Abstract
One well documented family of enzymes responsible for the proteolytic processes that occur in the extracellular matrix is the soluble and membrane-associated matrix metalloproteinases. Here we present the first theoretical model of the biochemical network describing the proteolysis of collagen I by matrix metalloproteinases 2 (MMP2) and membrane type 1 matrix metalloproteinases (MT1-MMP) in the presence of the tissue inhibitor of metalloproteinases 2 (TIMP2) in a bulk, cell-free, well stirred environment. The model can serve as a tool for describing quantitatively the activation of the MMP2 proenzyme (pro-MMP2), the ectodomain shedding of MT1-MMP, and the collagenolysis arising from both of the enzymes. We show that pro-MMP2 activation, a process that involves a trimer formation of the proenzyme with TIMP2 and MT1-MMP, is suppressed at high inhibitor levels and paradoxically attains maximum only at intermediate TIMP2 concentrations. We also calculate the conditions for which pro-MMP2 activation is maximal. Furthermore we demonstrate that the ectodomain shedding of MT1-MMP can serve as a mechanism controlling the MT1-MMP availability and therefore the pro-MMP2 activation. Finally the proteolytic synergism of MMP2 and MT1-MMP is introduced and described quantitatively. The model provides us a tool to determine the conditions under which the synergism is optimized. Our approach is the first step toward a more complete description of the proteolytic processes that occur in the extracellular matrix and include a wider spectrum of enzymes and substrates as well as naturally occurring or artificial inhibitors.
Highlights
A major mode of angiogenesis is capillary sprouting that involves the formation and stabilization of a sprouting bud built from a pool of proliferating endothelial cells near the basal lamina
In agreement with a previously proposed experiment-based hypothesis regarding the effects of tissue inhibitor of metalloproteinases 2 (TIMP2) on the pro-matrix metalloproteinases 2 (MMP2) activation, we demonstrate that low TIMP2 concentration is not able to initiate the activation of pro-MMP2, while high concentrations inhibit the zymogen processing
Model Formulation—Based on the extensive analysis of published experimental data, we represent the biochemical network of collagen I proteolysis induced by the membrane type proteinase membrane type 1 matrix metalloproteinases (MT1-matrix metalloproteinases (MMPs)) and the free diffusible species MMP2
Summary
A major mode of angiogenesis is capillary sprouting that involves the formation and stabilization of a sprouting bud built from a pool of proliferating endothelial cells near the basal lamina. The rate-determining step for this process is the disengagement of the natural barriers that restrict the unconfined migration of the proliferating cells into the neovascularized tissue [1,2,3] These barriers are comprised of the structural elements of the basement membrane and the extracellular matrix (ECM) including the different types of collagens, either. During angiogenesis and in response to various angiogenic factors such as vascular endothelial growth factor, MMPs are up-regulated at the level of expression as well as relocalized at the fronts of the migrating cells where they initiate the proteolytic pathway These proteins have been thoroughly examined experimentally, there is yet no integrative, quantitative description of the biochemical mechanisms responsible for the extracellular matrix degradation. This description follows a variety of experimental approaches where free MMP2s, the MT1-MMPs bound on membrane fragments, or the proteins devoid of their transmembrane domain that restricts them on the cell surface (⌬TM-MT1-MMP) interact with their substrates or inhibitors in bulk conditions
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