Abstract
Ubiquitin specific protease (USP) 2 is a multifunctional deubiquitinating enzyme. USP2 modulates cell cycle progression, and therefore carcinogenesis, via the deubiquitination of cyclins and Aurora-A. Other tumorigenic molecules, including epidermal growth factor and fatty acid synthase, are also targets for USP2. USP2 additionally prevents p53 signaling. On the other hand, USP2 functions as a key component of the CLOCK/BMAL1 complex and participates in rhythmic gene expression in the suprachiasmatic nucleus and liver. USP2 variants influence energy metabolism by controlling hepatic gluconeogenesis, hepatic cholesterol uptake, adipose tissue inflammation, and subsequent systemic insulin sensitivity. USP2 also has the potential to promote surface expression of ion channels in renal and intestinal epithelial cells. In addition to modifying the production of cytokines in immune cells, USP2 also modulates the signaling molecules that are involved in cytokine signaling in the target cells. Usp2 knockout mice exhibit changes in locomotion and male fertility, which suggest roles for USP2 in the central nervous system and male genital tract, respectively. In this review, we summarize the cellular events with USP2 contributions and list the signaling molecules that are upstream or downstream of USP2. Additionally, we describe phenotypic differences found in the in vitro and in vivo experimental models.
Highlights
Protein ubiquitination and deubiquitination are reversible processes that control the fate of target proteins and protein–protein interactions
We examine the pathophysiological events elicited by USP2 and summarize the cellular signaling that underlies the events in a comprehensive way
We previously demonstrated that in human macrophage-like HL-60 cells, USP2-1 suppressed the expression of adipose tissue inflammation–related genes for SERPINE1 plasminogen activator inhibitor-1 (PAI-1), adipocyte protein 2, HMGA4high mobility group protein A2 (HMGA2), and matrix metalloproteases (MMPs) [9]
Summary
Protein ubiquitination and deubiquitination are reversible processes that control the fate of target proteins and protein–protein interactions. We refer to the variants according to the nomenclature used by UniProt (O75604) to avoid confusion: isoforms 1, 2, 3, and 4 in human and their mouse orthologues are described as USP2-1, -2, -3, and -4. USP2 with other DUBs, some review articles have summarized the pathological roles of USP2 in specific functional areas, such as cancer promotion [14,15], muscle atrophy modification [16], and sodium channel regulation [17]. Another review focused on the expressional control of alternative splicing variants of USP2 [8]. Despite these examples in the literature, there have been no review articles summarizing USP2-associated signaling and its outcomes from a more comprehensive viewpoint. We examine the pathophysiological events elicited by USP2 and summarize the cellular signaling that underlies the events in a comprehensive way
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