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.
Wang
Ping
P
Department of Pharmacology, University of Minnesota School of Medicine, Minneapolis, Minnesota 55455, USA.
Nie
Jing
J
Pei
Duanqing
D
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology; D049109:Cell Proliferation; D003094:Collagen / Q000737:chemistry; D024042:Collagen Type I / Q000737:chemistry*; D003600:Cytosol / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism*; D006466:Hemopexin / Q000737:chemistry*; D006801:Humans; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism*; D018613:Microscopy, Confocal; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D014162:Transfection
D024042:Collagen Type I; D004792:Enzyme Precursors; D003094:Collagen; D006466:Hemopexin; D018093:Gelatinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; C069860:progelatinase