Characterization of matrix metalloproteinase-26, a novel metalloproteinase widely expressed in cancer cells of epithelial origin

Abstract

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].

MMP-21 is upregulated at early stages of melanoma progression but disappears with more aggressive phenotype

“…MMP-26 (endometase or matrilysin-2) is a rather novel MMP originally found in normal placenta and endometrium [17,26,29] but is also widely expressed in malignant tumors, such as endometrial, prostate, breast, and oral squamous cell cancers, and tumor cell lines [14,21,32]. We did not detect MMP-26 in melanoma cells in vivo.…”

RETRACTED: Expression of matrix metalloproteinase-26 (MMP-26) mRNA in mouse uterus during the estrous cycle and early pregnancy

“…MMP-26 is reported to be self-activated, and cleave fibrinogen and ECM proteins (De Coignac et al, 2000;Park et al, 2000Park et al, , 2002Marchenko et al, 2001). MMP-26 can also be able to activate pro-MMP-9 (Uria and Lopez-Otin, 2000).…”

“…It was also reported that MMP-26 was primarily expressed in epithelial cancers such as lung, breast, endometrial and prostate carcinomas and in the corresponding tumor cell lines (De Coignac et al, 2000;Park et al, 2000;Uria and Lopez-Otin, 2000;Marchenko et al, 2001;Chegini et al, 2003).…”

“…MMP-26 exhibits wide substrate specificity in cleaving ECM and basement membrane proteins. Its substrates include type-I gelatin, human plasma a1-proteinase inhibitor type-IV collagen, fibrinogen, fibronectin and vitronectin (Park et al, 2002;Uria and Lopez-Otin, 2000;Marchenko et al, 2001).…”

Crystal Structure of the Catalytic Domain of Human Matrix Metalloproteinase 10

“…Another zinc ion and one to three calcium ions are present in the catalytic domain with a structural role. 5 All but two of the human MMPs (MMP-7 and MMP-26) have a C-terminal hemopexin-like domain, 3,6 and two MMPs (MMP-2 and MMP-9) contain fibronectin insertions into their catalytic domains. 7,8 All MMPs share a marked sequence similarity, and the similarity is maximal for the catalytic domains, where the percentage of identical residues ranges from a minimum of 33% (between MMP-21 and MMP-23) to a maximum of 86% (between MMP-3 and MMP-10).…”