Ubiquitin Specific Protease 2: Structure% Isoforms% Cellular Function% Related Diseases and Its Inhibitors

Abstract

The ubiquitin-proteasome system (UPS) is an important pathway for cellular protein degradation. The components of this pathway, including the proteasome, ubiquitinase, and deubiquitinase, are highly specialized and strictly regulated. The ubiquitin-specific protease 2 (USP2) belongs to the ubiquitin-specific proteases, a subgroup of deubiquitinating enzymes. USP2 plays essential roles in regulating cell survival, cell cycle, circadian rhythm, cell metabolism, inflammatory response, antiviral response, and metastasis by interacting with certain proteins such as Cyclin D1, PER1, CRY1, HDM2/p53, FASN, LDLR, TRAF6, TBK1, and TGFBR1-TGFBR2 complex. Elevation of USP2 has been observed in a variety of cancers, including glioma, testicular cancer, breast cancer, prostate cancer, and some inflammatory diseases. Moreover, USP2 also plays an important role in many non-neoplastic diseases. At present, there is no officially approved USP2 inhibitor in clinic. A few existing inhibitors targeting USP2 have shown certain effects in the treatment of colorectal cancer, but their mechanism of action and binding site information are not clear. Moreover, the efficacy and selection specificity need to be further optimized. The catalytic centers of USP family are relatively conserved, so the design of compounds targeting allosteric site is expected to improve the specificity and inhibitory activity. In this review, we summarize the latest advances of USP2 in its cellular function, related diseases, and small-molecule inhibitors targeting USP2.

Comprehensive analysis of the role of ubiquitin-specific peptidases in colorectal cancer: A systematic review

“…LINC00668 promotes the tumorigenesis and migration of colon cancer cells and is highly expressed in CRC tissues[ 75 ]. It has been demonstrated that the TGF-β pathway has an effective role in metastasis; for instance, USP2 promotes EMT after interacting with TGFBR1 and TGFBR2 after TGF-β stimulation[ 76 ].…”

Targeting the deubiquitinase USP2 for malignant tumor therapy (Review)

“…The isomers of USP2 have similar structures, both consisting of an N-terminal structural domain of variable length and a C-terminal structural domain with 347 amino acids, where the C-terminus has the characteristic catalytic triad of the USP family (Cys, His, and Asp/Asn) (33). Specifically, USP2a has the largest N-terminal domain with 258 amino acids, while that of USP2b, USP2c and USP2-4 has 6, 15 and 49 amino acids, respectively (34)(35)(36)(37). The basic structure of USP2 is summarized in Fig.…”