Matrix metalloproteinases (MMPs), also designated matrixins, hydrolyze components of the extracellular matrix. These proteinases play a central role in many biological processes, such as embryogenesis, normal tissue remodeling, wound healing, and angiogenesis, and in diseases such as atheroma, arthritis, cancer, and tissue ulceration.

Matrix Metalloproteinases

The matrix metalloproteinases (MMPs), which are also known as matrixins, are a family of structurally and functionally related endoproteinases that are involved in the degradation of the extracellular matrix (ECM). To be classified as a matrix metalloproteinase, a protein must have conserved features of two domains, namely the prodomain and the histidine containing catalytic domain with an active Zn2+ site, the consensus sequence PRCXXPD, a hinge region, which is often proline-rich, and a hemopexin-like C-terminal domain. Cancer cells and their neighboring stroma release these metal requiring proteolytic enzymes. After their release, the MMPs initiate matrix degradation and thus result in the acquisition of the invasive phenotype. Physiologically, these enzymes play a role in normal tissue remodeling events such as embryonic development, angiogenesis, ovulation, mammary gland involution and wound healing. However, abnormal expression of these enzymes appears to contribute to various pathological processes including invasion and metastasis. Once malignant cells utilize adhesion molecules to gain access to the ECM, they release MMPs that dissolve basement membranes and other extracellular matrices. Contrary to the action of white blood cells that release MMPs to protect the body from infections, cancer cells use the proteolytic enzymes to remodel the connective tissue. These enzymes then penetrate and digest pre-existing matrix glycoproteins and proteoglycans, which are the major structural components of the connective tissue in the ECM.

Matrix metalloproteinases are a family of extracellular proteinases that regulate development and physiologic events. MMPs are a group of enzymes synthesized as secreted or transmembrane proenzymes and processed to an active form by the removal of an amino-terminal propeptide. Catalytic activity depends on the presence of zinc ions at the catalytic active site. Activation is usually accompanied by loss of a 10 kDa amino-terminal domain. Most cleave at least one component of the ECM. The propeptide is thought to keep the enzyme in latent form by the interaction of a cysteine residue in this peptide with the zinc moiety in the enzyme active site. It is clear that these enzymes are important for cell migration, invasion, proliferation, and apoptosis. They regulate many developmental processes, including branching morphogenesis, angiogenesis, wound healing, and extracellular matrix degradation.

Matrix metalloproteinase inhibitors

MMPs play key roles in the responses of cells to their microenvironment. Like other proteolytic enzymes, MMPs are initially synthesized as inactive proenzymes or zymogens. The activation of these precursor forms is generally converted to the active form by proteolysis. Thus, MMP activity can be regulated at three steps: (1) gene expression, (2) proenzyme processing, and (3) direct inhibition of enzymatic activity. Activation of the pro-enzyme form of the MMP to the active form is by proteolysis. The extracellular activation of most MMPs can be initiated by other already activated MMPs or by several serine proteinases that can cleave peptide bonds within MMP prodomains. The activation of MMP-2, however, is at the cell surface through a unique multistep pathway involving membrane-type MMPs (MTMMP) and the tissue inhibitors of metalloproteinases (TIMPs).

TIMPs are the major endogenous regulators of MMP activities in tissues. The TIMPs represent a family of at least four 20-29kDa secreted proteins (TIMPs 1-4) that reversibly inhibit the protease activity by forming a high-affinity 1:1 stoichiometric, non-covalent complex with the active MMPs. They share 37-51% overall sequence homology, a conserved gene structure, and 12 similarly separated cysteine residues. Most studies have indicated that the inhibitory activity of the TIMPs resides almost entirely in the N-terminal domain. This N-terminal domain of the TIMPs and the catalytic domain of the MMPs influence enzyme inhibitor binding.

Although TIMPs are the major cellular inhibitors of the MMP sub-family, they are not the only endogenous MMP inhibitors. Other proteins have modest inhibitory activity against some of the MMPs, including alpha2 (α2) micro globulin, reversion inducing cysteine-rich protein with Kazal motifs: (RECK), TIMP-like molecules, netrins, procollagen C-terminal proteinases enhancer (PCPE), and tissue factor pathway inhibitor (TFPI-2). Netrins and PCPE contain sequence similarity to the N-terminal sequence of the TIMPs and might act as MMP inhibitors. The TFPI-2 is a serine proteinase inhibitor and also has an internal region with sequence similarity to the TIMPs. This protein has been shown to inhibit MMPs -1,-2, -9, and -13. TFPI-2 mechanism of inhibition is described as sequestration given that it appears to bind and coprecipitate with the MMPs.


Molecular Analysis of Matrix Metalloproteinases and RECK Expression in Breast Cancer Cell Lines Derived from African-American and Caucasian Women

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