Location: Karagiannis, Popel, 2004 @ 513a314db7bb / Explanations.txt

Author:
Catherine Lloyd <c.lloyd@auckland.ac.nz>
Date:
2009-10-22 11:22 +1300
Desc:
Renamed the figures PDF to "reproduced_" etc. as recommended by the creator of the file as some of the figures contain slight variations from the figures in the original published paper. Also corrected a typo in Philippe Tracqui's name in the model status comment.
Permanent Source URI:
http://models.cellml.org/workspace/karagiannis_popel_2004/rawfile/513a314db7bbbf715ef068d00fab5aa48d0c7727/Explanations.txt

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	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

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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.




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