MMP7

The human MMP7 is located on chromosome 11 q22.3. MMP genes are clustered in q region of human Chromosome 11 including matrilysin, collagenase-1, stromelysin1, stromelysin-2, and metalloelastase genes. It consists of 267 amino acids. The cDNA of MMP7 is 49% homologous to stromelysin-1. The promoter of the human MMP7 contains a TATA box, an activator protein 1 (AP-1) site, and two inverted polyomavirus enhancer A-binding proteins 2 (PEA-3). The AP-1/PEA-3 binding motif is required and essential for MMP7 to be responsive to growth factors, oncogenes and phorbol ester. Also, the PEA and AP-1 are required for Matrilysin/CAT reporter constructs induced by tumor promoter 12-O-tetradecanoulphorbol-13-acetate (TPA) and epidermal growth factor (EGF). In addition, the high level expression of AP-1 and its binding proteins were found to be associated with mutant Ki-Ras suggesting the high expression of matrilysin in Ras activated cells is AP-1 dependent. The promoter region of the human MMP7 gene contains two or more sites that are homologous to the NR-IL6 binding sequences indicating MMP7 can bind to IL-1 and IL-6. In addition, the level of MMP7 mRNA is elevated followed the treatment of tumor necrosis factor α (TNF- α) and IL-1 β in human mesangial cells. MMP7 are commonly expressed in epithelial cells including ductal epithelium of exocrine glands in skin, salivary glands, pancreas, glandular epithelium of intestine and reproductive organ, liver, and breast. In addition, MMP7 is highly expressed in the luminal surface of dysplastic glands in human colorectal cancers. == Structure ==

A MMP7 protein is bounded by four metal ions including a catalytic zinc ion, a structural zinc ion, and two calcium ions. The catalytic zinc ion binds to three His residues in the HEXGHXXGXXH region in tetracoordination. The calcium ion binding play important role in stabilizing the secondary structure. MMP7 has a shallow hydrophobic substrate-binding pocket. In contrast to MMP9 which has the longest hinge, MMP7 lacks hemopexin and does not have a hinge. Instead, MMP7 contains a variable C-terminal hemopexin-like domain facilitates substrate specificity. The protein of MMP7 is secreted as zymogen. The prodoamin of MMP7 contains an approximately 9 kD highly conserved "cysteine switch" PRCGXPD sequence near the C-terminal containing cysteine residues. Cysteine residues bind to the catalytic zinc keeping the protein latent. The dissociation of cysteine –Zinc coordination starts from the cleavage of the first 30 amino acids of the prodomain, which leads to a conformation change, and further results in autoproteolysis and the cleavage of the whole prodomain at Glu-Tyr site. According to Woessner et al., the Mr of MMP7 is 28,000 for the latent form and 19,000 Mr for the active form after the cleavage of its prodomain. == Interactions ==

Promatrilysin (Pro-MMP7) is converted from the latent form to the active form by endoproteinases, and plasmin. Plasmin cleaves at the site recognizable to trypsin, is considered as the most possible physiological activator. In vitro, plasmin can activate pro-MMP7 to 50% of its full activity. Also, researchers used activated recombinant pro-MMP7 and purified substrates to investigate the proteolytic activity of MMp7 in vitro, and found that MMP7 cleaves many protein substrates mainly including ECM components, proMMPs, and nonmatrix proteins. MMP7 cleaves the glycoprotein entactin that links laminin and collagen IV at about 100-600 times faster than collagenase-1. In addition, MMP7 can activate other MMPs. Activated MMP7 and APMA can increase the activity of collagenase-1, and MMP7 can also convert the latent progelatinase A to its active form. == Function ==

Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. The enzyme encoded by this gene degrades proteoglycans, fibronectin, elastin and casein and differs from most MMP family members in that it lacks a conserved C-terminal protein domain. The enzyme is involved in wound healing, and studies in mice suggest that it regulates the activity of defensins in intestinal mucosa. MMP7 was initially characterized by Woessner et al. It digests components of the extracellular matrix, cleaves the α 2 (I) chain of gelatin more rapidly, and digests the B chain of insulin at Ala14-Leu and Tyr16-Leu, and has no action on collagen types I, II, IV, V. The optimal pH of MMP7 is at 7 and the pI is at 5.9. MMP4 is inhibited by α 2-macroglobulin and TIMP. Normal tissue development Quondamatteo et al. immunohistochemically stained MMP7, and localized MMP7 in early human liver development. They reported that MMP7 was presented in some hepatocytes and endothelial cells in the 6th gestational week, and only hematopoietic cells remained after that time. Tissue remodeling In order for MMPs to escape TIMP inhibition, active MMP7s are recruited to the plasma membrane of epithelium inducing membrane-associated growth factors processing for epithelial repair and proliferation. In human endometrium, the expression of MMP7 mRNA increases at menstruation and remains high during the proliferative phase. Also, MMP-7 binds to the plasma membrane of epithelium containing cholesterol-rich domain. The bounded MMP7 is active and resistant to TIMP inhibition. It promotes the activity of the epithelial plasma membrane and associated substrates including E-cadherin, β4-integrin, TNF-alpha, RAS, heparin-binding EGF, IGF binding proteins and plasminogen. Further, this process promotes epithelial cell migration, proliferation and apoptosis. For menstruation, it promotes the endometrium regeneration after menstrual breakdown. == Clinical significance ==

MMP7 cleaves collagen III/IV/V/IX/X/XI and proteoglycan indicating that MMP inhibitors can potentially be used in therapies that are involved in inhibition of tissue degradation, remodeling, anti-angiogenesis and inhibition of tumor invasion. In addition, Qasim et al. reported that MMP7 is highly expressed in advanced colorectal adenomatous polys with severe dysplasia. Further, MMP7 is involved in converting colorectal adenomas into malignant state and facilitating the growth. ==References==