Ubiquitin-specific-processing protease 2 (USP2a) (USP2a)

Ubiquitin-specific-processing protease 2 (USP2a) is a member of the deubiquitinating enzyme (DUB) family that plays a critical role in regulating protein stability by reversing ubiquitination [1.2.1, 1.6.1]. It acts as a cysteine protease, removing ubiquitin chains from specific substrates to prevent their degradation by the 26S proteasome [1.1.1, 1.4.1]. USP2a is particularly noted for its oncogenic properties, as it stabilizes several key proteins involved in cell cycle progression and survival, including Cyclin D1, Cyclin A1, and the E3 ubiquitin ligase Mdm2, which in turn promotes the degradation of the p53 tumor suppressor [1.2.2, 1.2.4]. Additionally, USP2a regulates lipid metabolism by stabilizing Fatty Acid Synthase (FASN) and influences signal transduction by preventing the endocytosis-mediated degradation of the Epidermal Growth Factor Receptor (EGFR) [1.3.1, 1.3.3]. Due to its frequent overexpression in malignancies such as prostate, bladder, and lung cancers, USP2a is considered a promising therapeutic target [1.2.4, 1.2.5]. Small-molecule inhibitors like ML364 have demonstrated the ability to induce apoptosis and inhibit tumor growth in preclinical models, although no USP2a-targeted therapies have yet reached clinical approval [1.2.4]. Beyond oncology, USP2a is involved in the regulation of circadian rhythms and systemic metabolism, which may present challenges for therapeutic window and safety [1.2.3, 1.5.1].

Other names

Ubiquitin carboxyl-terminal hydrolase 2Ubiquitin-specific-processing protease 2UBP-t2USP2-69Deubiquitinating enzyme 2

Inhibition of the deubiquitinating activity of USP2a, which leads to the destabilization and subsequent proteasomal degradation of oncogenic substrates such as Cyclin D1, Mdm2, and Fatty Acid Synthase (FASN) [1.1.1, 1.2.4].