A new member of the
matrix metalloproteinase (
MMP) family of
enzymes has been cloned from a human
breast carcinoma cDNA library. The isolated
cDNA contains an open reading frame 1554 bp long, encoding a
polypeptide of 518
amino acids. The predicted amino acid sequence displays a similar domain organization as the remaining
MMPs, including a prodomain with the activation locus, the
zinc-binding site, and the
hemopexin domain. In addition, it contains a C-terminal extension, rich in hydrophobic residues and similar in size to those present in the different membrane-type
MMPs (MT-
MMPs) identified to date. On the basis of these structural characteristics, this novel
MMP has been tentatively called
MT4-MMP, because it represents the fourth member of this subclass of
MMPs characterized mainly by the occurrence of putative transmembrane domain in their amino acid sequences.
MT4-MMP also contains a nine-residue insertion between the propeptide and the catalytic domain, which is a common feature of MT-
MMPs and stromelysin-3. This amino acid sequence insertion ends with the consensus sequence R-X-R/K-R, which seems to be essential in the activation of these
proteinases by
furin. Northern blot analysis of polyadenylated RNAs isolated from a variety of human tissues revealed that the
MT4-MMP gene (MMP-17) is expressed mainly in the brain, leukocytes, the colon, the ovary, and the testis. The expression of
MT4-MMP in leukocytes together with its putative membrane localization suggest that this
enzyme could be involved in the activation of membrane-bound precursors of
growth factors or inflammatory mediators such as
tumor necrosis factor-alpha. In addition,
MT4-MMP transcripts were detected in all
breast carcinomas, as well as in all
breast cancer cell lines analyzed in the present work. On the basis of these expression data in
breast tumors, a potential role for human
MT4-MMP in the tumoral process is also suggested.