Protein ubiquitination and deubiquitination are reversible processes catalyzed by ubiquitinating enzymes and deubiquitinating enzymes respectively. DUBs are categorized into five subfamilies-USP, UCH, OTU, MJD, and JAMM. Ubiquitin-specific protease 9, X-linked possesses a well-conserved catalytic domain with cysteine peptidase activity, which allows for cleavage of ubiquitin and polyubiquitin conjugates. USP9X is the mammalian homolog of the Drosophila fat-facets gene, which is essential for normal eye development and viability of the early fly embryo. While USP9X expression is also critical for normal mammalian development, many of its substrates are only beginning to be elucidated. There is mounting evidence that USP9X functions in the formation of epithelial cell-cell contacts through deubiquitination-dependent stabilization of molecules involved in maintaining the integrity of both adherens and tight junctions. Indeed, USP9X has been found to associate with AF-6, the β-catenin-E-cadherin complex, and EFA6. Research studies have also demonstrated that USP9X is an integral component of the TGF-β/BMP signaling cascade by opposing TRIM33-mediated monoubiquitination of SMAD4. USP9X is overexpressed in a variety of human cancers and contributes to enhanced cell survival, in part, through its ability to deubiquitinate and stabilize the Mcl-1 oncoprotein. There is some evidence, however, that suggests the role of USP9X in tumorigenesis is context dependent. Research studies have implicated USP9X in a tumor suppressor role during the early stages of pancreatic ductal adenocarcinoma and in an oncogenic role during advanced stages of PDAC.
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