What is matrix metalloproteinase?
The matrix metalloproteinases (MMPs) are one of the major families of proteinases that play key roles in the responses of cells to the microenvironment. MMPs are a family of calcium-dependent endopeptidases that form a subgroup of the metzincins. These proteins are characterized by a conserved motif containing three histidine residues, which bind a zinc ion at the catalytic site. There are about 24 human MMPs, and homologues can be identified in other species including mice, birds, zebrafish, fruit fly, nematodes, plants and even algae.
The MMPs have the combined capacity to degrade all the components of the ECM. The ECM is a complex and dynamic structure that supports adhesion of cells and transmits signals through cell-surface adhesion receptors. The ECM is composed of collagens, non-collagenous glycoproteins and proteoglycans. Alternative constituents of the ECM, such as tenascin, fibronectin and laminins, are found in tumors and might stimulate cancer progression. The basement membrane (BM) is specialized ECM that separates the epithelial cells from underlying stroma providing the first barrier against invasion of carcinomas. It is worth mentioning that other proteases, besides MMPs, are able to degrade ECM substrates. These include the family of cysteine proteases from which cathepsins are members and the family of serine proteases from which uPA is an important member with recognized functions in ECM degradation and remodeling.
In addition to degrading ECM components and activating other MMPs, MMP activity is responsible for making available active growth factors and cytokines such as insulin-like growth factor 1 (IGF-1), fibroblast growth factor (FGF), FGF receptor 1 (FGFR1), transforming growth factor-β (TGF-β), heparin-binding EGF (HB-EGF), tumor necrosis factor-α (TNF-α) and IL-8.
Structural diversity of MMPs
The MMPs were initially classified based on their specificity for ECM components: collagenases, gelatinases, stromelysins and matrilysins. As the list of MMPs grew, a numbering system has been adapted, and the MMPs are now classified according to their structure. There are seven distinct structural classes of MMPs: four are secreted and three are membrane-type MMPs (MT-MMPs).
All MMPs share a basic structural organization comprising a signal peptide domain that targets them for secretion, a pro-peptide domain necessary to maintain enzyme latency and an N-terminal catalytic domain. Most MMPs also have a hinge region, and a C-terminal hemopexin-like domain that contribute to substrate specificity and to interactions with endogenous inhibitors. The MT-MMPs localized to the plasma membrane through a C-terminal transmembrane domain (MT1-, MT2-, MT3-, and MT5-MMP) or by a glycosylphosphatidylinositol anchor (MT4- and MT6-MMP), The MT-MMPs also have an additional insertion of basic residues between the pro-peptide and catalytic domain, which is cleaved by furin-like serine proteases leading to the intracellular activation of the proenzymes, This furin-like cleavage site is also present in three secreted MMPs (MMP-11, MMP-21 and MMP-28). MMP-23 is an exceptional membrane bound MMP. It has unique cysteine-rich, proline-rich and IL-1 receptor type II like domains and might be initially anchored by an Nterminal transmembrane domain prior to propeptide processing.
Physiological roles of MMPs
The evolution of the MMP family to generate its structural diversity reflects the variety and complexity of biological processes in which these enzymes are involved.
Most MMP genes are highly expressed in a number of reproductive processes that include: the menstrual cycle, ovulation, and uterine, breast and prostrate involution. MMP-7, MMP-3, MMP-10, MMP-11 and MMP-2 are produced during the most active phases of the murine estrous cycle. These MMPs, as well as MMP-8 and MMP-13, are also upregulated during postpartum uterus involution, Interestingly, none of the mutant mice deficient in specific MMPs have shown a significant reproductive dysfunction. This observation suggests that functional redundancy among MMPs may compensate for the loss of any specific MMP.
The production of MMP-9 by invading trophoblasts seems to be critical for early implantation stages. Studies with MMP-9-deficient mice have also revealed the in vivo role of this protease in a number of developmental processes. These mice exhibit a defect in endochondral bone formation, delayed apoptosis of hypertrophic chondrocytes at the skeletal growth plates and deficient vascularization.
The role of MMPs in tissue remodeling is evident from several reports. MMP-2 and MMP-3 regulate mammary gland branching morphogenesis during puberty whereas MMP-2 and MMP-9 promote adipocyte differentiation, MMPs are also involved in wound healing, a tissue-remodeling process that includes the migration of keratinocytes at the edge of the wound to re-epithelialize the damage surface. In cell culture experiments, the proteolytic activity of MMP-1 is required for keratinocyte migration. The in vivo role of MMPs in this process has been shown by the study of MMP-3-deficient mice, which exhibit impaired wound contraction.
MMPs are necessary for angiogenesis. In vitro, endothelial cells express a wide range of MMPs. MMPs are required for endothelial cell proliferation, migration and tube formation. Endothelial MMP ex
In spite of the importance of MMPs in the angiogenic process, most MMP knockout mice do not overt angiogenic phenotypes likely due to overlapping and compensatory activities. MMP-9 knockout mice exhibit abnormal skeletal growth plate angiogenesis that is eventually compensated. MMP-2-null mice show reduced vascularization after different challenges. However, MMP-2/MMP-9-double deficient mice show severely impaired choroidal neovascularization, demonstrating a synergistic effect of both proteases in this process.
MMPs may regulate angiogenesis by acting as pericellular fibirinolysins during the neovascularization process. Moreover, many members of the MMP family show a dual ability to mobilize or activate pro-angiogenic factors or angiogenic inhibitors.
Matrix metallopeptidases Reference
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