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Matrilysin: an epithelial matrix metalloproteinase with potentially novel functions
1Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, TN 37232-2175, USA.
Abstract:
Matrilysin (MAT) is a member of the matrix metalloproteinase (MMP) family which is believed to degrade components of the extracellular matrix (ECM) during processes of tissue remodeling. Although MAT is similar to the stromelysins in its substrate specificity, and to interstitial collagenase in the crystal structure of its catalytic domain, this enzyme is unique in that it lacks the carboxy-terminal segments encoded by other MMP genes. Characterization of the human MAT gene has revealed that the promoter region contains typical MMP promoter elements such as AP-1 and PEA3, which mediate responsiveness to growth factors, oncogenes, and phorbol esters. Activated recombinant forms of human MAT cleave ECM and basement membrane proteins such as fibronectin, collagen type IV, laminin, and particularly elastin, entactin, and cartilage proteoglycan aggregates. Furthermore, MAT appears to mediate the proteolytic processing of other molecules (e.g. tumor necrosis factor alpha precursor, urokinase plasminogen activator). MAT is expressed in a variety of tumors ranging from adenomas to carcinomas and adenocarcinomas of the breast, colon, prostate, stomach, upper aerodigestive tract, lung, and skin, where it may be involved in tumor formation as well as the tissue degradation which accompanies tumor cell extravasation. Localization of MAT mRNA and protein to the tumor cells is unusual in that the majority of MMPs are produced in the stroma. This distinctive tissue-restricted pattern of MAT expression is a recapitulation of the expression pattern in normal human tissue, where MAT protein localizes to secretory and ductal epithelium in the endometrium and in various exocrine glands. In the mouse, high constitutive levels of MAT mRNA are found in epithelial cells in the uterus, small intestine, and extra-testicular ducts. Taken together, these findings suggest that MAT may have a specific role in normal gland and organ function, a possibility which can be explored further by the genetic manipulation of MAT levels in vivo.
Insights
Matrilysin (MAT), an matrix metalloproteinase (MMP), degrades extracellular matrix proteins and is uniquely expressed in tumor cells and normal glandular epithelium, suggesting a role in tissue remodeling and organ function.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Matrilysin (MAT) is a matrix metalloproteinase (MMP) involved in extracellular matrix (ECM) degradation.
- MAT uniquely lacks carboxy-terminal segments found in other MMPs.
- Its promoter region contains AP-1 and PEA3 elements responsive to growth factors and oncogenes.
Purpose of the Study:
- To characterize the human MAT gene and its promoter region.
- To investigate the substrate specificity and function of activated MAT.
- To determine the expression pattern of MAT in tumors and normal tissues.
Main Methods:
- Gene characterization of the human MAT promoter.
- Activation and enzymatic assays of recombinant human MAT.
- Analysis of MAT mRNA and protein localization in various human tumors and normal tissues.
Main Results:
- MAT cleaves ECM and basement membrane proteins, including fibronectin, collagen IV, laminin, elastin, entactin, and proteoglycan aggregates.
- MAT also processes precursor molecules like tumor necrosis factor alpha and urokinase plasminogen activator.
- MAT is expressed in various tumors and, unusually for MMPs, localizes to tumor cells, mirroring its expression in normal glandular epithelium.
Conclusions:
- MAT's unique expression pattern in tumor cells and normal glandular epithelium suggests a specific role in tissue remodeling and organ function.
- Further research involving genetic manipulation of MAT levels is warranted to explore its in vivo functions.