// DOQCS : http://doqcs.ncbs.res.in/ // Accession Name = mkp1_feedback_effects // Accession Number = 4 // Transcriber = Upinder S. Bhalla, NCBS // Developer = Upinder S. Bhalla, NCBS // Species = Generic mammalian // Tissue = NIH 3T3 Expression // Cell Compartment = Surface - nucleus // Notes = This is a network involving the MAPK-PKC feedback loop with input from the PDGFR in the synapse. The distinctive feature of this model is that it includes MKP-1 induction by MAPK, and the consequent inhibitory regulation of MAPK and the feedback loop. Lots of interesting dynamics arise from this. This link provides supplementary material for the paper Bhalla US et al. Science (2002) 297(5583):1018-23. In the form of several example simulations and demos for the figures in the paper. //genesis // kkit Version 11 flat dumpfile // Saved on Thu Dec 8 13:03:54 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 expanded movealone \ link 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Bhalla, NCBS" "Upinder S. Bhalla, NCBS" "citation here" \ "Generic Mammalian" "NIH 3T3 Expression" "Surface - nucleus" \ "Quantitative match to experiments" \ "( Peer-reviewed publication )" \ "Exact GENESIS implementation" \ "Replicates original data , Quantitatively predicts new data" 90 108 0 simundump xgraph /graphs/conc1 0 0 26000 0 0.12896 0 simundump xgraph /graphs/conc2 0 0 26000 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/conc1/nuc_MAPK*.Co 3 524288 \ "delete_plot.w ; edit_plot.D " 47 0 0 1 simundump xplot /graphs/conc1/tot_MAPK.Co 3 524288 \ "delete_plot.w ; edit_plot.D " blue 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/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 xplot /graphs/conc2/tot_MKP1.Co 3 524288 \ "delete_plot.w ; edit_plot.D " 30 0 0 1 simundump xgraph /moregraphs/conc3 0 0 26000 0 1 0 simundump xgraph /moregraphs/conc4 0 0 26000 0 1 0 simundump xcoredraw /edit/draw 0 13 113 -2 117 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 fb28c.g, cleaning up notes and in a couple of cases" \ "the naming of pools. No parameter changes." \ "This version has notes for all parameters." 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 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/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/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/MKP-2/MKP2-thr-deph /kinetics/MAPK* REAC sA 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*dephosph /kinetics/MKP-1 REAC B A addmsg /kinetics/MAPK/MKP1_synth /kinetics/MKP-1 REAC B A 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/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/phosph_PLC_g /kinetics/PDGFR/L.PDGFR REAC eA 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/L.PDGFR /kinetics/PDGFR/L.PDGFR/phosph_PLC_g ENZYME 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-1 /kinetics/tot_MKP1 SUMTOTAL n nInit addmsg /kinetics/MAPK/MKP-1-ser359* /kinetics/tot_MKP1 SUMTOTAL n nInit addmsg /kinetics/MAPK/MKP-1** /kinetics/tot_MKP1 SUMTOTAL n nInit 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* /kinetics/tot_MAPK SUMTOTAL n nInit addmsg /kinetics/MAPK/nuc_MAPK* /kinetics/tot_MAPK SUMTOTAL n nInit 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/MAPK/nuc_MAPK* /graphs/conc1/nuc_MAPK*.Co PLOT Co *nuc_MAPK*.Co *47 addmsg /kinetics/tot_MAPK /graphs/conc1/tot_MAPK.Co PLOT Co *tot_MAPK.Co *blue addmsg /kinetics/MKP-1 /graphs/conc2/MKP-1.Co PLOT Co *MKP-1.Co *hotpink 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 addmsg /kinetics/tot_MKP1 /graphs/conc2/tot_MKP1.Co PLOT Co *tot_MKP1.Co *30 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. [Porfiri E and McCormick F. (1996) J Biol Chem. 271(10):5871-5877]" 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 SJ, Klann E, Gower MC, Powell CM, Sessoms JS, Sweatt JD. (1993) Biochemistry 32(4):1032-9. 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/Ubiquitination/notes LOAD \ "This is a representation of generic ubiquitination followed" \ "by degradation. Since this pool is buffered to zero, anything" \ "that ends up here is removed from the model." call /kinetics/MAPK/turnover_MKP1/notes LOAD \ "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-ser359*/notes LOAD \ "Singly phosphorylated form of MKP-1. Slower" \ "ubiquitination. See Brondello et al 1999 Science 286:2514" \ "From the simulations, this form has a rather low and transient" \ "level. So I do not include it in the dephosphorylation of" \ "MAPK." call /kinetics/MAPK/MKP-1**/notes LOAD \ " Same enzyme activity as MKP-1, but different" \ "degradation rates. Brondello et al Science 286:2514 1999" \ "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 \ " 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 exponential falloff. " call /kinetics/MAPK/turnover_MKP1*/notes LOAD \ "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 exponential 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" \ "13 Apr 2001: MKP1* Goes down too fast, equil amount too small." \ "Note that tau for turnover is 150 min. Doesn't make sense " \ "to have this tau be so much less. Go for 1e-4" 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" \ "13 Apr 2001. Slowing down to 0.0001 to match turnover" \ "rates." call /kinetics/MAPK/translocation/notes LOAD \ "A nuclear translocation step. This lumps in all sorts of " \ "processes into a single set of rates constrained by time courses." \ "Furuno et al J Immunol 166:4416-4421 (2001):" \ "In within 6 min, out within 7. The outgoing path is dephosphorylated" \ "MAPK so this reac will be one-way." \ " Kf=0.01, Kb=0.005. The reaction is 2nd order in MAPK*," \ "to represent dimerization of transcription factors." call /kinetics/MAPK/nuc_MAPK*/notes LOAD \ "" \ "Cytoplasmic MAPK declines 20%, nuclear MAPK rises 100%." \ "Furuno et al J Immunol 166:4416 (2001)" \ "Assume nuc vol 1/5 that of cytoplasm" \ "so nuc vol = 2e-16" \ "Note therefore that the concentrations here will be higher" \ "for the same number of molecules." \ "" call /kinetics/MAPK/nuc_MAPK*/act_transcription/notes LOAD \ "" \ "This is a 'black box' representation of a lot of steps." \ " Constraint provided by" \ "determining rate of formation of MKP-1." call /kinetics/MAPK/MKP1-RNA/notes LOAD \ "The MKP-1 RNA is treated as the rate-limiting quantity" \ "for synthesis of MKP-1. " call /kinetics/MAPK/MKP1_synth/notes LOAD \ "This is a 'black box' approximation to the process of" \ "translation. I assume that there is unity stoichiometry, that is," \ "a single RNA gives a single protein. This is obviously" \ "wrong, but since the RNA level itself is just a ratio" \ "against baseline, the conversion factor is absorbed there." call /kinetics/MAPK/Nucleotides/notes LOAD \ "Infinite supply assumed for formation of mRNA." call /kinetics/MAPK/Basal_transcription/notes LOAD \ "This is just a basal rate of MKP-1 transcription" \ "scaled to give reasonable basal levels of the MKP-1." 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/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." \ "The Vmax is scaled down 10 fold to match the time-course" \ "of phosph by MAPK, from the Brondello paper." 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." \ "The Vmax is scaled down by 10 fold to match the time-courses" \ "from the Brondello experiment. " \ "" call /kinetics/MKP-1/notes LOAD \ "MKP-1 dephosphorylates and inactivates MAPK in vivo: Sun et al Cell 75 " \ "487-493 1993. " \ "See Charles et al PNAS 90:5292-5296 1993 and" \ "Charles et al Oncogene 7 187-190 for half-life of" \ "MKP1/3CH is 40 min. 80% deph of MAPK in 20 min" \ "The protein is 40 KDa." \ "" \ "22 Apr 2001: CoInit =0.4nM but this is really an emergent property" \ "of the rate of induction of the phosphatase at steady-state in balance" \ "with the degradation rate." call /kinetics/MKP-1/MKP1-tyr-deph/notes LOAD \ "The original kinetics from Bhalla and Iyengar Science 1999" \ "have now been modified to obey the k2 = 4 * k3 rule," \ "while keeping kcat and Km fixed. The main constraining" \ "data point is the time course of MAPK dephosphorylation, which this" \ "model satisfies." \ "See Charles et al 1993 PNAS 90:5292-5296 and" \ "Charles et al Oncogene 7:187-190" \ "" \ "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 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/L.PDGFR/phosph_PLC_g/notes LOAD \ "Hsu et al JBC 266:1 603-608 1991" \ "Km = 385 +- 100 uM, Vm = 5.1 +-1 pmol/min/ug for PLC-771." \ "Other sites have similar range, but are not stimulated as much" \ "by EGF." \ "k1 = 2.8e-2/385/6e5 = 1.2e-10. Phenomenally slow." \ "But Sherrill and Kyte say turnover # for angiotensin II is" \ "5/min for cell extt, and 2/min for placental. Also see" \ "Okada et al for Shc rates which are much faster." \ "In this model I do not use PLC-gamma as preliminary" \ "runs suggested that it has a relatively small effect" \ "on PKC and the MAPK pathway as compared to the direct" \ "effect through Ras." 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/tot_MKP1/notes LOAD \ "Total available active MKP-1. This sums the levels" \ "of the non-phosphorylated, singly phosphorylated and" \ "doubly phosphorylated forms. It is used primarily" \ "for graphing the total MKP-1 level." 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." 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/tot_MAPK/notes LOAD \ "Total available active MAPK. This sums the levels" \ "of the cytosolic and nuclear localized forms." call /kinetics/doqcsinfo/notes LOAD \ "This is a network involving the MAPK-PKC feedback loop with input from the PDGFR in the synapse. The distinctive feature of this model is that it includes MKP-1 induction by MAPK, and the consequent inhibitory regulation of MAPK and the feedback loop. Lots of interesting dynamics arise from this. This link provides supplementary material for the paper Bhalla US et al. Science (2002) 297(5583):1018-23. In the form of several example simulations and demos for the figures in the paper." complete_loading