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Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain
We have identified a human placenta cDNA coding for a new member of the matrix metalloproteinase (MMP) family. The isolated cDNA encodes a polypeptide of 261 amino acids, the smallest MMP identified to date, which contains several structural features of MMPs including the signal sequence, the prodomain involved in enzyme latency, and the catalytic domain with the zinc-binding site. However, it lacks the hinge region and hemopexin-domain present in most MMPs. According to these structural characteristics, the human MMP described herein has been called matrilysin-2 (MMP-26), because it exclusively shares with matrilysin this minimal domain organization required for secretion, latency, and activity. The amino acid sequence of matrilysin-2 also contains a threonine residue adjacent to the Zn-binding site that has been defined as a specific feature of matrilysin. Chromosomal location of the matrilysin-2 gene showed that it maps to the short arm of chromosome 11, a location distinct to that of other MMP genes. Matrilysin-2 was expressed in Escherichia coli, and, after purification and refolding, the recombinant protein was found to degrade synthetic substrates commonly used for assaying MMPs. Furthermore, this protein hydrolyzed type IV collagen, fibronectin, fibrinogen, and gelatin, which indicated that matrilysin-2 is a potent enzyme with a wide substrate specificity. In addition, it was found that matrilysin-2 is able to activate progelatinase B. Proteolytic activity of matrilysin-2 against all of these substrates was abolished by synthetic inhibitors and by tissue inhibitors of metalloproteinases. Expression analysis revealed that matrilysin-2 is detected not only in placenta and uterus but is widely expressed in malignant tumors from different sources as well as in diverse tumor cell lines. These data together with its broad spectrum of proteolytic activity, suggest that matrilysin-2 may play a role in some of the tissue-remodeling events associated with tumor progression.
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