Homophilic complex formation of MT1-MMP facilitates proMMP-2 activation on the cell surface and promotes tumor cell invasion

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Abstract
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.