Deubiquitinase with an ATP-independent isopeptidase activity, cleaving at the C-terminus of the ubiquitin moiety. Catalyzes its own deubiquitination. In vitro, isoform 2, but not isoform 3, shows deubiquitinating activity. Promotes plasma membrane localization of ARF6 and selectively regulates ARF6-dependent endocytic protein trafficking. Is able to initiate tumorigenesis by inducing the production of matrix metalloproteinases following NF-kappa-B activation. A chromosomal aberration involving USP6 is a common genetic feature of aneurysmal bone cyst, a benign osseous neoplasm. Translocation t(16,17)(q22,p13) with CDH11. The translocation generates a fusion gene in which the strong CDH11 promoter is fused to the entire USP6 coding sequence, resulting in USP6 transcriptional up-regulation.Synonyms: Deubiquitinating enzyme 6, HRP1, TRE-2, Ubiquitin carboxyl-terminal hydrolase 6, Ubiquitin thioesterase 6, Ubiquitin-specific-processing protease 6