5149-5153. This is partly due to" \ "basal levels of DAG, AA and Ca, but even when these are taken" \ "into account (see the derivations as per the PKC general notes)" \ "there is a small basal activity still to be accounted for. This" \ "reaction handles it by giving a 2% activity at baseline." call /kinetics/PKC/PKC-AA*/notes LOAD \ "This is the membrane-bound and active form of the PKC-AA complex." \ "" call /kinetics/PKC/PKC-act-by-AA/notes LOAD \ "AA stimulates PKC activity even at rather low Ca." \ "Schaechter and Benowitz 1993 J Neurosci 13(10):4361" \ "Note that this one reaction combines the initial interaction" \ "and also membrane translocation." call /kinetics/PKC/PKC-Ca-DAG/notes LOAD \ "This is the active PKC form involving Ca and DAG." \ "It has to translocate to the membrane." call /kinetics/PKC/PKC-n-DAG/notes LOAD \ "Binding of PKC to DAG, non-Ca dependent." \ "" \ "Kf based on Shinomura et al PNAS 88 5149-5153 1991" \ "Tau estimated as fast and here it is about the same time-course" \ "as the formation of DAG so it will not be rate-limiting." call /kinetics/PKC/PKC-DAG/notes LOAD \ "This is a DAG-bound intermediate used in synergistic activation" \ "of PKC by DAG and AA." call /kinetics/PKC/PKC-n-DAG-AA/notes LOAD \ "This is one of the more interesting steps. Mechanistically" \ "it does not seem necessary at first glance. Turns out that" \ "one needs this step to quantitatively match the curves" \ "in Schaechter and Benowitz 1993 J Neurosci 13(10):4361" \ "and Shinomura et al 1991 PNAS 88:5149-5153. There is" \ "a synergy between DAG and AA activation even at low" \ "Ca levels, which is most simply represented by this reaction." \ "Tau is assumed to be fast." \ "Kd comes from matching the experimental curves." call /kinetics/PKC/PKC-DAG-AA/notes LOAD \ "Complex of PKC, DAG and AA giving rise to synergistic" \ "activation of PKC by DAG and AA at resting Ca." \ "" call /kinetics/PKC/PKC-cytosolic/notes LOAD \ "Marquez et al J. Immun 149,2560(92) est 1e6/cell for chromaffin cells" \ "" \ "Kikkawa et al 1982 JBC 257(22):13341 have PKC levels in brain at " \ "about 1 uM." \ "" \ "The cytosolic form is the inactive PKC. This is really a composite" \ "of three isoforms: alpha, beta and gamma which have slightly" \ "different properties and respond to different combinations of" \ "Ca, AA and DAG." call /kinetics/DAG/notes LOAD \ "Baseline in model is 11.661 uM." \ "DAG is pretty nasty to estimate. In this model we just hold" \ "it fixed at this baseline level. Data sources are many and" \ "varied and sometimes difficult to reconcile. " \ "Welsh and Cabot 1987 JCB 35:231-245: DAG degradation" \ "Bocckino et al JBC 260(26):14201-14207: " \ " hepatocytes stim with vasopressin: 190 uM." \ "Bocckino et al 1987 JBC 262(31):15309-15315:" \ " DAG rises from 70 to 200 ng/mg wet weight, approx 150 to 450 uM." \ "Prescott and Majerus 1983 JBC 258:764-769: Platelets: 6 uM." \ " Also see Rittenhouse-Simmons 1979 J Clin Invest 63." \ "Sano et al JBC 258(3):2010-2013: Report a nearly 10 fold rise." \ "Habenicht et al 1981 JBC 256(23)12329-12335: " \ " 3T3 cells with PDGF stim: 27 uM" \ "Cornell and Vance 1987 BBA 919:23-36: 10x rise from 10 to 100 uM." \ "" \ "Summary: I see much lower rises in my PLC models," \ "but the baseline could be anywhere from" \ "5 to 100 uM. I have chosen about 11 uM based on the stimulus -response" \ "characteristics from the Schaechter and Benowitz paper and the" \ "Shinomura et al papers." \ "" \ "" \ "" call /kinetics/Ca/notes LOAD \ "This calcium pool is treated as being buffered to a" \ "steady 0.08 uM, which is the resting level. " call /kinetics/AA/notes LOAD \ "Arachidonic Acid. This messenger diffuses through membranes" \ "as well as cytosolically, has been suggested as a possible" \ "retrograde messenger at synapses. " call /kinetics/PKC-active/notes LOAD \ "This is the total active PKC. It is the sum of the respective" \ "activities of " \ "PKC-basal*" \ "PKC-Ca-memb*" \ "PKC-DAG-memb*" \ "PKC-Ca-AA*" \ "PKC-DAG-AA*" \ "PKC-AA*" \ "I treat PKC here in a two-state manner: Either it is in an active" \ "state (any one of the above list) or it is inactive. No matter what " \ "combination of stimuli activate the PKC, I treat it as having the same" \ "activity. The scaling comes in through the relative amounts of PKC" \ "which bind to the respecive stimuli." \ "The justification for this is the mode of action of PKC, which like" \ "most Ser/Thr kinases has a kinase domain normally bound to and blocked" \ "by a regulatory domain. I assume that all the activators simply free" \ "up the kinase domain." \ "A more general model would incorporate a different enzyme activity for" \ "each combination of activating inputs, as well as for each substrate." \ "The current model seems to be a decent and much simpler approximation" \ "for the available data." \ "One caveat of this way of representing PKC is that the summation" \ "procedure assumes that PKC does not saturate with its substrates. " \ "If this assumption fails, then the contributing PKC complexes would" \ "experience changes in availability which would affect their " \ "balance. Given the relatively low percentage of PKC usually activated," \ "and its high throughput as an enzyme, this is a safe assumption under" \ "physiological conditions." \ "" call /kinetics/PKC-active/PKC-act-raf/notes LOAD \ "Rate consts from Chen et al Biochem 32, 1032 (1993)" \ "k3 = 4" \ "Km for this substrate is trickier. Specific substrates are in the" \ "uM range, so we use a higher Km here. This may be too conservative" \ "in which case PKC would have a still higher effect on raf." \ "The presence of this phosphorylation and activation step is from" \ "Kolch et al 1993 Nature 364:249" \ "" \ "" call /kinetics/PKC-active/PKC-inact-GAP/notes LOAD \ "Rate consts are PKC generic rates." \ "This reaction inactivates GAP. The reaction is from the " \ "Boguski and McCormick 1993 review in Nature 366:643-654" \ "The phosphorylation Vmax is 6x higher to account for" \ "balance of GDP-Ras:GDP-Ras." call /kinetics/PKC-active/PKC-act-GEF/notes LOAD \ "Rate constants are generic PKC rates." \ "See Chen et al 1993 Biochem 32:1032" \ "This reaction activates GEF. Gives >= 2X stim of ras, and" \ "a 2X stim of MAPK over amount from direct phosph of" \ "c-raf. Note that it is a push-pull reaction, and also get" \ "effect through phosph and inact of GAPs." \ "" call /kinetics/MAPK/notes LOAD \ "The Mitogen Activated Protein Kinase (MAPK) cascade model " \ "here includes both the MAPK cascade and" \ "its regulation by two forms of MKP. MKP-1 is induced upon MAPK" \ "activation, whereas MKP-2 is treated as a steady level of" \ "protein. The phosphatase Protein phosphatase 2 A (PP2A) " \ "is also included in this model to balance the activity of" \ "the kinases." call /kinetics/MAPK/craf-1/notes LOAD \ "Strom et al 1990 Oncogene 5 pp 345-51 report high general expression" \ "in all tissues." \ "Huang and Ferrell 1996 PNAS 93(19):10078 use a value of 3 nM for oocytes." \ "Here we stick with a much higher expression based on the Strom report." \ "" call /kinetics/MAPK/craf-1*/notes LOAD \ "Singly phosphorylated form of c-raf-1. This is the form that gets" \ "best activated by GTP.Ras." call /kinetics/MAPK/MAPKK/notes LOAD \ "Conc is from Seger et al JBC 267:20 pp14373 (1992)" \ "mwt is 45/46 Kd" \ "We assume that phosphorylation on both ser and thr is needed for" \ "activiation. See Kyriakis et al Nature 358 417 1992" \ "Init conc of total is 0.18" \ "" call /kinetics/MAPK/MAPK/notes LOAD \ "Mol wt is 42 KDa." \ "conc is from Sanghera et al JBC 265 pp 52 (1990)" \ "They estimate MAPK is 1e-4x total protein, and protein is 15% of cell wt," \ "so MAPK is 1.5e-5g/ml = 0.36uM." \ "Lets use this." \ "Note though that Huang and Ferrell 1996 PNAS 93(19):10078" \ "report 1.2 uM in oocytes." \ "Also note that brain concs may be high." \ "Ortiz et al 1995 J. Neurosci 15(2):1285-1297 report " \ "0.3 ng/ug protein in Cingulate Gyrus and 1.2 ng/ug protein" \ "in nucleus accumbens. In hippocampus 270 ng/mg protein for ERK1 and" \ "820 ng/mg protein for ERK 2. " \ "If 15% of cell weight is protein, that means that about 300 * 0.15 ng/ul" \ "is ERK 1. ie, 45e-9g/1e-6 litre = 45 mg/litre or about 1 uM. " \ "For non-neuronal tissues a lower value may be better." call /kinetics/MAPK/craf-1**/notes LOAD \ "Negative feedback by MAPK* by hyperphosphorylating craf-1* gives" \ "rise to this pool." \ "Ueki et al JBC 269(22):15756-15761, 1994" \ "" call /kinetics/MAPK/MAPK-tyr/notes LOAD \ "Haystead et al FEBS Lett. 306(1) pp 17-22 show that phosphorylation" \ "is strictly sequential, first tyr185 then thr183." call /kinetics/MAPK/MAPKK*/notes LOAD \ "MAPKK phosphorylates MAPK on both the tyr and thr residues, first" \ "tyr then thr. Refs: Seger et al JBC267:20 pp 14373 1992" \ "The MAPKK itself is phosphorylated on ser as well as thr residues." \ "Let us assume that the ser goes first, and that the sequential phosphorylation" \ "is needed. See Kyriakis et al Nature 358 417-421 1992" call /kinetics/MAPK/MAPKK*/MAPKKtyr/notes LOAD \ "The actual MAPKK is 2 forms from Seger et al JBC 267:20 14373(1992)" \ "Vmax = 150nmol/min/mg" \ "From Haystead et al FEBS 306(1):17-22 we get Km=46.6nM for at least one" \ "of the phosphs." \ "Putting these together:" \ "k3=0.15/sec, ratio of 4 to get k2=0.6." \ "k1=0.75/46.6nM=2.7e-5" \ "In terms of Michaelis-Menten rates, " \ "Km = 0.046, Vmax = 0.15, ratio = 4." call /kinetics/MAPK/MAPKK*/MAPKKthr/notes LOAD \ "Rate consts same as for MAPKKtyr." call /kinetics/MAPK/MAPKK-ser/notes LOAD \ "Intermediately phophorylated, assumed inactive, form of MAPKK" call /kinetics/MAPK/RGR/notes LOAD \ "Shorthand name for Raf.GTP.Ras. This refers to the complex between" \ "GTP.Ras and the unphosphorylated Raf. I treat this as having the " \ "same enzyme activity as the Raf*.GTP.Ras form." call /kinetics/MAPK/RGR/RGR.1/notes LOAD \ "Kinetics are the same as for the craf-1* activity, ie.," \ "k1=5.5e-6, k2=.42, k3 =0.105" \ "These are based on Force et al PNAS USA 91 1270-1274 1994." \ "" call /kinetics/MAPK/RGR/RGR.2/notes LOAD \ "Same kinetics as other c-raf activated forms. See " \ "Force et al PNAS 91 1270-1274 1994." \ "k1 = 5.5e-6, k2 = .42, k3 = 0.105" \ "" call /kinetics/MAPK/Raf*-GTP-Ras/notes LOAD \ "This is the main activated form of craf. It requires binding to ras for" \ "activation, but the presence of the phosphorylation increases this" \ "binding. See Leevers 1994 Nature 369:411-414 and" \ "Hallberg et al 1994 JBC 269(6):3913-3916" call /kinetics/MAPK/Raf*-GTP-Ras/Raf*-GTP-Ras.1/notes LOAD \ "Kinetics are the same as for the craf-1* activity, ie.," \ "k1=1.1e-6, k2=.42, k3 =0.105" \ "These are based on Force et al PNAS USA 91 1270-1274 1994." \ "They report Km for MAPKK of 0.8 uM. and a Vmax of ~500 fm/min/ug." \ "These parms cannot reach the observed 4X stimulation of MAPK." \ "So we increase the affinity, ie, raise k1 5x to 5.5e-6" \ "which is equivalent to 5-fold reduction in Km to about 0.16." \ "This is, of course, dependent on the amount of MAPKK present." \ "" \ "" call /kinetics/MAPK/Raf*-GTP-Ras/Raf*-GTP-Ras.2/notes LOAD \ "Same kinetics as other c-raf activated forms. See " \ "Force et al PNAS 91 1270-1274 1994." \ "" call /kinetics/MAPK*/notes LOAD \ "This molecule is phosphorylated on both the tyr and thr residues and" \ "is active: Seger et al 1992 JBC 267(20):14373" \ "The rate consts are from two sources: Combine Sanghera et al" \ "JBC 265(1) :52-57 with Nemenoff et al JBC 93 pp 1960 to get" \ " k3 = 10, k2 = 40, k1 = 3.25e-6" call /kinetics/MAPK*/MAPK*-feedback/notes LOAD \ "Ueki et al JBC 269(22):15756-15761 show the presence of" \ "this step, but not the rate consts, which are derived from" \ "Sanghera et al JBC 265(1):52-57, 1990, see the deriv in the" \ "MAPK* notes." call /kinetics/MAPK*/MAPK*/notes LOAD \ "Km = 25uM @ 50 uM ATP and 1mg/ml MBP (huge XS of substrate)" \ "Vmax = 4124 pmol/min/ml at a conc of 125 pmol/ml of enz." \ "Numbers are from Sanghera et al JBC 265 pp 52 , 1990. " \ "From Nemenoff et al 1993 JBC 268(3):1960-1964 - using Sanghera's 1e-4 ratio" \ "of MAPK to protein, we get k3 = 7/sec from 1000 pmol/min/mg total " \ "protein in fig 5" \ "I take the Vmax to be higher for PLA2 given the fold activation of PLA2" \ "by MAPK. This is actually a balance term between MAPK and the dephosphorylation" \ "step." \ "" 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 about 1e-4, giving a Kf of 60 for Kb of 0.5" \ "and a tau of approx 2 sec." \ "Based on:" \ "Hallberg et al JBC 269:6 3913-3916 1994, 3% of cellular Raf is" \ "complexed with Ras." \ "This step needed to memb-anchor and activate Raf:" \ "Leevers et al Nature 369 411-414." \ "Also see Koide et al 1993 PNAS USA 90(18):8683-8686" call /kinetics/PPhosphatase2A/notes LOAD \ "Refs: Pato et al Biochem J 293:35-41(93);" \ "CoInit values span a range depending on source." \ "Pato et al 1993 Biochem J 293:35-41 and" \ "Cohen et al 1988 Meth Enz 159:390-408 estimate 80 nM from muscle" \ "" \ "Zolneierowicz et al 1994 Biochem 33:11858-11867 report" \ "levels of 0.4 uM again from muscle, but expression" \ "is also strong in brain." \ "Our estimate of 0.224 is between these two." \ "" \ "There are many substrates for PP2A in this model, so I put" \ "the enzyme rate calculations here:" \ "Takai&Mieskes Biochem J 275:233-239 have mol wt 36 KDa. They" \ "report Vmax of 119 umol/min/mg i.e. 125/sec for k3 for pNPP substrate," \ "Km of 16 mM. This is obviously unreasonable for protein substrates." \ "For chicken gizzard myosin light chan, we have Vmax = 13 umol/min/mg" \ "or about k3 = 14/sec." \ "" \ "Pato et al 1993 Biochem J 293:35-41 report" \ "caldesmon: Km = 2.2 uM, Vmax = 0.24 umol/min/mg. They do not think " \ "caldesmon is a good substrate. " \ "Calponin: Km = 14.3, Vmax = 5." \ "Our values approximate these." \ "" \ "" 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/MAPKK-deph-ser/notes LOAD \ "See parent PPhostphatase2A description for rate details" 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" \ "assumed to be PP2A." call /kinetics/PLA2/notes LOAD \ "Main 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" \ "Many inputs activate PLA2. In this model I simply take" \ "each combination of stimuli as binding to PLA2 to give a" \ "unique enzymatic activity. The Km and Vmax of these" \ "active complexes is scaled according to the" \ "relative activation reported in the papers above." call /kinetics/PLA2/PLA2-cytosolic/notes LOAD \ "cPLA2 IV form has mol wt of 85 Kd." \ "Glaser et al 1993 TIPS 14:92-98." \ "" \ "Calculated cytosolic concentration is ~300 nM from Wijkander and Sundler" \ "1991 Eur J Biochem 202:873" \ "Leslie and Channon 1990 BBA 1045:261 use about 400 nM. " \ "Decent match. Use 400 nM." \ "" call /kinetics/PLA2/PLA2-Ca-act/notes LOAD \ "Direct activation of PLA2 by Ca." \ "From Leslie and Channon BBA 1045 (1990) 261-270 fig6 pp267." call /kinetics/PLA2/PLA2-Ca*/notes LOAD \ "The generic Ca-activated form ofPLA2." \ "Leslie and Channon 1990 BBA 1045:261." call /kinetics/PLA2/PLA2-Ca*/kenz/notes LOAD \ "Based on Leslie and Channon 1990 BBA 1045:261, in relation to the" \ "other PLA2 inputs (not including MAPK). Ca alone is rather a " \ "weak input." call /kinetics/PLA2/PIP2-PLA2-act/notes LOAD \ "Activation of PLA2 by PIP2. From" \ "Leslie and Channon 1990 BBA 1045:261 the stimulation of PLA2" \ "activity by high PIP2 is 7x." \ "In this model we don't really expect any PIP2 stimulus." \ "" call /kinetics/PLA2/PIP2-PLA2*/kenz/notes LOAD \ "Based on Leslie and Channon 1990 BBA 1045:261." call /kinetics/PLA2/PIP2-Ca-PLA2-act/notes LOAD \ "Synergistic activation of PLA2 by Ca and PIP2. Again from " \ "Leslie and Channon 1990 BBA 1045:261" call /kinetics/PLA2/PIP2-Ca-PLA2*/kenz/notes LOAD \ "Based on AA generation by different stimuli according to" \ "Leslie and Channon 1990 BBA 1045:261" call /kinetics/PLA2/DAG-Ca-PLA2-act/notes LOAD \ "Synergistic activation of PLA2 by Ca and DAG. " \ "Based on Leslie and Channon 1990 BBA 1045:261" \ "The Kd is rather large and may reflect the complications" \ "in measuring DAG. For this model it is not critical " \ "since DAG is held fixed." call /kinetics/PLA2/DAG-Ca-PLA2*/kenz/notes LOAD \ "Based on Leslie and Channon 1990 BBA 1045:261." 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. For now it is treated as" \ "a buffered metabolite." call /kinetics/PLA2/Degrade-AA/notes LOAD \ "Degradation pathway for AA." \ "APC is a convenient buffered pool to dump it back into, though the" \ "actual metabolism is probably far more complex." \ "For the purposes of the full model we use a rate of degradation of" \ "0.4/sec to give a dynamic range of AA comparable to what is seen" \ "experimentally." \ "Wijkander and Sundler 1991 Eur J Biochem 202:873" \ "Leslie and Channon 1990 BBA 1045:261" call /kinetics/PLA2/PLA2*-Ca/notes LOAD \ "Phosphorylated and active form of PLA2. Several kinases act on it:" \ "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" \ "The Nemenoff assays are conducted in rather high Ca so I have" \ "assumed a Ca binding step." call /kinetics/PLA2/PLA2*-Ca/kenz/notes LOAD \ "This form should be 3 to 6 times as fast as the Ca-only form, from" \ "Lin et al 1993 Cell 269-278" \ "Nemenoff et al 1993 JBC 268:1960" \ "Several forms contribute to the Ca-stimulated form, so this rate has" \ "to be a factor larger than their total contribution. " \ "I assign Vmax as the scale factor here because there is lots of APC" \ "substrate, so all the PLA2 complex enzymes are limited primarily by Vmax." call /kinetics/PLA2/PLA2*/notes LOAD \ "Phosphorylated PLA2. The site differs from the site" \ "phosphorylated by PKC. See" \ "Nemenoff et al 1993 JBC 268(3):1960-1964" call /kinetics/PLA2/PLA2*-Ca-act/notes LOAD \ "Nemenoff et al 1993 JBC 268:1960 report a 2X to 4x activation of PLA2" \ "by MAPK, which seems dependent on Ca as well. This reaction " \ "represents this activation. Rates are scaled to give appropriate" \ "fold activation." call /kinetics/PLA2/dephosphorylate-PLA2*/notes LOAD \ "Dephosphorylation reaction to balance MAPK phosphorylation of PLA2." \ "This is probably mediated by PP2A. " \ "Rates determined to keep the balance of phosphorylated and" \ "non-phosphorylated PLA2 reasonable. The constraining factor" \ "is the fold activation of PLA2 by MAPK." call /kinetics/temp-PIP2/notes LOAD \ "This is a steady PIP2 input to PLA2. The sensitivity" \ "of PLA2 to PIP2 discussed below" \ "does not match with the reported free levels which are" \ "used by the phosphlipase Cs. My understanding is that" \ "there may be different pools of PIP2 available for stimulating" \ "PLA2 as opposed to being substrates for PLCs. For that reason" \ "I have given this PIP2 pool a separate identity. As it is" \ "a steady input this is not a problem in this model." \ "" \ "Majerus et al Cell 37:701-703 report a brain concentration of" \ "0.1 - 0.2 mole %" \ "Majerus et al Science 234:1519-1526 report a huge range of " \ "concentrations: from 1 to 10% of PI content, which is in turn" \ "2-8% of cell lipid. This gives 2e-4 to 8e-3 of cell lipid." \ "In concentrations in total volume of cell (a somewhat strange" \ "number given the compartmental considerations) this comes to" \ "anywhere from 4 uM to 200 uM." \ "" \ "PLA2 is stim 7x by PIP2 (Leslie and Channon BBA 1045:261(1990) " \ "Leslie and Channon say PIP2 is present at 0.1 - 0.2mol% range in membs," \ "so I'll use a value at the lower end of the scale for basal PIP2." call /kinetics/Ras/notes LOAD \ " The main refs for Ras 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 25542-25546" call /kinetics/Ras/dephosph-GEF/notes LOAD \ "This rate is based on the known ratio of GDP-Ras to GTP-Ras." \ "Basal: Ras.GTP = 7%" \ "Stimulated 15%" \ "Time course is within 10 min, probably much faster as not" \ "all early data points are there." \ "See Gibbs et al JBC 265(33):20437-20422" call /kinetics/Ras/inact-GEF/notes LOAD \ "This is the amount of inactive GEF available to the system." \ "The value is the same as the estimated amount of SoS, though" \ "I treat it here as a different pool. Probably several molecules" \ "can function as GEFs and this is a simplification." \ "Orita et al JBC 268(34):25542-25546" \ "Gulbins et al 1994 Mol Cell Biol 14(2):906-913" \ "" 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 from Orita et al JBC 268(34):25542-25546." \ "Note that the Vmax is slow, but it does match" \ "the slow GTP hydrolysis rates." \ "" 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 (kf = 1e-4), but it is significant as so little GAP actually" \ "gets complexed with it that the total GTP turnover rises only by" \ "2-3 X (see Gibbs et al, JBC 265(33) 20437-20422) and " \ "Eccleston et al JBC 268(36) 27012-27019" \ "There is no back reaction as we assume this to be a regular" \ "irreversible Michaelis-Menten zeroth order hydrolysis." \ "" call /kinetics/Ras/dephosph-GAP/notes LOAD \ "Assume a reasonably good rate for dephosphorylating it, 0.1/sec." \ "This fits well with resting levels of active kinase and the" \ "degree of activation as well as time-course of turnoff of Ras activation," \ "but data is quite indirect." call /kinetics/Ras/GAP*/notes LOAD \ "Phosphorylated and inactive GAP." \ "See Boguski and McCormick 1993 Nature 366:643-654 for a review." call /kinetics/Ras/GAP/notes LOAD \ "GTPase-activating proteins. See Boguski and McCormick 1993 Nature 366:643-654" \ "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%)." \ "The two sets of values are reasonably close." \ "k1 = 1.666e-3/sec, k2 = 1000/sec, k3 = 10/sec (note k3 is rate-limiting)" \ "This is one of the rare cases where we have direct info on the" \ "k3 being rate-limiting. Hence the ratio I use for the k2:k3 rates is" \ "100 rather than the usual 4." call /kinetics/Ras-act-unphosph-raf/notes LOAD \ "Based on rates of Ras-act-craf which has Kf=60, Kb= 0.5." \ "This reaction was introduced to account for the PKC-independent" \ "activation of MAPK." \ "This reac should have less affinity" \ "but similar tau as compared to the Ras-cat-craf," \ " since the phosphorylated Raf form has" \ "a greater effect on MAPK." \ "" \ "" call /kinetics/PDGFR/notes LOAD \ "Platelet Derived Growth Factor Receptor pathway." \ "Possible outputs include phosphorylation of Shc (which " \ "couples ot Sos and Grb2 to activate Ras) and" \ "phosphorylation of PLC-gamma. The latter is not" \ "implemented in this specific model." call /kinetics/PDGFR/PDGFR/notes LOAD \ "Berkers et al JBC 266 say 22K high affinity receptors per cell." \ "Sherrill and Kyte Biochemistry 35 use range 4-200 nM." \ "These values match reasonably." \ "Heidaran et al 1993 JBC 268(13):9287-9295" \ "use NIH3T3 cells and have 6.5e4 receptors/cell. This is" \ "also in the same general range. We use this last" \ "value because the cell type matches." call /kinetics/PDGFR/act_PDGFR/notes LOAD \ "From Heidaran et al JBC268(13):9287 Fig 5." \ "Kd is ~0.5 nM" call /kinetics/PDGFR/L.PDGFR/notes LOAD \ "This is terribly simplified: there are many interesting" \ "intermediate stages, including dimerization and assoc" \ "with adapter molecules like Shc, that contribute to the" \ "activation of the EGFR." call /kinetics/PDGFR/L.PDGFR/phosph_Shc/notes LOAD \ "Rates from Okada et al JBC 270:35 pp 20737 1995" \ "Km = 0.70 to 0.85 uM, Vmax = 4.4 to 5.0 pmol/min. Unfortunately" \ "the amount of enzyme is not known, the prep is only" \ "partially purified." \ "Tau phosph is max within 30 sec, falls back within" \ "20 min. Ref: Sasaoka et al JBC 269:51 32621 1994." \ "Use k3 = 0.1 based on this tau." \ "27 Apr 2001: Lowered k3 to 0.05 to fix conc-effect of SHC phosph" \ "by PDGF. This gives results for downstream effects in" \ "agreement with other papers, e.g., the Brondello papers." call /kinetics/PDGFR/PDGF/notes LOAD \ "Platelet-derived growth factor. Heterodimer Mol wt. is approx 30 KDa" \ "Deuel et al 1985 Cancer Surv. 4(4):633-53" \ "Conc of 50 ng/ml is close to saturating, and is used by P. Ram (personal" \ "communication). Other refs use 65 ng/ml" \ "Weise RJ et al 1995 JBC 270(7):3442-3446" \ "A stimulus of 5 min is commonly used." \ "Conversion factor: " \ "1ng/ml = (1e-9/30K)* 1000 Moles/litre = 3e-11M = 3e-5 uM" \ "So 50 ng/ml ~ 1.5 nM." call /kinetics/PDGFR/SHC/notes LOAD \ "There are 2 isoforms: 52 KDa and 46 KDa (See Okada et al" \ "JBC 270:35 pp 20737 1995). They are acted up on by the EGFR" \ "in very similar ways, and apparently both bind Grb2 similarly," \ "so we'll bundle them together here." \ "Sasaoka et al JBC 269:51 pp 32621 1994 show immunoprecs where" \ "it looks like there is at least as much Shc as Grb2. So" \ "we'll tentatively say there is 1 uM of Shc." call /kinetics/PDGFR/SHC*/notes LOAD \ "Phosphorylated form of SHC. Binds to the SoS.Grb2 " \ "complex to give the activated GEF form upstream" \ "of Ras." call /kinetics/PDGFR/dephosph_Shc/notes LOAD \ "Time course of decline of phosph is 20 min from Sasaoka" \ "et al 1994 JBC 269(51):32621. Part of this is" \ "the turnoff time of the EGFR itself. Lets assume a tau of" \ "10 min for this dephosphorylation as a first pass." \ "27 Apr 2001: Dephosph too slow, shifts SHC balance over to" \ "phosphorylated form. Increase Kf to 0.01. This gives a reasonable" \ "overall time-course." call /kinetics/PDGFR/Internal_L.PDGFR/notes LOAD \ "The internalized PDGFR is treated as a generic pool in equilibrium with" \ "the surface receptor. This simplifies the turnover processes but" \ "fits reasonably well with data." call /kinetics/PDGFR/Internalize/notes LOAD \ "Original model derived from EGFR model." \ "See Helin and Beguinot JBC 266:13 1991 pg 8363-8368." \ "In Fig 3 they have internalization tau about 10 min, " \ "equil at about 20% EGF available. So kf = 4x kb, and" \ "1/(kf + kb) = 600 sec so kb = 1/3K = 3.3e-4," \ "and kf = 1.33e-3. This doesn't take into account the" \ "unbound receptor, so we need to push the kf up a bit, to" \ "0.002" \ "26 apr 2001: Keq too low for the PDGF model." \ "Now Kf=0.001,Kb=0.00066" \ "The previously calculated internalization equilibrium" \ "led to very high internalization which shifted the effective" \ "dependence of the receptor on PDGF so it looked like the" \ "receptor binding was higher affinity than experimentally" \ "determined. Used two constraining factors: " \ "1. Time course of " \ "SHC phosphorylation/dephosphorylation which is fast on, but" \ "10-20 minutes off." \ "2. Conc dependence of MAPK on PDGF has a halfmax around 3ng/ml." \ "See Brondello et al 1997 JBC 272(2):1368-1376 and " \ "Brondello et al 1999 Science 286:2514-1517." \ "" \ "" \ "" call /kinetics/MKP-2/notes LOAD \ "MKP2 is modeled to act as a relatively steady," \ "unregulated phosphatase for controlling MAPK activity." \ "From Brondello et al JBC 272(2):1368-1376 (1997), the" \ "blockage of MKP-1 induction increases MAPK activity by" \ "no more than 2x. So this phosphatase will play the steady" \ "role and the fully stimulated MKP-1 can come up to the" \ "level of this steady level." \ "From Chu et al 1995 JBC 271(11):6497-6501 it looks like" \ "both MKP-1 and MKP-2 have similar activities in dephosphorylating" \ "ERK2. So I use the same enzymatic rates for both." \ "" \ "31 Jan 2002: For the purposes of making a bistable model without the" \ "complications of MKP-1 induction, I simply set the initial" \ "conc of MKP-2 up by 0.0004 uM which was the starting level of MKP-1." call /kinetics/MKP-2/MKP2-tyr-deph/notes LOAD \ "22 Apr 2001: Based on MKP1 parms." \ "The original kinetics have been modified to obey the k2 = 4 * k3 rule," \ "while keeping kcat and Km fixed. The only constraining" \ "data point is the time course of MAPK dephosphorylation, which this" \ "model satisfies." \ "" \ "The rates are treated as the same as for MKP-1, based on" \ "Chu et al 1995 JBC 271(11):6497-6501" call /kinetics/MKP-2/MKP2-thr-deph/notes LOAD \ "See MKP2-tyr-deph" call /kinetics/doqcsinfo/notes LOAD \ "Model for figure 1c in Bhalla US et al. Science (2002) 297(5583):1018-23.
The demo for this figure is available here. This synaptic signaling model is without the MKP-1 feedback, so it is bistable and remains so over long periods." complete_loading