--------------------------------------------------------------------- --------------------------------------------------------------------- CellML model for the model of Karagiannis and Popel 2004 Contribution by - Lucie GATTEPAILLE (lucie.gattepaille@gmail.com) - Eric FANCHON (eric.fanchon@imag.fr) - Philippe TRACQUI (philippe.tracqui@imag.fr) Lab: TIMC-IMAG, Grenoble Teams: Dynacell, TIMB --------------------------------------------------------------------- --------------------------------------------------------------------- In this file we explain how to get the figures 1 to 6 shown in the Karagiannis and Popel paper (JBC, 2004). ***************** THE MODEL: ***************** The model can be found in the KaragiannisPopel2004.cellml file. It describes the reactions system given in Figure 1 of the paper. Three Quasi-Steady State Approximations (QSSA) are made, one on the MT1-MT1 complex, one on the MT1-C1 complex and one on the MT1-T2-M2P-MT1 complex. The variables: There are 13 variables in the cellml model. Variable Associated protein --------------------------------------------------------------------- MT1 Membrane Type 1 Matrix MetalloProteinase (MT1-MMP) MT1cat The cleaved catalytic domain of MT1-MMP T2 Tissue Inhibitor of MetalloProteinases 2 (TIMP2) MT1T2 The MT1-MMP/TIMP2 complex M2 Matrix MetalloProteinase 2 (MMP2) M2P The proenzyme of MMP2 MT1T2M2P The MT1-MMP/T2/M2P complex M2T2 The MMP2/TIMP2 complex M2T2star A stable isoform of the MMP2/TIMP2 complex C1 Type 1 collagene M2C1 The MMP2/Collagene I complex C1dmt1 Collagene I degraded by MT1-MMP C1dm2 Collagene I degraded by MMP2 The chemical reactions: MT1 + MT1 (kshed_eff)---> MT1 + MT1cat MT1 + T2 <---(ki_MT1T2 / kon_MT1T2)---> MT1T2 MT1T2 + M2P <---(koff_MT1T2M2P / kon_MT1T2M2P)---> MT1T2M2P MT1T2M2P + MT1 (kact_eff_m2)---> MT1 + M2 M2 + T2 <---(ki_M2T2 / kon_M2T2)---> M2T2 M2T2 <---(k_iso_M2T2 / kiso_M2T2)---> M2T2star M2 + C1 <---(koff_M2C1 / kon_M2C1)---> M2C1 M2C1 (kcat_M2C1)---> C1dm2 + M2 MT1 + C1 (kcat_MT1C1/Km_MT1C1)---> C1dmt1 + MT1 ***************** THE FIGURES ***************** Figures 2A and 2B --------------------- They study the subsystem MT1 + T2 <---(ki_MT1T2 / kon_MT1T2)---> MT1T2 MT1T2 + M2P <---(koff_MT1T2M2P / kon_MT1T2M2P)---> MT1T2M2P So in the global model, one must set - kshed_eff=0 - kact_eff_m2=0 - all the initial conditions to 0, except MT1, T2 and M2P We found the very same curves, in replacing [T2]_0=4 nM by [T2]_0=2 nM Figure 2C --------------------- They study the subsystem MT1T2M2P + MT1 (kact_eff_m2)---> MT1 + M2 So in the global model, one must set - kshed_eff=0 - koff_MT1T2M2P=0 - all the initial conditions to 0, except... - [MT1]_0=0.09e-6 M - [MT1T2M2P]_0=0.9e-6 M This part is meant at finding a kact_eff_m2 that would best fit the data. We found the value of 3.62e3 to have a better fit than 2.8e3 given in the paper and yeild a Figure 2D that look more like the figure plotted in the paper. Figure 2D --------------------- The two previous subsystems are combined to study the proportion of MMP2 that gets activated. MT1 + T2 <---(ki_MT1T2 / kon_MT1T2)---> MT1T2 MT1T2 + M2P <---(koff_MT1T2M2P / kon_MT1T2M2P)---> MT1T2M2P MT1T2M2P + MT1 (kact_eff_m2)---> MT1 + M2 So in the global model, one must set - kshed_eff=0 - kon_m2t2=0 - all the initial conditions to 0, except MT1, T2 and M2P Figures 3A, 3B, 3C and 3D --------------------- The ectodomain-shedding of MT1-MMP is added to the previous subsystem. MT1 + MT1 (kshed_eff)---> MT1 + MT1cat MT1 + T2 <---(ki_MT1T2 / kon_MT1T2)---> MT1T2 MT1T2 + M2P <---(koff_MT1T2M2P / kon_MT1T2M2P)---> MT1T2M2P MT1T2M2P + MT1 (kact_eff_m2)---> MT1 + M2 So in the global model, one must set - kon_m2t2=0 - all the initial conditions to 0, except MT1, T2 and M2P, depending on the figure. We could not get the exact same curves, expecially for 3B and 3D, but the shapes are extremely similar. Figures 4A and 4B --------------------- The equilibrium between the two isoforms of the MMP2/TIMP2 complex is considered. We study the two following reactions : M2 + T2 <---(ki_M2T2 / kon_M2T2)---> M2T2 M2T2 <---(k_iso_M2T2 / kiso_M2T2)---> M2T2star So in the global model, one must set - all the initial conditions to 0 except M2 and T2, varying according to the desired ratios Figure 5B --------------------- Comparison between the one isoform... M2 + T2 <---(ki_M2T2 / kon_M2T2)---> M2T2 ...and the two isoforms approaches M2 + T2 <---(ki_M2T2 / kon_M2T2)---> M2T2 M2T2 <---(k_iso_M2T2 / kiso_M2T2)---> M2T2star So in the global model, one must set - all the initial conditions to 0 except M2 and T2, varying according to the desired ratios - ki_M2T2=7.2e-9 and kiso_M2T2=0 for the one isoform approach The curves we found have a similar shape but differ a bit from the paper quantitatively. It may be some parameter difference between our model and tyhe one used by Karagiannis and Popel to simulate the results. Figure 5C --------------------- Same comparison as in figure 5B, with added collagenolysis. So, is compared M2 + T2 <---(ki_M2T2 / kon_M2T2)---> M2T2 M2 + C1 <---(koff_M2C1 / kon_M2C1)---> M2C1 M2C1 (kcat_M2C1)---> C1dm2 + M2 with M2 + T2 <---(ki_M2T2 / kon_M2T2)---> M2T2 M2T2 <---(k_iso_M2T2 / kiso_M2T2)---> M2T2star M2 + C1 <---(koff_M2C1 / kon_M2C1)---> M2C1 M2C1 (kcat_M2C1)---> C1dm2 + M2 So in the global model, one must set - all the initial conditions to 0 except M2 and T2, varying according to the desired ratios, and C1 - ki_M2T2=7.2e-9 and kiso_M2T2=0 for the one isoform approach The initial value for C1 has been omitted in the paper but for 1e-6 M, the shape of the simulated curves are the same, though the values are different. Figures 6A and 6B --------------------- In this figure, the whole model is considered. All the modules that have been studied separately are now combined together. The one isoform approach is used and the constant of the ectodomain shedding reaction of MT1-MMP is divided by ten. So one must set - ki_M2T2=7.2e-9 - kiso_M2T2=0 - kshed_eff=0.28e3 - all the initial conditions to 0 except MT1, M2, T2, M2P and C1 Once again, the shapes of the curves we obtain are similar, but the curves are a bit different quantitatively. If you have any question, please contact us.