Regulation of MMP-1 and MMP-2 production through CD147/extracellular matrix metalloproteinase inducer interactions.
Extracellular matrix metalloproteinase inducer (EMMPRIN; CD147) is a heavily glycosylated protein containing two immunoglobulin superfamily domains. It is enriched on the surface of tumor cells and stimulates the production of matrix metalloproteinases (MMPs) by adjacent stromal cells. Here we use CD147 transfectants and immobilized recombinant CD147-Fc fusion protein to show that CD147/FMMPRIN engages in a homophilic interaction, predominantly through the first immunoglobulin domain. Anti-CD147 antibody 8G6 and recombinant CD147-Fc fusion protein markedly inhibited not only homophilic interaction, but also the production of secreted MMP-2 by breast cancer cell line MDA-435 and the MMP-2-dependent invasion of MDA-435 cells through reconstituted basement-membrane Matrigel. Purified native CD147 induced the production of secreted MMP not only by dermal fibroblasts (MMP-1) but also by MDA-435 cells themselves (MMP-2), suggesting homophilic CD147-binding may occur in the context of both heterotypic and homotypic cell-cell interactions. Purified deglycosylated CD147 failed to induce MMP-1 or MMP-2, but instead antagonized the MMP-1-inducing activity of purified native CD147. Our results suggest that homophilic CD147 interactions may play a key role in MMP-2 production and tumor cell invasion, and that perturbation of this molecule may have potential therapeutic uses in the prevention of MMP-2 and MMP-1-dependent cancer metastasis.
Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
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Sun
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ME
Hemler
D000818:Animals; D015703:Antigens, CD; D000951:Antigens, Neoplasm / Q000502:physiology*; D000954:Antigens, Surface; D030161:Avian Proteins; D051926:Basigin; D001798:Blood Proteins; D019556:COS Cells; D002448:Cell Adhesion / Q000502:physiology; D006224:Cricetinae; D005354:Fibrosarcoma / Q000201:enzymology / Q000473:pathology; D006031:Glycosylation; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D008562:Membrane Glycoproteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D009361:Neoplasm Invasiveness; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D030161:Avian Proteins; C497886:BSG protein, human; D001798:Blood Proteins; C102624:Bsg protein, Gallus gallus; C079432:Bsg protein, rat; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D051926:Basigin; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1