# CMM for MCF7 cell line # 03/01/18 by Cemal ERDEM # # This is the BioNetGen model of early-stage signaling through # InsR and IGF1R. Parameters are fit to RPPA data from MCF7 cells # as described in the main text. # # To Run: Change the file extension from '.txt' to '.bngl' and # use as input to BioNetGen. Details on BioNetGen can be found # at bionetgen.org # # MODEL details: # 1) IGF1-IGF1R and insulin-InsR binding only # 2) ONE phospho sites at each receptor # 3) NO basal phosphorylation # 4) Rate parameters are in log10 # 5) FOUR observables begin model begin parameters IGF1_0 1e5 INS_0 0 IGF1R_0 25000.0 INSR_0 25000.0 IRS_0 92766.0 SOS_0 90075.0 RAS_0 230642.0 RAF_0 126069.0 MEK_0 1098164.0 ERK_0 763172.0 PI3K_0 64009.0 PDK1_0 186081.0 AKT_0 432907.0 TSC2_0 131339.0 MTOR_0 83469.0 RPS6K_0 121978.0 # Ligand-receptor interactions kf1 0.4837 kf1b -2.9153 kf1c 2.9865 kf1d 1.2052 kf2 4.6312 kf2b -0.8667 kf2c 4.8758 kf2d -2.6526 # Downstream interactions kf3 -2.7913 kf4 -3.1902 kf5 -0.6920 kf6 4.1250 kf7 -3.0400 kf8 -4.5760 kf9 0.3532 kf10 4.3309 kf11 -6.9315 kf12 -3.8016 kf13 -6.2483 kf14 1 kf15 -6.7787 kf16 -7.7887 kf17 -7.7124 # -P rates kf101 -0.0831 kf102 -6.4728 kf103 0.0477 kf104 3.9039 kf105 0.7593 kf106 0.5137 kf107 -0.8678 kf108 -3.3447 kf109 -4.5098 kf110 6.3930 kf111 -2.7962 kf112 -2.8996 # Feedback events kf201 2.7628 kf202 4.0772 kf203 -5.4445 kf204 0.2274 kf206 -6.3512 kf207 -6.3752 kf208 -5.0059 # Re-sensitization events kf301 -3.0943 kf302 -0.9807 kf303 4.2786 kf304 -5.6559 ## Recepter recycling kf401 -3.1016 kf402 -2.9249 kf403 -3.4193 kf404 -7.0807 end parameters begin molecule types # 16 species IGF1(rec) Ins(rec) IGF1R(lig,phos~U~P,int~N~Y) InsR(lig,phos~U~P,int~N~Y) IRS(phos~U~P,inh~N~Y) SOS(act~N~Y,inh~N~Y) Ras(gtp~N~Y) Raf(phos~U~P,inh~N~Y) MEK(phos~U~P,inh~N~Y) PI3K(act~N~Y) PDK1(act~N~Y) TSC2(phos~U~P) mTOR(act~N~Y) Akt(phos~U~P) RPS6K(phos~U~P) ERK(phos~U~P) end molecule types begin seed species IGF1(rec) IGF1_0 Ins(rec) INS_0 IGF1R(lig,phos~U,int~N) IGF1R_0 InsR(lig,phos~U,int~N) INSR_0 IRS(phos~U,inh~N) IRS_0 SOS(act~N,inh~N) SOS_0 Ras(gtp~N) RAS_0 Raf(phos~U,inh~N) RAF_0 MEK(phos~U,inh~N) MEK_0 PI3K(act~N) PI3K_0 PDK1(act~N) PDK1_0 TSC2(phos~U) TSC2_0 mTOR(act~N) MTOR_0 Akt(phos~U) AKT_0 RPS6K(phos~U) RPS6K_0 ERK(phos~U) ERK_0 end seed species begin observables Species pRecTot_free IGF1R(int~N,phos~P),InsR(int~N,phos~P) Species pAkt308_free Akt(phos~P) Species pRPS6K_free RPS6K(phos~P) Species pERK_free ERK(phos~P) end observables begin reaction rules # Initial ligand-receptor binding IGF1(rec) + IGF1R(lig,int~N,phos~U) <-> IGF1(rec!1).IGF1R(lig!1,int~N,phos~U) 10^kf1,10^kf1b IGF1R(lig!+,int~N,phos~U) -> IGF1R(lig!+,int~N,phos~P) 10^kf1c IGF1R(lig!+,int~N,phos~P) -> IGF1R(lig,int~N,phos~U) 10^kf1d Ins(rec) + InsR(lig,int~N,phos~U) <-> Ins(rec!1).InsR(lig!1,int~N,phos~U) 10^kf2,10^kf2b InsR(lig!+,int~N,phos~U) -> InsR(lig!+,int~N,phos~P) 10^kf2c InsR(lig!+,int~N,phos~P) -> InsR(lig,int~N,phos~U) 10^kf2d # pReceptor-IRS binding and activation IGF1R(int~N,phos~P) + IRS(inh~N,phos~U) -> IGF1R(int~N,phos~P) + IRS(inh~N,phos~P) 10^kf3 InsR(int~N,phos~P) + IRS(inh~N,phos~U) -> InsR(int~N,phos~P) + IRS(inh~N,phos~P) 10^kf4 # pReceptor-SOS binding and activation IGF1R(int~N,phos~P) + SOS(inh~N,act~N) -> IGF1R(int~N,phos~P) + SOS(inh~N,act~Y) 10^kf5 InsR(int~N,phos~P) + SOS(inh~N,act~N) -> InsR(int~N,phos~P) + SOS(inh~N,act~Y) 10^kf6 # SOS activation by IRS1 IRS(inh~N,phos~P) + SOS(inh~N,act~N) -> IRS(inh~N,phos~P) + SOS(inh~N,act~Y) 10^kf7 # Ras activation by SOS SOS(inh~N,act~Y) + Ras(gtp~N) -> SOS(inh~N,act~Y) + Ras(gtp~Y) 10^kf8 # Raf activation by Ras Ras(gtp~Y) + Raf(inh~N,phos~U) -> Ras(gtp~Y) + Raf(inh~N,phos~P) 10^kf9 # MEK activation by Raf Raf(inh~N,phos~P) + MEK(inh~N,phos~U) -> Raf(inh~N,phos~P) + MEK(inh~N,phos~P) 10^kf10 # ERK activation by MEK MEK(inh~N,phos~P) + ERK(phos~U) -> MEK(inh~N,phos~P) + ERK(phos~P) 10^kf11 # PI3K activation by IRS1 IRS(inh~N,phos~P) + PI3K(act~N) -> IRS(inh~N,phos~P) + PI3K(act~Y) 10^kf12 # PDK1 activation PI3K PI3K(act~Y) + PDK1(act~N) -> PI3K(act~Y) + PDK1(act~Y) 10^kf13 # Akt activation by PDK1 PDK1(act~Y) + Akt(phos~U) -> PDK1(act~Y) + Akt(phos~P) 10^kf14 # TSC2 inactivation by Akt Akt(phos~P) + TSC2(phos~U) -> Akt(phos~P) + TSC2(phos~P) 10^kf15 # mTOR activation by inactive TSC2 TSC2(phos~P) + mTOR(act~N) -> TSC2(phos~P) + mTOR(act~Y) 10^kf16 # RPS6K activation by mTOR mTOR(act~Y) + RPS6K(phos~U) -> mTOR(act~Y) + RPS6K(phos~P) 10^kf17 # De-phosphorylation (-P) events IRS(phos~P) -> IRS(phos~U) 10^kf101 SOS(act~Y) -> SOS(act~N) 10^kf102 Ras(gtp~Y) -> Ras(gtp~N) 10^kf103 Raf(phos~P) -> Raf(phos~U) 10^kf104 MEK(phos~P) -> MEK(phos~U) 10^kf105 PI3K(act~Y) -> PI3K(act~N) 10^kf106 PDK1(act~Y) -> PDK1(act~N) 10^kf107 TSC2(phos~P) -> TSC2(phos~U) 10^kf108 mTOR(act~Y) -> mTOR(act~N) 10^kf109 Akt(phos~P) -> Akt(phos~U) 10^kf110 RPS6K(phos~P) -> RPS6K(phos~U) 10^kf111 ERK(phos~P) -> ERK(phos~U) 10^kf112 #### Negative feedbacks # SOS inactivation by pERK ERK(phos~P) + SOS(inh~N,act~N) -> ERK(phos~P) + SOS(inh~Y,act~N) 10^kf201 # MEK inactivation by pERK ERK(phos~P) + MEK(inh~N,phos~U) -> ERK(phos~P) + MEK(inh~Y,phos~U) 10^kf202 # IRS1 inhibition by pRPS6K RPS6K(phos~P) + IRS(inh~N,phos~U) -> RPS6K(phos~P) + IRS(inh~Y,phos~U) 10^kf203 # Raf inactivation by pAkt Akt(phos~P) + Raf(inh~N,phos~U) -> Akt(phos~P) + Raf(inh~Y,phos~U) 10^kf204 # IRS inactivation by pERK ERK(phos~P) + IRS(inh~N,phos~U) -> ERK(phos~P) + IRS(inh~Y,phos~U) 10^kf206 # Akt inactivation by pERK ERK(phos~P) + Akt(phos~P) -> ERK(phos~P) + Akt(phos~U) 10^kf207 # IRS inactivation by pAkt Akt(phos~P) + IRS(inh~N,phos~U) -> Akt(phos~P) + IRS(inh~Y,phos~U) 10^kf208 #### Re-sensitization IRS(inh~Y) -> IRS(inh~N) 10^kf301 SOS(inh~Y) -> SOS(inh~N) 10^kf302 Raf(inh~Y) -> Raf(inh~N) 10^kf303 MEK(inh~Y) -> MEK(inh~N) 10^kf304 ## Recepter recycling IGF1R(lig!+,int~N,phos~P) -> IGF1R(lig!+,int~Y,phos~P) 10^kf401 IGF1(rec!1).IGF1R(lig!1,int~Y,phos~P) -> IGF1R(lig,int~N,phos~U) 10^kf402 InsR(lig!+,int~N,phos~P) -> InsR(lig!+,int~Y,phos~P) 10^kf403 Ins(rec!1).InsR(lig!1,int~Y,phos~P) -> InsR(lig,int~N,phos~U) 10^kf404 end reaction rules end model # actions begin actions generate_network({overwrite=>1}) #simulate({method=>"ode",t_end=>172800,sample_times=>[0,300,600,1800,21600,86400,172800]}) #simulate({method=>"ode",t_end=>2e5}) simulate({method=>"ode",t_start=>0,t_end=>1800,n_steps=>2e4}) #writeMexfile({t_start=>0,t_end=>2e5,n_steps=>10001,atol=>1e-6,rtol=>1e-9,max_num_steps=>10000,max_err_test_fails=>20}) #writeMfile_all() writeLatex() #writeXML() end actions