Identification of expanding roles for matrix metalloproteinases (MMPs) in complex regulatory processes of tissue remodelling has stimulated the search for genes encoding proteinases with unique functions, regulation and expression patterns. By using a novel cloning strategy, we identified three previously unknown human MMPs, i.e. MMP-21, MMP-26 and MMP-28, in comprehensive gene libraries. The present study is focused on the gene and the protein of a novel MMP, MMP-26. Our findings show that MMP-26 is specifically expressed in cancer cells of epithelial origin, including carcinomas of lung, prostate and breast. Several unique structural and regulatory features, including an unusual ‘cysteine-switch’ motif, discriminate broad-spectrum MMP-26 from most other MMPs. MMP-26 efficiently cleaves fibrinogen and extracellular matrix proteins, including fibronectin, vitronectin and denatured collagen. Protein sequence, minimal modular domain structure, exon–intron mapping and computer modelling demonstrate similarity between MMP-26 and MMP-7 (matrilysin). However, substrate specificity and transcriptional regulation, as well as the functional role of MMP-26 and MMP-7 in cancer, are likely to be distinct. Despite these differences, matrilysin-2 may be a suitable trivial name for MMP-26. Our observations suggest an important specific function for MMP-26 in tumour progression and angiogenesis, and confirm and extend the recent findings of other authors [Park, Ni, Gerkema, Liu, Belozerov and Sang (2000) J. Biol. Chem. 275, 20540–20544; Uría and López-Otín (2000) Cancer Res. 60, 4745–4751; de Coignac, Elson, Delneste, Magistrelli, Jeannin, Aubry, Berthier, Schmitt, Bonnefoy and Gauchat (2000) Eur. J. Biochem. 267, 3323–3329].
- epithelial cancer
Abbreviations used: AP, activator protein; DMEM, Dulbecco's modified Eagle's medium; Dpa, 3(2,4-dinitrophenyl)diaminopropionic acid; Dnp, dinitrophenyl; DTT, dithiothreitol; IPTG, isopropyl β-d-thiogalactoside; Mca, 7-methoxycoumarin; MMP, matrix metalloproteinase; MT-MMPs, membrane-type MMPs; MTC, multiple tissue cDNA; Nva, norvaline; PEA3, polyoma virus enhancer A-binding protein-3; RACE, rapid amplification of cDNA ends; RT-PCR, reverse-transcriptase PCR; TIMPs, tissue inhibitors of metalloproteinases.
- The Biochemical Society, London ©2001