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USP6 is a deubiquitinase with an ATP-independent isopeptidase activity, cleaving at the C-terminus of the ubiquitin moiety. It catalyzes its own deubiquitination. In vitro, isoform2, but not isoform3, shows deubiquitinating activity. USP6 promotes plasma membrane localization of ARF6 and selectively regulates ARF6-dependent endocytic protein trafficking. It is able to initiate tumorigenesis by inducing the production of matrix metalloproteinases following NF-kappa-B activation.
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