USP2 active domain (human recombinant)

Ubiquitin-specific protease 2 (USP2), also known as ubiquitin carboxyl-terminal hydrolase 2, is a cysteine protease involved in intracellular protein degradation by deubiquitinating degraded protein, including Mdm2, Mdm4, and CCND1.^1,2,3 In both normal and cancer cells, it regulates G₁/S cell-cycle transition.² It may regulate p53-dependent pathways by deubiquitinating Mdm2, indirectly promoting p53 degradation and limiting its activity.^1,4,5. Regulated by androgen, USP2 is over-expressed in prostate cancer and stabilizes fatty acid synthase (FASN), which is associated with the malignancy of some aggressive prostate cancers.^4,6 Some of these oncogenic properties may be linked to its deubiquitinating activity. One hypothesis is that USP2 may stabilize short-lived proteins that may act to induce apoptosis.⁷ USP2 has also been shown to regulate the intrinsic circadian rhythm and its capacity to respond to external cues, in a non-degradative manner by acting on the core clock component PER1.⁸ This protein is a truncation containing the active catalytic domain (residues 259-605) of USP2 and a C-terminal His-tag.

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1. Stevenson, L.F., Sparks, A.A., Allende-Vega, N., et al. The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2. EMBO J. 26(4), 976-986 (2007).

2. Shan, J., Zhao, W., and Gu, W. Suppression of cancer cell growth by promoting cyclin D1 degradation. Mol. Cell. 36(3), 469-476 (2009).

3. Allende-Vega, N., Sparks, A., Lane, D.P., et al. MdmX is a substrate for the deubiquitinating enzyme USP2a. Oncogene 29(3), 432-441 (2010).

4. Priolo, C., Tang, D., Brahamandan, M., et al. The isopeptidase USP2a protects human prostate cancer from apoptosis. Cancer Res. 66(17), 8625-8632 (2006).

5. Renatus, M., Parrado, S.G., D'Arcy, A., et al. Structural basis of ubiquitin recognition by the deubiquitinating protease USP2. Structure 14(8), 1293-1302 (2006).

6. Graner, E., Tang, D., Rossi, S., et al. The isopeptidase USP2a regulates the stability of fatty acid synthase in prostate cancer. Cancer Cell 593), 253-261 (2004).

7. Gewies, A., and Grimm, S. UBP41 is a proapoptotic ubiquitin-specific protease. Cancer Res. 63(3), 682-688 (2003).

8. Stojkovic, K., Wing, S., and Cermakian, N. A central role for ubiquitination within a circadian clock protein modification code. Front. Mol. Neurosci. 7(69), (2014).