/* * Differential Feedback Regulation of the MAPK Cascade Underlies * the Quantitative Differences in EGF and NGF Signalling in PC12 * Cells * * Model Status * * This is the initial translation of the model into CellML. Concentrations * have no dimensions in order to balance units. The percentage * activation variables used to produce the graphs in the paper * have not yet been added to this model. The model can therefore * run in Opencell and COR but does not reproduce the figures in * the paper. * * Model Structure * * ABSTRACT: Although epidermal growth factor (EGF) induces transient * activation of Ras and the mitogen-activated protein kinase (MAPK) * cascade in PC12 cells, whereas nerve growth factor (NGF) stimulates * sustained activation, the basis for these contrasting responses * is not known. We have developed a computer simulation of EGF-induced * MAPK cascade activation, which provides quantitative evidence * that feedback inhibition of the MAPK cascade is the most important * factor in determining the duration of cascade activation. Hence, * we propose that the observed quantitative differences in EGF * and NGF signalling can be accounted for by differential feedback * regulation of the MAPK cascade. * * The complete original paper reference is cited below: * * Differential feedback regulation of the MAPK cascade underlies * the quantitative differences in EGF and NGF signalling in PC12 * cells, Frances A. Brightman, David A. Fell, 2000,Federation * of European Biochemical Societies Letters, 482(3), 169-174. * PubMed ID: 11024454 * * reaction diagram * * [[Image file: brightman_2000.png]] * * Schematic representation of the computer simulation of EGF signal * transduction. */ import nsrunit; unit conversion on; unit minute=60 second^1; unit first_order_rate_constant=.01666667 second^(-1); math main { realDomain time minute; time.min=0; extern time.max; extern time.delta; real Rs(time) dimensionless; when(time=time.min) Rs=11100; real v1(time) first_order_rate_constant; real v3(time) first_order_rate_constant; real RL(time) dimensionless; when(time=time.min) RL=0; real v2(time) first_order_rate_constant; real v4(time) first_order_rate_constant; real Ri(time) dimensionless; when(time=time.min) Ri=3900; real v6(time) first_order_rate_constant; real L(time) dimensionless; when(time=time.min) L=0.0000001; real R2L2(time) dimensionless; when(time=time.min) R2L2=0; real v5(time) first_order_rate_constant; real v7(time) first_order_rate_constant; real R2_CPP(time) dimensionless; when(time=time.min) R2_CPP=0; real v8(time) first_order_rate_constant; real Li(time) dimensionless; when(time=time.min) Li=0; real R2i(time) dimensionless; when(time=time.min) R2i=0; real Shc(time) dimensionless; when(time=time.min) Shc=30000; real v9(time) first_order_rate_constant; real v10(time) first_order_rate_constant; real ShcP(time) dimensionless; when(time=time.min) ShcP=0; real v11(time) first_order_rate_constant; real v27(time) first_order_rate_constant; real ShcGS(time) dimensionless; when(time=time.min) ShcGS=0; real v13(time) first_order_rate_constant; real v12(time) first_order_rate_constant; real GS(time) dimensionless; when(time=time.min) GS=20000; real v28(time) first_order_rate_constant; real GSP(time) dimensionless; when(time=time.min) GSP=0; real RasGDP(time) dimensionless; when(time=time.min) RasGDP=19800; real v15(time) first_order_rate_constant; real Ras_ShcGS(time) dimensionless; when(time=time.min) Ras_ShcGS=0; real RasGTP(time) dimensionless; when(time=time.min) RasGTP=200; real v17(time) first_order_rate_constant; real v14(time) first_order_rate_constant; real v16(time) first_order_rate_constant; real GAP(time) dimensionless; when(time=time.min) GAP=15000; real Ras_GAP(time) dimensionless; when(time=time.min) Ras_GAP=0; real Raf(time) dimensionless; when(time=time.min) Raf=10000; real v18(time) first_order_rate_constant; real Ras_Raf(time) dimensionless; when(time=time.min) Ras_Raf=0; real Rafa(time) dimensionless; when(time=time.min) Rafa=0; real v19(time) first_order_rate_constant; real v21(time) first_order_rate_constant; real MEK(time) dimensionless; when(time=time.min) MEK=360000; real v20(time) first_order_rate_constant; real MEKP(time) dimensionless; when(time=time.min) MEKP=0; real v22(time) first_order_rate_constant; real MEKPP(time) dimensionless; when(time=time.min) MEKPP=0; real ERK(time) dimensionless; when(time=time.min) ERK=750000; real v24(time) first_order_rate_constant; real v23(time) first_order_rate_constant; real ERKP(time) dimensionless; when(time=time.min) ERKP=0; real v26(time) first_order_rate_constant; real v25(time) first_order_rate_constant; real ERKPP(time) dimensionless; when(time=time.min) ERKPP=0; real t(time) dimensionless; when(time=time.min) t=0; real v29 first_order_rate_constant; real X(time) dimensionless; when(time=time.min) X=0; real v30(time) first_order_rate_constant; real k1 first_order_rate_constant; k1=384210000; real kn1 first_order_rate_constant; kn1=0.73; real v2.DT dimensionless; v2.DT=6.5; real v2.E dimensionless; v2.E=0.12; real k2 first_order_rate_constant; k2=0.7; real v2.f dimensionless; v2.f=0.2; real v3.DT dimensionless; v3.DT=6.5; real v3.E dimensionless; v3.E=0.12; real kn3 first_order_rate_constant; kn3=0.7; real v3.f dimensionless; v3.f=0.2; real k3 first_order_rate_constant; k3=0.0484; real k2_4 first_order_rate_constant; k2_4=0.0000001; real k4 first_order_rate_constant; k4=0.001383; real v5.DT dimensionless; v5.DT=6.5; real v5.E dimensionless; v5.E=0.12; real k5 first_order_rate_constant; k5=0.35; real v5.f dimensionless; v5.f=0.2; real v6.DT dimensionless; v6.DT=6.5; real v6.E dimensionless; v6.E=0.12; real k6 first_order_rate_constant; k6=0.35; real k7 first_order_rate_constant; k7=1; real v7.f dimensionless; v7.f=0.2; real kn7 first_order_rate_constant; kn7=0.000347; real v8.DT dimensionless; v8.DT=6.5; real v8.E dimensionless; v8.E=0.12; real k8 first_order_rate_constant; k8=0.35; real k9 first_order_rate_constant; k9=12; real K_9 dimensionless; K_9=6000; real V_10 first_order_rate_constant; V_10=300000; real K_10 dimensionless; K_10=6000; real k11 first_order_rate_constant; k11=0.002; real kn11 first_order_rate_constant; kn11=3.81; real k12 first_order_rate_constant; k12=0.0163; real kn12 first_order_rate_constant; kn12=10; real k_13 first_order_rate_constant; k_13=15; real k14 first_order_rate_constant; k14=0.005; real kn14 first_order_rate_constant; kn14=60; real k15 first_order_rate_constant; k15=720; real k16 first_order_rate_constant; k16=0.0012; real kn16 first_order_rate_constant; kn16=3; real k17 first_order_rate_constant; k17=27; real V_18 first_order_rate_constant; V_18=97000; real K_18 dimensionless; K_18=6000; real k19 first_order_rate_constant; k19=50; real K_19 dimensionless; K_19=9000; real V_20 first_order_rate_constant; V_20=920000; real K_20 dimensionless; K_20=600000; real k21 first_order_rate_constant; k21=50; real K_21 dimensionless; K_21=9000; real V_22 first_order_rate_constant; V_22=920000; real K_22 dimensionless; K_22=600000; real k23 first_order_rate_constant; k23=8.3; real K_23 dimensionless; K_23=90000; real V_24 first_order_rate_constant; V_24=200000; real K_24 dimensionless; K_24=600000; real k25 first_order_rate_constant; k25=8.3; real K_25 dimensionless; K_25=90000; real V_26 first_order_rate_constant; V_26=400000; real K_26 dimensionless; K_26=600000; real k27 first_order_rate_constant; k27=1.6; real K_27 dimensionless; K_27=600000; real V_28 first_order_rate_constant; V_28=75; real K_28 dimensionless; K_28=20000; real v_1 first_order_rate_constant; v_1=1; real k_11 first_order_rate_constant; k_11=0; // // Rs:time=(v3-v1); // RL:time=(v1-v2-v4); // Ri:time=(v2+v3+v6); // L:time=((-1)*v1); // R2L2:time=(v4-v5-v7); // R2_CPP:time=(v7-v8); // Li:time=(v2+v6); // R2i:time=(v5+v8-v6); // Shc:time=(v10-v9); // ShcP:time=(v27-v10-v11); // ShcGS:time=(v13+v11-v27-v12); // GS:time=(v28-v11); // GSP:time=(v27-v28); // RasGDP:time=(v15-v12); // Ras_ShcGS:time=(v12-v13); // RasGTP:time=(v13+v17-v14-v16); // GAP:time=(v15-v14); // Ras_GAP:time=(v14-v15); // Raf:time=(v18-v16); // Ras_Raf:time=(v16-v17); // Rafa:time=(v17-v19-v21-v18); // MEK:time=(v20-v19); // MEKP:time=(v19+v22-v20-v21); // MEKPP:time=(v21-v22); // ERK:time=(v24-v23); // ERKP:time=(v23+v26-v24-v25); // ERKPP:time=(v25-v26); // t:time=v29; // X:time=v30; // v1=(k1*Rs*L-kn1*RL); // v2=(v2.f*k2*(v2.E+(1-v2.E)*(1-exp((-1)*(t/v2.DT)^3)))*RL); // v3=(k3*Ri-v3.f*kn3*(v3.E+(1-v3.E)*(1-exp((-1)*(t/v3.DT)^3)))*Rs); // v4=(k4*RL*RL-k2_4*R2L2); // v5=(v5.f*k5*(v5.E+(1-v5.E)*(1-exp((-1)*(t/v5.DT)^3)))*R2L2); // v6=(k6*(v6.E+(1-v6.E)*(1-exp((-1)*(t/v6.DT)^3)))*R2i); // v7=(k7*v7.f*R2L2-kn7*R2_CPP); // v8=(k8*(v8.E+(1-v8.E)*(1-exp((-1)*(t/v8.DT)^3)))*R2_CPP); // v9=(k9*2*(R2L2+R2i+R2_CPP)*Shc/(K_9+Shc)); // v10=(V_10*ShcP/(K_10+ShcP)); // v11=(k11*ShcP*GS-kn11*ShcGS); // v12=(k12*RasGDP*ShcGS-kn12*Ras_ShcGS); // v13=(k_13*Ras_ShcGS); // v14=(k14*RasGTP*GAP-kn14*Ras_GAP); // v15=(k15*Ras_GAP); // v16=(k16*RasGTP*Raf-kn16*Ras_Raf); // v17=(k17*Ras_Raf); // v18=(V_18*Rafa/(K_18+Rafa)); // v19=(Rafa*MEK*k19/(K_19+MEK)); // v20=(V_20*MEKP/(K_20+MEKP)); // v21=(Rafa*MEKP*k21/(K_21+MEKP)); // v22=(V_22*MEKPP/(K_22+MEKPP)); // v23=(k23*ERK*(MEKP+MEKPP)/(K_23+ERK)); // v24=(V_24*ERKP/(K_24+ERKP)); // v25=(k25*ERKP*(MEKP+MEKPP)/(K_25+ERKP)); // v26=(V_26*ERKPP/(K_26+ERKPP)); // v27=(ERKPP*ShcGS*k27/(K_27+ShcGS)); // v28=(V_28*GSP/(K_28+GSP)); // v29=v_1; // v30=(k_11*t); }