Matrilysin-2, a new matrix metalloproteinase expressed in human tumors andshowing the minimal domain organization required for secretion, latency, and activity

We have identified a human placenta cDNA coding for a new member of the mat rix metalloproteinase (MMP) family. The isolated cDNA encodes a polypeptide of 261 amino acids, the smallest MMP identified to date, which contains se veral structural features of MMPs including the signal sequence, the prodom ain involved in enzyme latency, and the catalytic domain with the zinc-bind ing site. However, it lacks the hinge region and hemopexin-domain present i n most MMPs. According to these structural characteristics, the human MMP d escribed herein has been called matrilysin-2 (MMP-26), because it exclusive ly shares with matrilysin this minimal domain organization required for sec retion, 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 m atrilysin-2 gene showed that it maps to the short arm of chromosome 11, a l ocation distinct to that of other MMP genes. Matrilysin-2 was expressed in Escherichia coli, and, after purification and refolding, the recombinant pr otein was found to degrade synthetic substrates commonly used for assaying MMPs, Furthermore, this protein hydrolyzed type IV collagen, fibronectin, f ibrinogen, and gelatin, which indicated that matrilysin-2 is a potent enzym e with a wide substrate specificity. In addition, it was found that matrily sin-2 is able to activate progelatinase B, Proteolytic activity of matrilys in-2 against all of these substrates was abolished by synthetic inhibitors and by tissue inhibitors of metalloproteinases, Expression analysis reveale d that matrilysin-2 is detected not only in placenta and uterus but is wide ly expressed in malignant tumors from different sources as well as in diver se tumor cell lines. These data together with its broad spectrum of proteol ytic activity, suggest that matrilysin-2 may play a role in some of the tis sue-remodeling events associated with tumor progression.