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.
Immunochimie des Régulations Cellulaires et des Interactions Virales, INSERM U.354, Centre INSERM, Hôpital Saint-Antoine, Paris, France. frade354@easynet.fr
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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