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MT6-MMP/MMP-25 is the latest member of the membrane-type matrix metalloproteinase (MT-MMP) subgroup in the MMP family and is expressed in neutrophils and some brain tumors. The proteolytic activity of MT6-MMP has been studied using recombinant catalytic fragments and shown to degrade several components of the extracellular matrix. However, the activity is possibly modulated further by the C-terminal hemopexin-like domain, because some MMPs are known to interact with other proteins through this domain. To explore the possible function of this domain, we purified a recombinant MT6-MMP with the hemopexin-like domain as a soluble form using a Madin-Darby canine kidney cell line as a producer. Mature and soluble MT6-MMP processed at the furin motif was purified as a 45-kDa protein together with a 46-kDa protein having a single cleavage in the hemopexin-like domain. Interestingly, 73- and 70-kDa proteins were co-purified with the soluble MT6-MMP by forming stable complexes. They were identified as clusterin, a major component of serum, by N-terminal amino acid sequencing. MT1-MMP that also has a hemopexin-like domain did not form a complex with clusterin. MT6-MMP forming a complex with clusterin was detected in human neutrophils as well. The enzyme activity of the soluble MT6-MMP was inactive in the clusterin complex. Purified clusterin was inhibitory against the activity of soluble MT6-MMP. On the other hand, it had no effect on the activities of MMP-2 and soluble MT1-MMP. Because clusterin is an abundant protein in the body fluid in tissues, it may act as a negative regulator of MT6-MMP in vivo.

Original publication




Journal article


J Biol Chem

Publication Date





36350 - 36357


Amino Acid Motifs, Animals, Blotting, Western, COS Cells, Catalytic Domain, Cell Line, Cell Line, Tumor, Chromatography, Gel, Clusterin, DNA, Complementary, Dogs, Dose-Response Relationship, Drug, Electrophoresis, Polyacrylamide Gel, Epitopes, Furin, GPI-Linked Proteins, Gene Expression Regulation, Genetic Vectors, Glycoproteins, Humans, Hydrogen-Ion Concentration, Kinetics, Matrix Metalloproteinases, Matrix Metalloproteinases, Membrane-Associated, Models, Genetic, Molecular Chaperones, Neutrophils, Plasmids, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Recombinant Proteins, Silver Staining, Time Factors, Transfection