Structure and functions of proteases which cleave human C3 and are expressed on normal or tumor human cells: some are involved in tumorigenic and metastatic properties of human melanoma cells.
Human C3 is a multipotent molecule which participates to different events involved in immune response as complement activation, antigen presentation, cell-cell interactions and cell proliferation. Thus, proteinases which cleave C3 may modify C3-dependent cellular functions. This led us to identify two membrane-associated proteinases which cleave human C3: (a) A p57 serine proteinase expressed on human erythrocyte membranes--This p57 proteinase shared antigenic determinants with ankyrine and may be involved in clearance of immune complexes; (b) A p41 cysteine proteinase, which shares antigenic determinants, amino-acid sequence and specific activity with procathepsin-L--This p41 C3-cleaving cyteine proteinase is also involved in tumorigenic and metastatic properties of human melanoma in nude mice. Indeed, pretreatment of highly tumorigenic and metastatic melanoma cells with anti-p39 Ab totally abolished their tumorigenicity and significantly decreased the number of experimental lung metastases in nude mice. Furthermore, overexpression of procathepsin-L in nonmetastatic melanoma cells increased their tumorigenicity and switched their phenotype to highly metastatic cells in nude mice. Altogether, these data support that expression and secretion of procathepsin-L, which cleaves human C3, might be one of the multiple mechanisms by which tumor cells escape the immune surveillance.
Frade
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Immunochimie des Régulations Cellulaires et des Interactions Virales, INSERM U.354, Centre INSERM, Hôpital Saint-Antoine, Paris, France. frade354@easynet.fr
D000595:Amino Acid Sequence; D000818:Animals; D003176:Complement C3 / Q000276:immunology / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000201:enzymology* / Q000276:immunology / Q000473:pathology* / Q000556:secondary; D008969:Molecular Sequence Data; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000378:metabolism*; D013329:Structure-Activity Relationship
D003176:Complement C3; D012697:Serine Endopeptidases; D003546:Cysteine Endopeptidases