begin parameters egf_0 1.2e6 egfr_0 1.8e5 Grb2_0 1.0e5 Shc_0 2.7e5 Sos_0 1.3e4 Grb2_Sos_0 4.9e4 kp1 1.667e-06 # ligand-monomer binding (scaled) km1 0.06 # ligand-monomer dissociation kp2 5.556e-06 # aggregation of bound monomers (scaled) km2 0.1 # dissociation of bound monomers kp3 0.5 # dimer transphosphorylation km3 4.505 # dimer dephosphorylation kp14 3 # Shc transphosphorylation km14 0.03 # Shc dephosphorylation km16 0.005 # Shc cytosolic dephosphorylation kp9 8.333e-07 # binding of Grb2 to receptor (scaled) km9 0.05 # dissociation of Grb2 from receptor kp10 5.556e-06 # binding of Sos to receptor (scaled) km10 0.06 # dissociation of Sos from receptor kp11 1.25e-06 # binding of Grb2-Sos to receptor (scaled) km11 0.03 # diss. of Grb2-Sos from receptor kp13 2.5e-05 # binding of Shc to receptor (scaled) km13 0.6 # diss. of Shc from receptor kp15 2.5e-07 # binding of ShcP to receptor (scaled) km15 0.3 # diss. of ShcP from receptor kp17 1.667e-06 # binding of Grb2 to RP-ShcP (scaled) km17 0.1 # diss. of Grb2 from RP-ShcP kp18 2.5e-07 # binding of ShcP-Grb2 to receptor (scaled) km18 0.3 # diss. of ShcP-Grb2 from receptor kp19 5.556e-06 # binding of Sos to RP-ShcP-Grb2 (scaled) km19 0.0214 # diss. of Sos from RP-ShcP-Grb2 kp20 6.667e-08 # binding of ShcP-Grb2-Sos to receptor (scaled) km20 0.12 # diss. of ShcP-Grb2-Sos from receptor kp24 5e-06 # binding of Grb2-Sos to RP-ShcP (scaled) km24 0.0429 # diss. of Grb2-Sos from RP-ShcP kp21 1.667e-06 # binding of ShcP to Grb2 in cytosol (scaled) km21 0.01 # diss. of Grb2 and SchP in cytosol kp23 1.167e-05 # binding of ShcP to Grb2-Sos in cytosol (scaled) km23 0.1 # diss. of Grb2-Sos and SchP in cytosol kp12 5.556e-08 # binding of Grb2 to Sos in cytosol (scaled) km12 0.0015 # diss. of Grb2 and Sos in cytosol kp22 1.667e-05 # binding of ShcP-Grb2 to Sos in cytosol (scaled) km22 0.064 # diss. of ShcP-Grb2 and Sos in cytosol # PLC phosphorylation/dephosphorylation kp6 0.5 km6 0.025 #PLC binding to dimerized receptor kp5 0.03 km5 0.2 #PLCp binding to dimerized receptor kp7 0.003 km7 0.3 loop1= (kp9/km9)*(kp10/km10)/((kp11/km11)*(kp12/km12)) loop2= (kp15/km15)*(kp17/km17)/((kp21/km21)*(kp18/km18)) loop3= (kp18/km18)*(kp19/km19)/((kp22/km22)*(kp20/km20)) loop4= (kp12/km12)*(kp23/km23)/((kp22/km22)*(kp21/km21)) loop5= (kp15/km15)*(kp24/km24)/((kp20/km20)*(kp23/km23)) end parameters begin molecule types egfr(l,r,Y992~Y~pY,Y1068~Y~pY,Y1148~Y~pY) egf(r) Shc(PTB,Y317~Y~pY) Grb2(SH2,SH3) Sos(dom) PLCgamma(dom~Y~pY) end molecule types begin species egf(r) egf_0 Grb2(SH2,SH3) Grb2_0 Shc(PTB,Y317~Y) Shc_0 Sos(dom) Sos_0 egfr(l,r,Y1068~Y,Y1148~Y,Y992~Y) egfr_0 Grb2(SH2,SH3!1).Sos(dom!1) Grb2_Sos_0 end species begin reaction rules #Box 1 # Ligand-receptor binding 1 egfr(l,r) + egf(r) <-> egfr(l!1,r).egf(r!1) kp1, km1 #ligand-monomer # Note changed multiplicity # Receptor-aggregation 2 egfr(l!1,r) + egfr(l!2,r) <-> egfr(l!1,r!3).egfr(l!2,r!3) kp2,km2 #Box 2 # Transphosphorylation of egfr by RTK 3 egfr(r!1,Y1068~Y) -> egfr(r!1,Y1068~pY) kp3 3 egfr(r!1,Y1148~Y) -> egfr(r!1,Y1148~pY) kp3 # and also (ndg) 3 egfr(r!1,Y992~Y) -> egfr(r!1,Y992~pY) kp3 #Dephosphorylayion 4 egfr(Y1068~pY) -> egfr(Y1068~Y) km3 4 egfr(Y1148~pY) -> egfr(Y1148~Y) km3 # and also (ndg) 4 egfr(Y992~pY) -> egfr(Y992~Y) km3 # Box 3 # Shc transphosph 14 egfr(r!2,Y1148~pY!1).Shc(PTB!1,Y317~Y) -> egfr(r!2,Y1148~pY!1).Shc(PTB!1,Y317~pY) kp14 14 Shc(PTB!1,Y317~pY) -> Shc(PTB!1,Y317~Y) km14 # Y1068 activity 9 egfr(Y1068~pY) + Grb2(SH2,SH3) <-> egfr(Y1068~pY!1).Grb2(SH2!1,SH3) kp9,km9 11 egfr(Y1068~pY) + Grb2(SH2,SH3!2) <-> egfr(Y1068~pY!1).Grb2(SH2!1,SH3!2) kp11,km11 10 egfr(Y1068~pY!1).Grb2(SH2!1,SH3) + Sos(dom) <-> egfr(Y1068~pY!1).Grb2(SH2!1,SH3!2).Sos(dom!2) kp10,km10 # Y1148 activity 13 egfr(Y1148~pY) + Shc(PTB,Y317~Y) <-> egfr(Y1148~pY!1).Shc(PTB!1,Y317~Y) kp13,km13 15 egfr(Y1148~pY) + Shc(PTB,Y317~pY) <-> egfr(Y1148~pY!1).Shc(PTB!1,Y317~pY) kp15,km15 18 egfr(Y1148~pY) + Shc(PTB,Y317~pY!1).Grb2(SH2!1,SH3) <-> \ egfr(Y1148~pY!2).Shc(PTB!2,Y317~pY!1).Grb2(SH2!1,SH3) kp18,km18 20 egfr(Y1148~pY) + Shc(PTB,Y317~pY!1).Grb2(SH2!1,SH3!3).Sos(dom!3) <-> \ egfr(Y1148~pY!2).Shc(PTB!2,Y317~pY!1).Grb2(SH2!1,SH3!3).Sos(dom!3) kp20,km20 17 egfr(Y1148~pY!1).Shc(PTB!1,Y317~pY) + Grb2(SH2,SH3) <-> \ egfr(Y1148~pY!1).Shc(PTB!1,Y317~pY!2).Grb2(SH2!2,SH3) kp17,km17 24 egfr(Y1148~pY!1).Shc(PTB!1,Y317~pY) + Grb2(SH2,SH3!3).Sos(dom!3) <-> \ egfr(Y1148~pY!1).Shc(PTB!1,Y317~pY!2).Grb2(SH2!2,SH3!3).Sos(dom!3) kp24,km24 19 Shc(PTB!1,Y317~pY!2).Grb2(SH2!2,SH3) + Sos(dom) <-> \ Shc(PTB!1,Y317~pY!2).Grb2(SH2!2,SH3!3).Sos(dom!3) kp19,km19 # Cytosolic 21 Shc(PTB,Y317~pY) + Grb2(SH2,SH3) <-> Shc(PTB,Y317~pY!1).Grb2(SH2!1,SH3) kp21,km21 23 Shc(PTB,Y317~pY) + Grb2(SH2,SH3!2) <-> Shc(PTB,Y317~pY!1).Grb2(SH2!1,SH3!2) kp23,km23 16 Shc(PTB,Y317~pY) -> Shc(PTB,Y317~Y) km16 12 Grb2(SH2,SH3) + Sos(dom) <-> Grb2(SH2,SH3!1).Sos(dom!1) kp12,km12 22 Shc(PTB,Y317~pY!2).Grb2(SH2!2,SH3) + Sos(dom) <-> \ Shc(PTB,Y317~pY!2).Grb2(SH2!2,SH3!3).Sos(dom!3) kp22,km22 # Box 4 5 egfr(Y992~pY) + PLCgamma(dom~Y) <-> egfr(Y992~pY!1).PLCgamma(dom~Y!1) kp5,km5 7 egfr(Y992~pY) + PLCgamma(dom~pY) <-> egfr(Y992~pY!1).PLCgamma(dom~pY!1) kp7,km7 6 PLCgamma(dom~pY) <-> PLCgamma(dom~Y) kp6,km6 end reaction rules begin observables Molecules Dimers egfr.egfr Molecules Sos_act Shc(PTB!1,Y317~pY!2).Grb2(SH2!2,SH3!3).Sos(dom!3) egfr(Y1068~pY!1).Grb2(SH2!1,SH3!2).Sos(dom!2) Molecules RP egfr(Y1068~pY!?) egfr(Y1148~pY!?) Molecules Shc_Grb Shc(Y317~pY!1).Grb2(SH2!1) Molecules Shc_Grb_Sos Shc(Y317~pY!1).Grb2(SH2!1,SH3!2).Sos(dom!2) Molecules R_Grb2 egfr(Y1068~pY!1).Grb2(SH2!1) Molecules R_Shc egfr(Y1148~pY!1).Shc(PTB!1,Y317~Y) Molecules R_ShcP egfr(Y1148~pY!1).Shc(PTB!1,Y317~pY!?) Molecules ShcP Shc(Y317~pY!?) Molecules R_G_S egfr(Y1068~pY!1).Grb2(SH2!1,SH3!2).Sos(dom!2) # Strong differences are seen for R_G_S in comparison with path model Molecules R_S_G_S egfr(Y1148~pY!1).Shc(PTB!1,Y317~pY!2).Grb2(SH2!2,SH3!3).Sos(dom!3) Molecules Efgr_tot egfr Molecules Shc_tot Shc Molecules Sos_tot Sos Molecules Grb2_tot Grb2 end observables generate_network({}); # Equilibration setConcentration("egf(r)",0); simulate_ode({t_end=>100000,n_steps=>10,sparse=>1,steady_state=>1}); # Kinetics setConcentration("egf(r)","egf_0"); writeSBML({}); simulate_ode({t_end=>120,n_steps=>120,atol=>1e-8,rtol=>1e-8,sparse=>1});