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Activation of proMMP-2 by MT1-MMP is considered to be a critical event in cancer cell invasion. In the activation step, TIMP-2 bound to MT1-MMP on the cell surface acts as a receptor for proMMP-2. Subsequently, adjacent TIMP-2-free MT1-MMP activates the proMMP-2 in the ternary complex. In this study, we demonstrate that MT1-MMP forms a homophilic complex through the hemopexin-like (PEX) domain that acts as a mechanism to keep MT1-MMP molecules close together to facilitate proMMP-2 activation. Deletion of the PEX domain in MT1-MMP, or swapping the domain with the one derived from MT4-MMP, abolished the ability to activate proMMP-2 on the cell surface without affecting the proteolytic activities. In addition, expression of the mutant MT1-MMP lacking the catalytic domain (MT1PEX-F) efficiently inhibited complex formation of the full-length enzymes and activation of pro MMP-2. Furthermore, expression of MT1PEX-F inhibited proMMP-2 activation and Matrigel invasion activity of invasive human fibrosarcoma HT1080 cells. These findings elucidate a new function of the PEX domain: regulating MT1-MMP activity on the cell surface, which accelerates cellular invasiveness in the tissue.

Original publication




Journal article



Publication Date





4782 - 4793


Animals, Binding Sites, COS Cells, Cell Membrane, Chlorocebus aethiops, Collagen, Dimerization, Drug Combinations, Enzyme Activation, Enzyme Precursors, Fibrosarcoma, Gelatin, Gelatinases, Humans, Laminin, Matrix Metalloproteinases, Membrane-Associated, Metalloendopeptidases, Neoplasm Invasiveness, PHEX Phosphate Regulating Neutral Endopeptidase, Proteins, Proteoglycans, Recombinant Fusion Proteins, Recombinant Proteins, Tissue Inhibitor of Metalloproteinase-2, Transfection, Tumor Cells, Cultured