/* * Quantification of Short Term Signaling by the Epidermal Growth * Factor Receptor * * Model Status * * This CellML model runs in both COR and OpenCell to reproduce * the graphs in Figure 5 of the Kholodenko et al. 1999 publication. * * Model Structure * * ABSTRACT: During the past decade, our knowledge of molecular * mechanisms involved in growth factor signaling has proliferated * almost explosively. However, the kinetics and control of information * transfer through signaling networks remain poorly understood. * This paper combines experimental kinetic analysis and computational * modeling of the short term pattern of cellular responses to * epidermal growth factor (EGF) in isolated hepatocytes. The experimental * data show transient tyrosine phosphorylation of the EGF receptor * (EGFR) and transient or sustained response patterns in multiple * signaling proteins targeted by EGFR. Transient responses exhibit * pronounced maxima, reached within 15-30 s of EGF stimulation * and followed by a decline to relatively low (quasi-steady-state) * levels. In contrast to earlier suggestions, we demonstrate that * the experimentally observed transients can be accounted for * without requiring receptor-mediated activation of specific tyrosine * phosphatases, following EGF stimulation. The kinetic model predicts * how the cellular response is controlled by the relative levels * and activity states of signaling proteins and under what conditions * activation patterns are transient or sustained. EGFR signaling * patterns appear to be robust with respect to variations in many * elemental rate constants within the range of experimentally * measured values. On the other hand, we specify which changes * in the kinetic scheme, rate constants, and total amounts of * molecular factors involved are incompatible with the experimentally * observed kinetics of signal transfer. Quantitation of signaling * network responses to growth factors allows us to assess how * cells process information controlling their growth and differentiation. * * The original paper reference is cited below: * * Quantification of Short Term Signaling by the Epidermal Growth * Factor Receptor, Boris N. Kholodenko, Oleg V. Demin, Gisela * Moehren, and Jan B. Hoek, 1999, The Journal of Biological Chemistry, * 274, 30169-30181. PubMed ID: 10514507 * * reaction diagram * * [[Image file: kholodenko_1999.png]] * * Kinetic scheme of EGFR signalling mediated by adapter and target * proteins. */ import nsrunit; unit conversion on; // unit nanomolar predefined unit flux=1E-6 meter^(-3)*second^(-1)*mole^1; unit first_order_rate_constant=1 second^(-1); unit second_order_rate_constant=1E6 meter^3*second^(-1)*mole^(-1); math main { realDomain time second; time.min=0; extern time.max; extern time.delta; real EGF(time) nanomolar; when(time=time.min) EGF=680; real v1(time) flux; real R(time) nanomolar; when(time=time.min) R=100; real Ra(time) nanomolar; when(time=time.min) Ra=0; real v2(time) flux; real R2(time) nanomolar; when(time=time.min) R2=0; real v3(time) flux; real v4(time) flux; real RP(time) nanomolar; when(time=time.min) RP=0; real v7(time) flux; real v11(time) flux; real v15(time) flux; real v18(time) flux; real v20(time) flux; real v5(time) flux; real v9(time) flux; real v13(time) flux; real R_PL(time) nanomolar; when(time=time.min) R_PL=0; real v6(time) flux; real R_PLP(time) nanomolar; when(time=time.min) R_PLP=0; real R_G(time) nanomolar; when(time=time.min) R_G=0; real v10(time) flux; real R_G_S(time) nanomolar; when(time=time.min) R_G_S=0; real R_Sh(time) nanomolar; when(time=time.min) R_Sh=0; real v14(time) flux; real R_ShP(time) nanomolar; when(time=time.min) R_ShP=0; real v24(time) flux; real v17(time) flux; real R_Sh_G(time) nanomolar; when(time=time.min) R_Sh_G=0; real v19(time) flux; real R_Sh_G_S(time) nanomolar; when(time=time.min) R_Sh_G_S=0; real G_S(time) nanomolar; when(time=time.min) G_S=0; real v23(time) flux; real v12(time) flux; real ShP(time) nanomolar; when(time=time.min) ShP=0; real v21(time) flux; real v16(time) flux; real Sh_G(time) nanomolar; when(time=time.min) Sh_G=0; real v22(time) flux; real Sh_G_S(time) nanomolar; when(time=time.min) Sh_G_S=0; real PLC_gamma(time) nanomolar; when(time=time.min) PLC_gamma=105; real v8(time) flux; real PLC_gamma_P(time) nanomolar; when(time=time.min) PLC_gamma_P=0; real v25(time) flux; real PLC_gamma_P_I(time) nanomolar; when(time=time.min) PLC_gamma_P_I=0; real Grb(time) nanomolar; when(time=time.min) Grb=85; real Shc(time) nanomolar; when(time=time.min) Shc=150; real SOS(time) nanomolar; when(time=time.min) SOS=34; real k1 second_order_rate_constant; k1=0.003; real k1_ first_order_rate_constant; k1_=0.06; real k2 second_order_rate_constant; k2=0.01; real k2_ first_order_rate_constant; k2_=0.1; real k3 first_order_rate_constant; k3=1; real k3_ first_order_rate_constant; k3_=0.01; real K4 nanomolar; K4=50; real V4 flux; V4=450; real k5 second_order_rate_constant; k5=0.06; real k5_ first_order_rate_constant; k5_=0.2; real k6 first_order_rate_constant; k6=1; real k6_ first_order_rate_constant; k6_=0.05; real k7 first_order_rate_constant; k7=0.3; real k7_ second_order_rate_constant; k7_=0.006; real K8 nanomolar; K8=100; real V8 flux; V8=1; real k9 second_order_rate_constant; k9=0.003; real k9_ first_order_rate_constant; k9_=0.05; real k10 second_order_rate_constant; k10=0.01; real k10_ first_order_rate_constant; k10_=0.06; real k11 first_order_rate_constant; k11=0.03; real k11_ second_order_rate_constant; k11_=4.5e-3; real k12 first_order_rate_constant; k12=1.5e-3; real k12_ second_order_rate_constant; k12_=1e-4; real k13 second_order_rate_constant; k13=0.09; real k13_ first_order_rate_constant; k13_=0.6; real k14 first_order_rate_constant; k14=6; real k14_ first_order_rate_constant; k14_=0.06; real k15 first_order_rate_constant; k15=0.3; real k15_ second_order_rate_constant; k15_=9e-4; real K16 nanomolar; K16=340; real V16 flux; V16=1.7; real k17 second_order_rate_constant; k17=0.003; real k17_ first_order_rate_constant; k17_=0.1; real k18 first_order_rate_constant; k18=0.3; real k18_ second_order_rate_constant; k18_=9e-4; real k19 second_order_rate_constant; k19=0.01; real k19_ first_order_rate_constant; k19_=2.14e-2; real k20 first_order_rate_constant; k20=0.12; real k20_ second_order_rate_constant; k20_=2.4e-4; real k21 second_order_rate_constant; k21=0.003; real k21_ first_order_rate_constant; k21_=0.1; real k22 second_order_rate_constant; k22=0.03; real k22_ first_order_rate_constant; k22_=0.064; real k23 first_order_rate_constant; k23=0.1; real k23_ second_order_rate_constant; k23_=0.021; real k24 second_order_rate_constant; k24=0.009; real k24_ first_order_rate_constant; k24_=4.29e-2; real k25 first_order_rate_constant; k25=1; real k25_ first_order_rate_constant; k25_=0.03; real totEGFRphos(time) nanomolar; real totPLCgammaphos(time) nanomolar; real totGrb_EGFR(time) nanomolar; real totGrb_Shc(time) nanomolar; real totShcphos(time) nanomolar; real totShc_EGFR(time) nanomolar; real totSOS_EGFR(time) nanomolar; // // EGF:time=((-1)*v1); // R:time=((-1)*v1); // Ra:time=(v1-2*v2); // R2:time=(v2+v4-v3); // RP:time=(v3+v7+v11+v15+v18+v20-(v4+v5+v9+v13)); // R_PL:time=(v5-v6); // R_PLP:time=(v6-v7); // R_G:time=(v9-v10); // R_G_S:time=(v10-v11); // R_Sh:time=(v13-v14); // R_ShP:time=(v14-(v24+v15+v17)); // R_Sh_G:time=(v17-(v18+v19)); // R_Sh_G_S:time=(v19+v24-v20); // G_S:time=(v11+v23-(v12+v24)); // ShP:time=(v15+v23-(v21+v16)); // Sh_G:time=(v18+v21-v22); // Sh_G_S:time=(v20+v22-v23); // PLC_gamma:time=(v8-v5); // PLC_gamma_P:time=(v7-(v8+v25)); // PLC_gamma_P_I:time=v25; // Grb:time=(v12-(v9+v17+v21)); // Shc:time=(v16-v13); // SOS:time=(v12-(v10+v19+v22)); // v1=(k1*R*EGF-k1_*Ra); // v2=(k2*Ra*Ra-k2_*R2); // v3=(k3*R2-k3_*RP); // v4=(V4*RP/(K4+RP)); // v5=(k5*RP*PLC_gamma-k5_*R_PL); // v6=(k6*R_PL-k6_*R_PLP); // v7=(k7*R_PLP-k7_*RP*PLC_gamma_P); // v8=(V8*PLC_gamma_P/(K8+PLC_gamma_P)); // v9=(k9*RP*Grb-k9_*R_G); // v10=(k10*R_G*SOS-k10_*R_G_S); // v11=(k11*R_G_S-k11_*RP*G_S); // v12=(k12*G_S-k12_*Grb*SOS); // v13=(k13*RP*Shc-k13_*R_Sh); // v14=(k14*R_Sh-k14_*R_ShP); // v15=(k15*R_ShP-k15_*ShP*RP); // v16=(V16*ShP/(K16+ShP)); // v17=(k17*R_ShP*Grb-k17_*R_Sh_G); // v18=(k18*R_Sh_G-k18_*RP*Sh_G); // v19=(k19*R_Sh_G*SOS-k19_*R_Sh_G_S); // v20=(k20*R_Sh_G_S-k20_*Sh_G_S*RP); // v21=(k21*ShP*Grb-k21_*Sh_G); // v22=(k22*Sh_G*SOS-k22_*Sh_G_S); // v23=(k23*Sh_G_S-k23_*ShP*G_S); // v24=(k24*R_ShP*G_S-k24_*R_Sh_G_S); // v25=(k25*PLC_gamma_P-k25_*PLC_gamma_P_I); // totEGFRphos=(2*(RP+R_PL+R_PLP+R_G+R_G_S+R_Sh+R_ShP+R_Sh_G+R_Sh_G_S)); totPLCgammaphos=(R_PLP+PLC_gamma_P); totShcphos=(R_ShP+R_Sh_G+R_Sh_G_S+ShP+Sh_G+Sh_G_S); totGrb_EGFR=(R_G+R_G_S+R_Sh_G+R_Sh_G_S); totGrb_Shc=(R_Sh_G+Sh_G+R_Sh_G_S+Sh_G_S); totShc_EGFR=(R_ShP+R_Sh_G+R_Sh_G_S); totSOS_EGFR=(R_G_S+R_Sh_G_S); }