The hemopexin domain of membrane-type matrix metalloproteinase-1 (MT1-MMP) Is not required for its activation of proMMP2 on cell surface but is essential for MT1-MMP-mediated invasion in three-dimensional type I collagen.

Membrane-type matrix metalloproteinase-1 (MT1-MMP) plays a key role in tumor invasion and metastasis by degrading the extracellular matrix and activating proMMP2. Here we show that the conserved hemopexin domain is required for MT1-MMP-mediated invasion and growth in three-dimensional type I collagen matrix but not proMMP2 activation. Deletion of the hemopexin domains in MT1-, MT2-, MT3-, MT5-, and MT6-MMP does not impair their abilities to activate proMMP2. In fact, hemopexin-less MT5- and MT6-MMP activate proMMP2 better than their wild type counterparts. On the other hand, hemopexin-less MT1-MMP fails to promote cell invasion into type I collagen but retains the capacity to enhance the growth of Madin-Darby canine kidney cells as cysts in three-dimensional collagen matrix. Moreover, the hemopexin domain is also required for MT1-MMP-mediated invasion/scattering of MCF-7 cells in three-dimensional collagen matrix. Because growth and invasion in a three-dimensional model may correlate with tumor invasiveness in vivo, our data suggest that the hemopexin domains of MT-MMPs should be targeted for the development of anti-cancer therapies by employing screening assays developed for three-dimensional models rather than their enzymatic activity toward proMMP2.