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Malignant gliomas are the most common and deadly primary brain tumors, due to their infiltrative invasion of the normal neural tissue that makes them virtually impossible to completely eliminate. We have previously identified and characterized the proteoglycan BEHAB/brevican in gliomas and have demonstrated that upregulation and cleavage of this CNS-specific molecule promote glioma invasion. Here, we have further investigated if the proteolytic processing of BEHAB/brevican by metalloproteases of the ADAMTS family is a necessary step in mediating its pro-invasive effect in glioma. By generating a site-specific (396SRG398 → NVY) mutant form resistant to ADAMTS cleavage, we have shown that the predominant proteolytic processing of BEHAB/brevican by glioma cells occurs only at this site. More importantly, “uncleavable” BEHAB/brevican is unable to enhance glioma cell invasion in vitro and tumor progression in vivo. In addition, our results suggest that the full-length protein and its cleavage products may act independently because the mutant form does not exert a dominant negative effect on normal BEHAB/brevican expression or cleavage. These results illustrate how the regulated processing of major components of the neural extracellular matrix has important functional implications in glioma progression. In addition, our findings underscore the relevance of the ADAMTS family of metalloproteases as attractive targets for novel pharmacological approaches in glioma therapy.