O-Glycosylation Regulates Autolysis of Cellular Membrane Type-1 Matrix Metalloproteinase (MT1-MMP)

• Published in: The Journal of biological chemistry 2006-06, Vol.281 (25), p.16897-16905
• Main Authors: Remacle, Albert G., Chekanov, Alexei V., Golubkov, Vladislav S., Savinov, Alexei Y., Rozanov, Dmitri V., Strongin, Alex Y.
• Format: Article
• Language: English
• Subjects: Animals; Catalytic Domain; Cell Line, Tumor; Cell Membrane - metabolism; CHO Cells; Cricetinae; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glycosylation; Humans; Matrix Metalloproteinase 14; Matrix Metalloproteinases - chemistry; Matrix Metalloproteinases - metabolism; Matrix Metalloproteinases, Membrane-Associated; Mice; Mice, Inbred BALB C; Models, Genetic; Neoplasm Transplantation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M600295200

MT1-MMP is a key enzyme in cancer cell invasion and metastasis. The activity of cellular MT1-MMP is regulated by furin-like proprotein convertases, TIMPs, shedding, autoproteolysis, dimerization, exocytosis, endocytosis, and recycling. Our data demonstrate that, in addition to these already known mechanisms, MT1-MMP is regulated by O-glycosylation of its hinge region. Insignificant autolytic degradation is characteristic for naturally expressed, glycosylated, MT1-MMP. In turn, extensive autolytic degradation, which leads to the inactivation of the protease and the generation of its C-terminal membrane-tethered degraded species, is a feature of overexpressed MT1-MMP. We have determined that incomplete glycosylation stimulates extensive autocatalytic degradation and self-inactivation of MT1-MMP. Self-proteolysis commences during the secretory process of MT1-MMP through the cell compartment to the plasma membrane. The strongly negatively charged sialic acid is the most important functional moiety of the glycopart of MT1-MMP. We hypothesize that sialic acid of the O-glycosylation cassette restricts the access of the catalytic domain to the hinge region and to the autolytic cleavage site and protects MT1-MMP from autolysis. Overall, our results point out that there is a delicate balance between glycosylation and self-proteolysis of MT1-MMP in cancer cells and that when this balance is upset the catalytically potent MT1-MMP pool is self-proteolyzed.