# The primary focus of the model developed by Kholodenko # is the cascade of signaling events that lead to # recruitment of cytosolic Sos to the inner cell membrane. # EGF binds to EGFR, which leads to the formation of signaling-competent # receptor dimers. A dimer then can be transphoshorylated. # The cytosolic adapter proteins Grb2 and Shc are recruited to # phosphorylated dimer. # When Shc is bound to a dimer, it can be phosphorylated by EGFR. # The phosphorylated form of Shc interacts with Grb2, which # interacts constitutively with Sos. begin parameters EGF_tot 1.2e6 Rec_tot 1.8e5 Grb2_tot 1.0e5 Shc_tot 2.7e5 SOS_tot 1.3e4 Grb2_SOS_tot 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 1 # dimer transphosphorylation km3 9 # dimer dephosphorylation kp14 6 # Shc transphosphorylation km14 0.06 # Shc dephosphorylation km16 0.005 # Shc cytosolic dephosphorylation kp9 1.666e-6 # 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 2.5e-06 # binding of Grb2-Sos to receptor (scaled) km11 0.03 # diss. of Grb2-Sos from receptor kp13 5e-05 # binding of Shc to receptor (scaled) km13 0.6 # diss. of Shc from receptor kp15 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 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 1.333e-07 # 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 end parameters begin species EGF EGF_tot Grb2 Grb2_tot Grb2_Sos Grb2_SOS_tot Shc Shc_tot ShcP 0 ShcP_Grb2 0 ShcP_Grb2_Sos 0 Sos SOS_tot R Rec_tot RA 0 R2 0 RP 0 R_Sh 0 R_ShP 0 R_Sh_G 0 R_Sh_G_S 0 R_G 0 R_G_S 0 end species begin reaction rules R + EGF <-> RA kp1,km1 RA + RA <-> R2 kp2,km2 R2 <-> RP kp3,km3 RP + Grb2 <-> R_G kp9,km9 R_G + Sos <-> R_G_S kp10,km10 RP + Grb2_Sos <-> R_G_S kp11,km11 RP + Shc <-> R_Sh kp13,km13 R_Sh <-> R_ShP kp14,km14 RP + ShcP <-> R_ShP kp15,km15 R_ShP + Grb2 <-> R_Sh_G kp17,km17 RP + ShcP_Grb2 <-> R_Sh_G kp18,km18 R_Sh_G + Sos <-> R_Sh_G_S kp19,km19 RP + ShcP_Grb2_Sos <-> R_Sh_G_S kp20,km20 R_ShP + Grb2_Sos <-> R_Sh_G_S kp24,km24 ShcP + Grb2 <-> ShcP_Grb2 kp21,km21 ShcP + Grb2_Sos <-> ShcP_Grb2_Sos kp23,km23 ShcP -> Shc km16 Grb2 + Sos <-> Grb2_Sos kp12,km12 ShcP_Grb2 + Sos <-> ShcP_Grb2_Sos kp22,km22 end reaction rules begin observables Total R RA R2 RP R_G R_G_S R_Sh R_ShP R_Sh_G R_Sh_G_S R2 RP R_G R_G_S R_Sh R_ShP R_Sh_G R_Sh_G_S ShcTotal R_Sh R_ShP R_Sh_G R_Sh_G_S Shc ShcP ShcP_Grb2 ShcP_Grb2_Sos Grb2Total R_Sh_G R_Sh_G_S R_G R_G_S Grb2 Grb2_Sos ShcP_Grb2 ShcP_Grb2_Sos SosTotal Sos Grb2_Sos ShcP_Grb2_Sos R_G_S R_Sh_G_S Dimers R2 RP R_G R_G_S R_Sh R_ShP R_Sh_G R_Sh_G_S RPTotal RP R_G R_G_S R_Sh R_ShP R_Sh_G R_Sh_G_S SosRecruited R_G_S R_Sh_G_S ShcGrb R_Sh_G R_Sh_G_S ShcP_Grb2 ShcP_Grb2_Sos ShcGrbSos R_Sh_G_S ShcP_Grb2_Sos RGrb2 R_G R_G_S R_Sh_G R_Sh_G_S RShc R_Sh RShcP R_ShP R_Sh_G R_Sh_G_S ShcP R_ShP R_Sh_G R_Sh_G_S ShcP ShcP_Grb2 ShcP_Grb2_Sos RGS R_G_S RSGS R_Sh_G_S end observables generate_network({overwrite=>1}); # Equilibration setConcentration("EGF",0); simulate_ode({t_end=>100000,n_steps=>10,sparse=>1,steady_state=>1}); # Kinetics setConcentration("EGF","EGF_tot"); writeSBML({suffix=>"kinetics"}); simulate_ode({suffix=>"kinetics",t_end=>120,n_steps=>120,atol=>1e-8,rtol=>1e-8,sparse=>1});