Links between CD147 function, glycosylation, and caveolin-1.
Cell surface CD147 shows remarkable variations in size (31-65 kDa) because of heterogeneous N-glycosylation, with the most highly glycosylated forms functioning to induce matrix metalloproteinase (MMP) production. Here we show that all three CD147 N-glycosylation sites make similar contributions to both high and low glycoforms (HG- and LG-CD147). l-Phytohemagglutinin lectin binding and swainsonine inhibition experiments indicated that HG-CD147 contains N-acetylglucosaminyltransferase V-catalyzed, beta1,6-branched, polylactosamine-type sugars, which account for its excess size. Therefore, CD147, which is itself elevated on invasive tumor cells, may make a major contribution to the abundance of beta1,6-branched polylactosamine sugars that appear on invasive tumor cells. It was shown previously that caveolin-1 associates with CD147, thus inhibiting CD147 self-aggregation and MMP induction; now we show that caveolin-1 associates with LG-CD147 and restricts the biosynthetic conversion of LG-CD147 to HG-CD147. In addition, HG-CD147 (but not LG-CD147) was preferentially captured as a multimer after treatment of cells with a homobifunctional cross-linking agent and was exclusively recognized by monoclonal antibody AAA6, a reagent that selectively recognizes self-associated CD147 and inhibits CD147-mediated MMP induction. In conclusion, we have 1) determined the biochemical basis for the unusual size variation in CD147, 2) established that CD147 is a major carrier of beta1,6-branched polylactosamine sugars on tumor cells, and 3) determined that caveolin-1 can inhibit the conversion of LG-CD147 to HG-CD147. Because it is HG-CD147 that self-aggregates and stimulates MMP induction, we now have a mechanism to explain how caveolin-1 inhibits these processes. These results help explain the previously established tumor suppressor functions of caveolin-1.
Tang
Wei
W
Dana-Farber Cancer Institute and Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Chang
Sharon B
SB
Hemler
Martin E
ME
D000606:Amino Sugars / Q000737:chemistry / Q000378:metabolism; D015703:Antigens, CD / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051926:Basigin; D051242:Caveolin 1; D022461:Caveolins / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents; D004790:Enzyme Induction; D006031:Glycosylation; D006801:Humans; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D008954:Models, Biological; D046912:Multiprotein Complexes; D011134:Polysaccharides / Q000737:chemistry / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D000606:Amino Sugars; D015703:Antigens, CD; D000951:Antigens, Neoplasm; C497886:BSG protein, human; C495540:CAV1 protein, human; D051242:Caveolin 1; D022461:Caveolins; D003432:Cross-Linking Reagents; D046912:Multiprotein Complexes; D011134:Polysaccharides; D011993:Recombinant Fusion Proteins; C066929:polylactosamine; D051926:Basigin; D020782:Matrix Metalloproteinases