USP15 (Ubiquitin Specific Peptidase 15) [B5]

The ubiquitin pathway involves three sequential enzymatic steps that facilitate the conjugation of ubiquitin and ubiquitin-like molecules to specific protein substrates. Protein ubiquitination and deubiquitination are reversible processes catalyzed by ubiquitinating enzymes and deubiquitinating enzymes respectively. The USP15 gene is amplified in glioblastoma and other solid tumors and its high expression correlates with a poor prognosis. Research studies demonstrate that USP15 is a positive regulator of oncogenic TGF-β signaling and that USP15 deubiquitinates monoubiquitinated R-SMADs to enhance target gene promoter binding (5). USP15 also promotes oncogenic TGF-β signaling by opposing SMURF2-mediated ubiquitination of the type I TGF-β receptor, which facilitates receptor stabilization. USP15 contributes to oncogenesis by negatively regulating T cell-mediated antitumor responses through the deubiquitination and stabilization of the E3 ubiquitin ligase MDM2. This observation supports USP15 as a potential target for cancer therapeutics.