Matrix metalloproteinase-2 activation modulates glioma cell migration.
Stable transfection of U251.3 glioma cells with cDNA encoding MT-MMP-1 resulted in increased cell surface expression of MT-MMP-1 and TIMP-2, constitutive activation of MMP-2 proenzyme and increased collagen degradation. In tumor spheroid outgrowth assays, cell migration of MT-MMP-1 transfectants relative to control was enhanced on collagen and decreased on vitronectin and fibronectin. These effects were reversed by TIMP-2 and were not associated with any substantial changes in cell adhesion. Binding of U251.3 cells to the C-terminal domain of MMP-2 was specifically inhibited by anti-(alpha)vss3 integrin blocking antibody indicating that MMP-2 interacts with (alpha)vss3 through the enzyme's C-terminal portion at or near the integrin's matrix adhesion sites. We propose that these mechanisms could govern directed matrix degradation in the tumor cells' microenvironment by sequestration of active MMP-2 on the cell surface. Our data suggest that activation of MMP-2 and its proteolytic activity localized to the cell surface could differentially modulate tumor cell migration in response to particular matrix proteins by altering both composition of the extracellular matrix and expression of adhesion receptors on the cell surface.
Deryugina
E I
EI
La Jolla Institute for Experimental Medicine, CA, USA.
Bourdon
M A
MA
Luo
G X
GX
Reisfeld
R A
RA
Strongin
A
A
D000595:Amino Acid Sequence; D001667:Binding, Competitive; D002462:Cell Membrane / Q000201:enzymology; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D003094:Collagen / Q000378:metabolism; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000096:biosynthesis; D016326:Extracellular Matrix Proteins / Q000235:genetics; D018093:Gelatinases / Q000378:metabolism*; D005910:Glioma / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D046911:Macromolecular Substances; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000378:metabolism*; D008969:Molecular Sequence Data; D019030:Receptors, Vitronectin / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
D004792:Enzyme Precursors; D016326:Extracellular Matrix Proteins; D046911:Macromolecular Substances; D019030:Receptors, Vitronectin; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2