# egfr_extended.bngl # EGF receptor signaling model, extended through Ras, Raf, Mek and Erk. # # Aggregated by Niketh Nair and Lori Stover (at Faeder Lab, U. Pitt, 2011-2012), # based on previous modeling work by: # (1) ML Blinov, JR Faeder, B Goldstein, WS Hlavacek. # "A network model of early events in epidermal growth factor # receptor signaling that accounts for combinatorial complexity." # BioSystems 83, 136–151 (2006). # (2) EC Stites, PC Trampont, Z Ma, KS Ravichandran. # "Network analysis of oncogenic Ras activation in cancer." # Science 318, 463–467 (2007). # (3) A Fujioka, et al. # "Dynamics of the Ras/ERK MAPK cascade as monitored by fluorescent probes." # J. Biol. Chem. 281, 8917–8926 (2006). begin model begin parameters # fundamental parameters and geometry NA 6.0221e23 # /mol, Avogadro's number f 0.01 # no units, fraction of cell to simulate Vext 0.94e-12*f # L, volume of extracellular space (per cell) Vcyt 0.94e-12*f # L, volume of cytoplasm (ref:Fujioka2006,HeLa) Vnuc 0.22e-12*f # L, volume of nucleus (ref:Fujioka2006,HeLa) # initial species counts Egf_0 680e-9*Vext*NA # counts (ref:Blinov2006 680 nM) Egfr_0 100e-9*Vcyt*NA # counts (ref:Blinov2006 100 nM) PLCg_0 105e-9*Vcyt*NA # counts (ref:Blinov2006 105 nM) Shc_0 150e-9*Vcyt*NA # counts (ref:Blinov2006 150 nM) Grb2_0 (58e-9 + 27e-9)*Vcyt*NA # counts (ref:Blinov2006 58 nM Grb2 + 27 nM Grb2-Sos) Sos_0 ( 7e-9 + 27e-9)*Vcyt*NA # counts (ref:Blinov2006 7 nM Sos + 27 nM Grb2-Sos) # kinetic parameters kelim 5e-3 # /s, elimination rate for free ligand kp1 0.003e9/Vext/NA # /s, ligand-receptor binding (ref:Blinov2006) km1 0.06 # /s kp2 0.01e9/Vcyt/NA # /s, receptor dimerization (ref:Blinov2006) km2 0.1 # /s kp3 0.5 # /s, receptor tyrosine phosphorylation (ref:Blinov2006) km3 4.505 # /s, receptor tyrosine dephosphorylation (ref:Blinov2006) kp5 0.03e9/Vcyt/NA # /s, binding of PLCg to pY992 (ref:Blinov2006) km5 0.2 # /s kp6 0.5 # /s, transphosphorylation of PLCg (ref:Blinov2006) km6 0.025 # /s kp7 0.003e9/Vcyt/NA # /s, binding of PLCg-Y to pY992 (ref:Blinov2006) km7 0.3 # /s km8 0.01 # /s, dephosphorylation of PLCg (ref:Blinov2006) kp9 0.0015e9/Vcyt/NA # /s, binding of Grb2 to pY1068 (ref:Blinov2006) km9 0.05 # /s kp10 0.01e9/Vcyt/NA # /s, binding of Sos to pY1068-Grb2 (ref:Blinov2006) km10 0.06 # /s kp11 0.00225e9/Vcyt/NA # /s, binding of Grb2-Sos to pY1068 (ref:Blinov2006) km11 0.03 # /s kp12 0.0001e9/Vcyt/NA # /s, cytosolic binding of Grb2 and Sos (ref:Blinov2006) km12 0.0015 # /s kp13 0.045e9/Vcyt/NA # /s, binding of Shc to pY1148 (ref:Blinov2006) km13 0.6 # /s kp14 3.0 # /s, phosphorylation of Shc (ref:Blinov2006) km14 0.03 # /s kp15 0.00045e9/Vcyt/NA # /s, binding of ShcP to pY1148 (ref:Blinov2006) km15 0.3 # /s, diss. of ShcP from receptor (ref:Blinov2006) km16 0.005 # /s, cytosolic ShcP dephosphorylation (ref:Blinov2006) kp17 0.003e9/Vcyt/NA # /s, binding of Grb2 to pY1148-ShcP (ref:Blinov2006) km17 0.1 # /s kp18 0.00045e9/Vcyt/NA # /s, binding of ShcP-Grb2 to pY1148 (ref:Blinov2006) km18 0.3 # /s kp19 0.01e9/Vcyt/NA # /s, binding of Sos to pY1148-ShcP-Grb2 (ref:Blinov2006) km19 0.0214 # /s kp20 0.00012e9/Vcyt/NA # /s,ShcP-Grb2-Sos binding to pY1148 (ref:Blinov2006) km20 0.12 # /s kp21 0.003e9/Vcyt/NA # /s, cytosolic binding of Grb2 to ShcP (ref:Blinov2006) km21 0.1 # /s kp22 0.03e9/Vcyt/NA # /s, cytosolic binding of Sos to ShcP-Grb2 (ref:Blinov2006) km22 0.064 # /s kp23 0.021e9/Vcyt/NA # /s, cytosolic binding of Grb2-Sos to ShcP (ref:Blinov2006) km23 0.1 # /s kp24 0.009e9/Vcyt/NA # /s, binding of Grb2-Sos to pY1148-ShcP (ref:Blinov2006) km24 0.0429 # /s kp25 1.0 # /s, inactivation of PLCg-P (ref:Blinov2006) km25 0.03 # /s, activation of PLCg-PI (ref:Blinov2006) # initial species counts GTP 180e-6*Vcyt*NA # counts, cellular GTP (ref:stites2007) GDP 18e-6*Vcyt*NA # counts, cellular GDP (ref:stites2007) GAP_0 1e-9*Vcyt*NA # counts (60 pM), basally active GAP (ref:stites2007) Ras_0 0.40e-6*Vcyt*NA # counts, total Ras (ref:fujioka2006, HeLa) Raf_0 0.013e-6*Vcyt*NA # counts, total Ras (ref:fujioka2006, HeLa) MEK_0 1.4e-6*Vcyt*NA # counts, total MEK (ref:fujioka2006, HeLa) ERK_0 0.96e-6*Vcyt*NA # counts, total ERK (ref:fujioka2006, HeLa) # Membrane recruitment enhancement factor D 1000 # no units (D=250, ref:stites2007) # Ras kinetic parameters khyd 3.5e-4 # /s, GTP hydrolysis by Ras (ref:stites2007) kdgdp 1.1e-4 # /s, GDP dissociation from Ras (ref:stites2007) kdgtp 2.5e-4 # /s, GTP dissociation from Ras (ref:stites2007) kagdp 2.3e6*GDP/NA/Vcyt # /s, association of GDP to Ras (ref:stites2007) kagtp 2.2e6*GTP/NA/Vcyt # /s, association of GTP to Ras (ref:stites2007) # GEF activity (membrane Sos) kcatgdp 3.9 # /s, kcat for RasGDP -> RasGTP by membrane Sos (ref:stites2007) kcatgtp 7.2e-1 # /s, kcat for RasGTP -> RasGDP by membrane Sos (ref:stites2007) Kmgdp 0.156e-6*Vcyt*NA # no units (3.86e-4 M, ref:stites2007), Michaelis constant for RasGDP->RasGTP by membrane Sos Kmgtp 0.156e-6*Vcyt*NA # no units (3e-4 M, ref:stites2007), Michaelis constant for RasGTP->RasGTP by membrane Sos # the Michaelis constant is given by Km := (kr + kcat)/kf # assume kf_basal*D = kf; while kcat, kr remain unchanged kfgdp (2.5e4*D)/NA/Vcyt # /s, membrane Sos binding to RasGDP, derived krgdp 1e-12 # # /s, derived from relation Km := (kr + kcat)/kf [Note: (Kmgdp * kfgdp) - kcatgdp ~= 0] kfgtp (2.5e4*D)/NA/Vcyt # /s, membrane Sos binding to RasGTP, derived krgtp (Kmgtp*kfgtp) - kcatgtp # /s, derived from relation Km := (kr + kcat)/kf # GAP activity kcat_GAP 5.40 # /s, catalytic rate for RasGTP->RasGDP in presence of GAP (ref:stites2007) Km_GAP 0.23e-6*Vcyt*NA # no units, Michaelis constant for RasGTP->RasGDP catalyzed by GAP (ref:stites2007) kf_GAP (1e5*D)/Vcyt/NA # /s, arbitrary kr_GAP (Km_GAP*kf_GAP) - kcat_GAP # /s, derived from Km := (kr + kcat)/kf # Fujioka2006 parameters kp_f1 0.49e6 # /M/s, activated Ras binds Raf (ref:fujioka2006, step 1f) km_f1 0.049 # /s, activated Ras unbinds Raf (ref:fujioka2006, step 1r) kp_f2 0.65e6 # /M/s, Ras-RafP binds MEK (ref:fujioka2006, step 2f) km_f2 0.065 # /s, Ras-RafP unbinds MEK (ref:fujioka2006, step 2r) kp_f3 0.88e6 # /M/s, MEKP-ERK Binding (ref:fujioka2006, step 3f,4f,13f,14f) km_f3 0.088 # /s, MEKP-ERK Unbinding (ref:fujioka2006, step 3r,4r,13r,14r) Vm_f6 0.18 # /s, Ras-Raf-MEK -> Ras-Raf + pMERK (ref:fujioka2006, step 6) Vm_f5 0.22 # /s, pMEK-ERK -> pMEK + pERK (ref:fujioka2006, step 5,15) k_f16 0.010 # /s, pMEK -> MEK (ref:fujioka2006, step 16,18) k_f17 0.014 # /s, pERK -> ERK (ref:fujioka2006, step 17,19) kex_f7 0.61 # /s, MEKnuc -> MEKcyt (ref:fujioka2006, step 7) kin_f7 0.046 # /s, MEKcyt -> MEKnuc (ref:fujioka2006, step 7) kex_f10 0.54 # /s, pMEKnuc -> pMEKcyt (ref:fujioka2006, step 10) kin_f10 0.040 # /s, pMEKcyt -> pMEKnuc (ref:fujioka2006, step 10) kex_f9 0.018 # /s, ERKnuc -> ERKcyt (ref:fujioka2006, step 9) kin_f9 0.0086 # /s, ERKcyt -> ERKnuc (ref:fujioka2006, step 9) kex_f8 0.26 # /s, (p)MEK-ERKnuc -> (p)MEK-ERKcyt (ref:fujioka2006, step 8,12) kin_f8 0.035 # /s, (p)MEK-ERKcyt -> (p)MEK-ERKnuc (ref:fujioka2006, step 8,12) kex_f11 0.013 # /s, pERKnuc -> pERKcyt (ref:fujioka2006, step 11) kin_f11 0.0070 # /s, pERKcyt -> pERKnuc (ref:fujioka2006, step 11) end parameters begin molecule types ## EGF-EGFR-SHC-Grb2-Sos Egf(r) Egfr(l,d,Y992~Y~pY,Y1068~Y~pY,Y1148~Y~pY) Shc(PTB,Y317~Y~pY) Grb2(SH2,SH3) Sos(dom,ras) PLCg(a,b~0~P,c~0~I) ## Ras-Raf-MEK-ERK Ras(nuc~U~GDP~GTP,raf,cat) Raf(ras,bind,phos~P~U) GAP(ras) MEK(bind,phos~U~P,loc~cyt~nuc) ERK(bind,phos~U~P,loc~cyt~nuc) end molecule types begin seed species # pre-equilibrated Egf(r) 384933*f Grb2(SH2,SH3) 32825*f Shc(PTB,Y317~Y) 84912*f Sos(dom,ras) 3931*f Egfr(Y992~Y,Y1068~Y,Y1148~Y,d,l) 56608*f PLCg(a,b~0,c~0) 59438*f Raf(bind,phos~U,ras) 5057*f GAP(ras) 529*f MEK(bind,loc~cyt,phos~U) 391192*f ERK(bind,loc~cyt,phos~U) 43988*f Grb2(SH2,SH3!1).Sos(dom!1,ras) 15198*f Ras(cat,nuc~GDP,raf) 214883*f Ras(cat,nuc~GTP,raf) 9093*f ERK(bind!1,loc~cyt,phos~U).MEK(bind!1,loc~cyt,phos~U) 298315*f MEK(bind,loc~nuc,phos~U) 30348*f ERK(bind,loc~nuc,phos~U) 60758*f Ras(cat!1,nuc~GDP,raf).Sos(dom,ras!1) 12*f Grb2(SH2,SH3!1).Ras(cat!2,nuc~GDP,raf).Sos(dom!1,ras!2) 46*f Ras(cat!1,nuc~GTP,raf).Sos(dom,ras!1) 12*f Grb2(SH2,SH3!1).Ras(cat!2,nuc~GTP,raf).Sos(dom!1,ras!2) 47*f GAP(ras!1).Ras(cat!1,nuc~GTP,raf) 37*f Raf(bind,phos~P,ras!1).Ras(cat,nuc~GTP,raf!1) 812*f ERK(bind!1,loc~nuc,phos~U).MEK(bind!1,loc~nuc,phos~U) 38240*f MEK(bind!1,loc~cyt,phos~U).Raf(bind!1,phos~P,ras!2).Ras(cat,nuc~GTP,raf!2) 1489*f MEK(bind,loc~cyt,phos~P) 24956*f ERK(bind!1,loc~cyt,phos~U).MEK(bind!1,loc~cyt,phos~P) 5465*f MEK(bind,loc~nuc,phos~P) 1858*f ERK(bind!1,loc~nuc,phos~U).MEK(bind!1,loc~nuc,phos~P) 646*f ERK(bind,loc~cyt,phos~P) 72077*f ERK(bind,loc~nuc,phos~P) 23946*f end seed species begin observables ## EGF-EGFR-SHC-Grb2-Sos Molecules Dimers Egfr(d!0).Egfr(d!0) Molecules RP Egfr(Y992~pY!?), Egfr(Y1068~pY!?), Egfr(Y1148~pY!?) Molecules Shc_Grb Shc(Y317~pY!0).Grb2(SH2!0) Molecules Shc_Grb_Sos Shc(Y317~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1) Molecules R_Grb2 Egfr(Y1068~pY!0).Grb2(SH2!0) Molecules R_Shc Egfr(Y1148~pY!0).Shc(PTB!0,Y317~Y) Molecules R_ShcP Egfr(Y1148~pY!0).Shc(PTB!0,Y317~pY!?) Molecules R_pY992 Egfr(Y992~pY!?) Molecules R_PLCg Egfr(Y992~pY!0).PLCg(a!0) Molecules ShcP Shc(Y317~pY!?) Molecules PLCgP PLCg(b~P,c~0) Molecules PLCgPI PLCg(b~P,c~I) Molecules Sos_mem Shc(PTB!+,Y317~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1), Egfr(Y1068~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1) Molecules Sos_cyt Shc(PTB,Y317~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1), Grb2(SH2,SH3!1).Sos(dom!1), Sos(dom) Molecules RasGDP Ras(nuc~GDP) Molecules RasGTP Ras(nuc~GTP) Molecules RafU Raf(phos~U!?) Molecules RafP Raf(phos~P!?) Molecules MEK_act MEK(phos~P!?) Molecules ERK_act ERK(phos~P!?) Molecules MEK_nuc MEK(loc~nuc) Molecules ERK_nuc ERK(loc~nuc) Molecules MEK_P_nuc MEK(phos~P!?,loc~nuc) Molecules ERK_P_nuc ERK(phos~P!?,loc~nuc) # totals Molecules Egf_tot Egf() Molecules Egfr_tot Egfr() Molecules PLCg_tot PLCg() Molecules Shc_tot Shc() Molecules Grb2_tot Grb2() Molecules Sos_tot Sos() Molecules GAP_tot GAP() Molecules Ras_tot Ras() Molecules Raf_tot Raf() Molecules MEK_tot MEK() Molecules ERK_tot ERK() end observables begin reaction rules # EGF elimination EGF_elim: Egf(r) -> 0 kelim ## EGF-EGFR-SHC-Grb2-Sos # Ligand-receptor binding B1: Egfr(l,d) + Egf(r) <-> Egfr(l!0,d).Egf(r!0) kp1, km1 # Receptor-aggregation B2: Egfr(l!+,d) + Egfr(l!+,d) <-> Egfr(l!+,d!0).Egfr(l!+,d!0) kp2, km2 # Transphosphorylation of Egfr by RTK B3p_992: Egfr(d!+,Y992~Y) -> Egfr(d!+,Y992~pY) kp3 B3p_1068: Egfr(d!+,Y1068~Y) -> Egfr(d!+,Y1068~pY) kp3 B3p_1148: Egfr(d!+,Y1148~Y) -> Egfr(d!+,Y1148~pY) kp3 # Dephosphorylayion B3m_992: Egfr(Y992~pY) -> Egfr(Y992~Y) km3 B3m_1068: Egfr(Y1068~pY) -> Egfr(Y1068~Y) km3 B3m_1148: Egfr(Y1148~pY) -> Egfr(Y1148~Y) km3 # Shc transphosph B14p: Egfr(d!+,Y1148~pY!0).Shc(PTB!0,Y317~Y) \ -> Egfr(d!+,Y1148~pY!0).Shc(PTB!0,Y317~pY) kp14 B14m: Shc(PTB!+,Y317~pY) -> Shc(PTB!+,Y317~Y) km14 # PLCg transphosph B6p: Egfr(d!+,Y992~pY!1).PLCg(a!1,b~0) \ -> Egfr(d!+,Y992~pY!1).PLCg(a!1,b~P) kp6 # PLCg dephosphorylation at membrane B6m: Egfr(Y992~pY!1).PLCg(a!1,b~P) \ -> Egfr(Y992~pY!1).PLCg(a!1,b~0) km6 # Y992 activity B5: Egfr(Y992~pY) + PLCg(a,b~0,c~0) \ <-> Egfr(Y992~pY!1).PLCg(a!1,b~0,c~0) kp5, km5 B7: Egfr(Y992~pY) + PLCg(a,b~P,c~0) \ <-> Egfr(Y992~pY!1).PLCg(a!1,b~P,c~0) kp7, km7 # Y1068 activity B9: Egfr(Y1068~pY) + Grb2(SH2,SH3) \ <-> Egfr(Y1068~pY!0).Grb2(SH2!0,SH3) kp9, km9 B10_cyt: Egfr(Y1068~pY!0).Grb2(SH2!0,SH3) + Sos(dom,ras) \ <-> Egfr(Y1068~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1,ras) kp10, km10 B10_mem: Egfr(Y1068~pY!0).Grb2(SH2!0,SH3) + Sos(dom,ras!+) \ <-> Egfr(Y1068~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1,ras!+) D*kp10, km10 B11_cyt: Egfr(Y1068~pY) + Grb2(SH2,SH3!0).Sos(dom!0,ras) \ <-> Egfr(Y1068~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1,ras) kp11, km11 B11_mem: Egfr(Y1068~pY) + Grb2(SH2,SH3!0).Sos(dom!0,ras!+) \ <-> Egfr(Y1068~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1,ras!+) D*kp11, km11 # Y1148 activity B13: Egfr(Y1148~pY) + Shc(PTB,Y317~Y) \ <-> Egfr(Y1148~pY!0).Shc(PTB!0,Y317~Y) kp13, km13 B15: Egfr(Y1148~pY) + Shc(PTB,Y317~pY) \ <-> Egfr(Y1148~pY!0).Shc(PTB!0,Y317~pY) kp15, km15 B18: Egfr(Y1148~pY) + Shc(PTB,Y317~pY!0).Grb2(SH2!0,SH3) \ <-> Egfr(Y1148~pY!1).Shc(PTB!1,Y317~pY!0).Grb2(SH2!0,SH3) kp18, km18 B20_cyt: Egfr(Y1148~pY) + Shc(PTB,Y317~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1,ras) \ <-> Egfr(Y1148~pY!2).Shc(PTB!2,Y317~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1,ras) kp20, km20 B20_mem: Egfr(Y1148~pY) + Shc(PTB,Y317~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1,ras!+) \ <-> Egfr(Y1148~pY!2).Shc(PTB!2,Y317~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1,ras!+) D*kp20, km20 B17: Egfr(Y1148~pY!0).Shc(PTB!0,Y317~pY) + Grb2(SH2,SH3) \ <-> Egfr(Y1148~pY!0).Shc(PTB!0,Y317~pY!1).Grb2(SH2!1,SH3) kp17, km17 B24_cyt: Egfr(Y1148~pY!0).Shc(PTB!0,Y317~pY) + Grb2(SH2,SH3!1).Sos(dom!1,ras) \ <-> Egfr(Y1148~pY!0).Shc(PTB!0,Y317~pY!2).Grb2(SH2!2,SH3!1).Sos(dom!1,ras) kp24, km24 B24_mem: Egfr(Y1148~pY!0).Shc(PTB!0,Y317~pY) + Grb2(SH2,SH3!1).Sos(dom!1,ras!+) \ <-> Egfr(Y1148~pY!0).Shc(PTB!0,Y317~pY!2).Grb2(SH2!2,SH3!1).Sos(dom!1,ras!+) D*kp24, km24 B19_cyt: Shc(PTB!+,Y317~pY!0).Grb2(SH2!0,SH3) + Sos(dom,ras) \ <-> Shc(PTB!+,Y317~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1,ras) kp19, km19 B19_mem: Shc(PTB!+,Y317~pY!0).Grb2(SH2!0,SH3) + Sos(dom,ras!+) \ <-> Shc(PTB!+,Y317~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1,ras!+) D*kp19, km19 # Cytosolic activity B21: Shc(PTB,Y317~pY) + Grb2(SH2,SH3) \ <-> Shc(PTB,Y317~pY!0).Grb2(SH2!0,SH3) kp21, km21 B23: Shc(PTB,Y317~pY) + Grb2(SH2,SH3!0).Sos(dom!0) \ <-> Shc(PTB,Y317~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1) kp23, km23 B16: Shc(PTB,Y317~pY) -> Shc(PTB,Y317~Y) km16 B12: Grb2(SH2,SH3) + Sos(dom) \ <-> Grb2(SH2,SH3!0).Sos(dom!0) kp12, km12 B22: Shc(PTB,Y317~pY!0).Grb2(SH2!0,SH3) + Sos(dom) \ <-> Shc(PTB,Y317~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1) kp22, km22 B8: PLCg(a,b~P,c~0) -> PLCg(a,b~0,c~0) km8 B25: PLCg(a,b~P,c~0) <-> PLCg(a,b~P,c~I) kp25, km25 # Ras binds GDP (ref:stites2007) S1: Ras(nuc~U,raf,cat) <-> Ras(nuc~GDP,raf,cat) kagdp, kdgdp # Ras binds GTP (ref:stites2007) S2: Ras(nuc~U,raf,cat) <-> Ras(nuc~GTP,raf,cat) kagtp, kdgtp # RasGTP -> RasGDP, intrinsic (ref:stites2007) S3: Ras(nuc~GTP,raf,cat) -> Ras(nuc~GDP,raf,cat) khyd # RasGDP binding cytosolic Sos S4: Sos(dom,ras) + Ras(cat,nuc~GDP,raf) <-> Sos(dom,ras!0).Ras(cat!0,nuc~GDP,raf) kfgdp/D, krgdp S5: Grb2(SH2,SH3!0).Sos(dom!0,ras) + Ras(cat,nuc~GDP,raf) \ <-> Grb2(SH2,SH3!0).Sos(dom!0,ras!1).Ras(cat!1,nuc~GDP,raf) kfgdp/D, krgdp S6: Shc(PTB,Y317~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1,ras) + Ras(cat,nuc~GDP,raf) \ <-> Shc(PTB,Y317~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1,ras!2).Ras(cat!2,nuc~GDP,raf) kfgdp/D, krgdp # RasGDP binding membrane Sos (enhanced by membrane localization) S7: Shc(PTB!+,Y317~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1,ras) + Ras(cat,nuc~GDP,raf) \ <-> Shc(PTB!+,Y317~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1,ras!2).Ras(cat!2,nuc~GDP,raf) kfgdp, krgdp S8: Egfr(Y1068~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1,ras) + Ras(cat,nuc~GDP,raf) \ <-> Egfr(Y1068~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1,ras!2).Ras(cat!2,nuc~GDP,raf) kfgdp, krgdp # RasGTP binding cytosolic Sos S9: Sos(dom,ras) + Ras(cat,nuc~GTP,raf) <-> Sos(dom,ras!0).Ras(cat!0,nuc~GTP,raf) kfgtp/D, krgtp S10: Grb2(SH2,SH3!0).Sos(dom!0,ras) + Ras(cat,nuc~GTP,raf) \ <-> Grb2(SH2,SH3!0).Sos(dom!0,ras!1).Ras(cat!1,nuc~GTP,raf) kfgtp/D, krgtp S11: Shc(PTB,Y317~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1,ras) + Ras(cat,nuc~GTP,raf) \ <-> Shc(PTB,Y317~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1,ras!2).Ras(cat!2,nuc~GTP,raf) kfgtp/D, krgtp # RasGTP binding membrane Sos (enhanced by membrane localization) S12: Shc(PTB!+,Y317~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1,ras) + Ras(cat,nuc~GTP,raf) \ <-> Shc(PTB!+,Y317~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1,ras!2).Ras(cat!2,nuc~GTP,raf) kfgtp, krgtp S13: Egfr(Y1068~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1,ras) + Ras(cat,nuc~GTP,raf) \ <-> Egfr(Y1068~pY!0).Grb2(SH2!0,SH3!1).Sos(dom!1,ras!2).Ras(cat!2,nuc~GTP,raf) kfgtp, krgtp # RasGDP <-> RasGTP, catalyzed Sos (ref:stites2007) S14: Sos(ras!0).Ras(cat!0,nuc~GDP,raf) <-> Sos(ras!0).Ras(cat!0,nuc~GTP,raf) kcatgdp, kcatgtp # RasGTP bdinging GAP (ref:stites2007) S15: Ras(nuc~GTP,raf,cat) + GAP(ras) <-> Ras(nuc~GTP,raf,cat!0).GAP(ras!0) kf_GAP, kr_GAP # RasGTP -> RasGDP, catalyzed by GAP (ref:stites2007) S16: Ras(nuc~GTP,raf,cat!0).GAP(ras!0) -> Ras(nuc~GDP,raf,cat) + GAP(ras) kcat_GAP # RasGTP + Raf (ref:fujioka2006, [1]) F1: Ras(nuc~GTP,raf,cat) + Raf(ras,bind,phos~U) <-> Ras(nuc~GTP,raf!0,cat).Raf(ras!0,bind,phos~P) kp_f1/NA/Vcyt, km_f1 # Raf-P binds MEK (ref:fujioka2006, [2]) F2: Ras(nuc~GTP,raf!0).Raf(ras!0,bind,phos~P) + MEK(bind,phos~U,loc~cyt) \ <-> Ras(nuc~GTP,raf!0).Raf(ras!0,bind!1,phos~P).MEK(bind!1,phos~U,loc~cyt) kp_f2/NA/Vcyt, km_f2 # RasGTP-Raf-P phosphorylates MEK (ref:fujioka2006, [6]) F6: Ras(nuc~GTP,raf!0).Raf(ras!0,bind!1,phos~P).MEK(bind!1,phos~U,loc~cyt) \ -> Ras(nuc~GTP,raf!0).Raf(ras!0,bind,phos~P) + MEK(bind,phos~P,loc~cyt) Vm_f6 # MEK binds ERK (ref:fujioka2006, [3,4,13,14]) F3: MEK(bind,loc~cyt) + ERK(bind,phos~U,loc~cyt) <-> MEK(bind!0,loc~cyt).ERK(bind!0,phos~U,loc~cyt) kp_f3/NA/Vcyt, km_f3 F13: MEK(bind,loc~nuc) + ERK(bind,phos~U,loc~nuc) <-> MEK(bind!0,loc~nuc).ERK(bind!0,phos~U,loc~nuc) kp_f3/NA/Vcyt, km_f3 # MEK-P phosphorylates ERK (ref:fujioka2006, [5,15]) F5: MEK(bind!0,phos~P).ERK(bind!0,phos~U) -> MEK(bind,phos~P) + ERK(bind,phos~P) Vm_f5 ## Nuclear transport # MEK (ref:fujioka2006, [7,10]) F7: MEK(bind,phos~U,loc~nuc) <-> MEK(bind,phos~U,loc~cyt) kex_f7, kin_f7 F10: MEK(bind,phos~P,loc~nuc) <-> MEK(bind,phos~P,loc~cyt) kex_f10, kin_f10 # MEK-ERK (ref:fujioka2006, [8,12]) F8: MEK(bind!0,loc~nuc).ERK(bind!0,loc~nuc) <-> MEK(bind!0,loc~cyt).ERK(bind!0,loc~cyt) kex_f8, kin_f8 # ERK (ref:fujioka2006, [9]) F9: ERK(bind,phos~U,loc~nuc) <-> ERK(bind,phos~U,loc~cyt) kex_f9, kin_f9 F11: ERK(bind,phos~P,loc~nuc) <-> ERK(bind,phos~P,loc~cyt) kex_f11, kin_f11 ## dephosphorylation # MEK (ref:fujioka2006, [16,18]) F16: MEK(bind,phos~P) -> MEK(bind,phos~U) k_f16 # ERK (ref:fujioka2006, [17,19]) F17: ERK(bind,phos~P) -> ERK(bind,phos~U) k_f17 end reaction rules end model