ID UBP2_HUMAN Reviewed; 605 AA. AC O75604; B0YJB8; E9PPM2; Q8IUM2; Q8IW04; Q96MB9; Q9BQ21; DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot. DT 27-MAR-2002, sequence version 2. DT 27-MAR-2024, entry version 205. DE RecName: Full=Ubiquitin carboxyl-terminal hydrolase 2; DE EC=3.4.19.12; DE AltName: Full=41 kDa ubiquitin-specific protease; DE AltName: Full=Deubiquitinating enzyme 2; DE AltName: Full=Ubiquitin thioesterase 2; DE AltName: Full=Ubiquitin-specific-processing protease 2; GN Name=USP2; Synonyms=UBP41; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RC TISSUE=Placenta; RA Gong L., Yeh E.T.H.; RT "Cloning and expression of the human and mouse UBP41."; RL Submitted (JUL-1998) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4). RC TISSUE=Prostate cancer; RA Rossi S., Graner E., Weinstein L.J., Loda M.; RT "Molecular cloning and characterization of USP2b in the human prostate RT cancer cell line LNCaP."; RL Submitted (OCT-2001) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 4). RC TISSUE=Testis; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NHLBI resequencing and genotyping service (RS&G); RL Submitted (FEB-2007) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16554811; DOI=10.1038/nature04632; RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G., RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., RA Hattori M., Rogers J., Lander E.S., Sakaki Y.; RT "Human chromosome 11 DNA sequence and analysis including novel gene RT identification."; RL Nature 440:497-500(2006). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3). RC TISSUE=Lymph, and Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP FUNCTION, INTERACTION WITH MDM2, AND MUTAGENESIS OF HIS-549. RX PubMed=17290220; DOI=10.1038/sj.emboj.7601567; RA Stevenson L.F., Sparks A., Allende-Vega N., Xirodimas D.P., Lane D.P., RA Saville M.K.; RT "The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting RT Mdm2."; RL EMBO J. 26:976-986(2007). RN [9] RP FUNCTION, INTERACTION WITH CCND1, AND MUTAGENESIS OF CYS-276. RX PubMed=19917254; DOI=10.1016/j.molcel.2009.10.018; RA Shan J., Zhao W., Gu W.; RT "Suppression of cancer cell growth by promoting cyclin D1 degradation."; RL Mol. Cell 36:469-476(2009). RN [10] RP FUNCTION, INTERACTION WITH MDM2 AND MDM4, INDUCTION, AND MUTAGENESIS OF RP HIS-549. RX PubMed=19838211; DOI=10.1038/onc.2009.330; RA Allende-Vega N., Sparks A., Lane D.P., Saville M.K.; RT "MdmX is a substrate for the deubiquitinating enzyme USP2a."; RL Oncogene 29:432-441(2010). RN [11] RP TISSUE SPECIFICITY. RX PubMed=20403044; DOI=10.1111/j.1440-1827.2010.02496.x; RA Wang S., Wu H., Liu Y., Sun J., Zhao Z., Chen Q., Guo M., Ma D., Zhang Z.; RT "Expression of USP2-69 in mesangial cells in vivo and in vitro."; RL Pathol. Int. 60:184-192(2010). RN [12] RP INTERACTION WITH KCNQ1. RX PubMed=22024150; DOI=10.1016/j.hrthm.2011.10.026; RA Krzystanek K., Rasmussen H.B., Grunnet M., Staub O., Olesen S.P., RA Abriel H., Jespersen T.; RT "Deubiquitylating enzyme USP2 counteracts Nedd4-2-mediated downregulation RT of KCNQ1 potassium channels."; RL Heart Rhythm 9:440-448(2012). RN [13] RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 251-605. RG Structural genomics consortium (SGC); RT "Covalent ubiquitin-usp2 complex."; RL Submitted (FEB-2009) to the PDB data bank. RN [14] RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 258-605 IN COMPLEX WITH UBIQUITIN RP AND ZINC-BINDING, AND ACTIVITY REGULATION. RX PubMed=16905103; DOI=10.1016/j.str.2006.06.012; RA Renatus M., Parrado S.G., D'Arcy A., Eidhoff U., Gerhartz B., Hassiepen U., RA Pierrat B., Riedl R., Vinzenz D., Worpenberg S., Kroemer M.; RT "Structural basis of ubiquitin recognition by the deubiquitinating protease RT USP2."; RL Structure 14:1293-1302(2006). CC -!- FUNCTION: Hydrolase that deubiquitinates polyubiquitinated target CC proteins such as MDM2, MDM4 and CCND1 (PubMed:17290220, CC PubMed:19917254, PubMed:19838211). Isoform 1 and isoform 4 possess both CC ubiquitin-specific peptidase and isopeptidase activities (By CC similarity). Deubiquitinates MDM2 without reversing MDM2-mediated CC p53/TP53 ubiquitination and thus indirectly promotes p53/TP53 CC degradation and limits p53 activity (PubMed:17290220, PubMed:19838211). CC Has no deubiquitinase activity against p53/TP53 (PubMed:17290220). CC Prevents MDM2-mediated degradation of MDM4 (PubMed:17290220). Plays a CC role in the G1/S cell-cycle progression in normal and cancer cells CC (PubMed:19917254). Regulates the circadian clock by modulating its CC intrinsic circadian rhythm and its capacity to respond to external cues CC (By similarity). Associates with clock proteins and deubiquitinates CC core clock component PER1 but does not affect its overall stability (By CC similarity). Regulates the nucleocytoplasmic shuttling and nuclear CC retention of PER1 and its repressive role on the clock transcription CC factors CLOCK and BMAL1 (By similarity). Plays a role in the regulation CC of myogenic differentiation of embryonic muscle cells (By similarity). CC {ECO:0000250|UniProtKB:O88623, ECO:0000250|UniProtKB:Q5U349, CC ECO:0000269|PubMed:17290220, ECO:0000269|PubMed:19838211, CC ECO:0000269|PubMed:19917254}. CC -!- FUNCTION: [Isoform 4]: Circadian clock output effector that regulates CC Ca(2+) absorption in the small intestine. Probably functions by CC regulating protein levels of the membrane scaffold protein NHERF4 in a CC rhythmic manner, and is therefore likely to control Ca(2+) membrane CC permeability mediated by the Ca(2+) channel TRPV6 in the intestine. CC {ECO:0000250|UniProtKB:O88623}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide CC and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76- CC residue protein attached to proteins as an intracellular targeting CC signal).; EC=3.4.19.12; CC -!- ACTIVITY REGULATION: Cleavage is inhibited by ubiquitin in a dosage- CC dependent manner. Cleavage is blocked by ubiquitin aldehyde. CC {ECO:0000269|PubMed:16905103}. CC -!- SUBUNIT: Homooligomer (By similarity). Found in trimeric complex with CC MDM2 and MDM4 and USP2. Interacts with CCND1; the interaction is direct CC and promotes its stabilization by antagonizing ubiquitin-dependent CC degradation. Interacts (via N-terminus and C-terminus) with MDM2. CC Interacts with MDM4. Interacts with PER1 (By similarity). Interacts CC with KCNQ1; counteracts the NEDD4L-specific down-regulation of I(Ks) CC and restore plasma membrane localization of KCNQ1 (PubMed:22024150). CC Isoform 4: Interacts with NHERF4 and CLTC (By similarity). CC {ECO:0000250|UniProtKB:O88623, ECO:0000250|UniProtKB:Q5U349, CC ECO:0000269|PubMed:17290220, ECO:0000269|PubMed:19838211, CC ECO:0000269|PubMed:19917254, ECO:0000269|PubMed:22024150}. CC -!- INTERACTION: CC O75604; Q9NYB9-2: ABI2; NbExp=3; IntAct=EBI-743272, EBI-11096309; CC O75604; P12814: ACTN1; NbExp=3; IntAct=EBI-743272, EBI-351710; CC O75604; P35609: ACTN2; NbExp=3; IntAct=EBI-743272, EBI-77797; CC O75604; Q08043: ACTN3; NbExp=3; IntAct=EBI-743272, EBI-2880652; CC O75604; Q86U10: ASPG; NbExp=3; IntAct=EBI-743272, EBI-19946665; CC O75604; Q86V38: ATN1; NbExp=3; IntAct=EBI-743272, EBI-11954292; CC O75604; P56945: BCAR1; NbExp=3; IntAct=EBI-743272, EBI-702093; CC O75604; Q8TD16-2: BICD2; NbExp=3; IntAct=EBI-743272, EBI-11975051; CC O75604; Q96CA5: BIRC7; NbExp=3; IntAct=EBI-743272, EBI-517623; CC O75604; A2RRN7: CADPS; NbExp=3; IntAct=EBI-743272, EBI-10179719; CC O75604; Q13137: CALCOCO2; NbExp=3; IntAct=EBI-743272, EBI-739580; CC O75604; Q9H257-2: CARD9; NbExp=3; IntAct=EBI-743272, EBI-11530605; CC O75604; Q96JN2-2: CCDC136; NbExp=3; IntAct=EBI-743272, EBI-10171416; CC O75604; Q2TAC2: CCDC57; NbExp=3; IntAct=EBI-743272, EBI-2808286; CC O75604; A6NC98: CCDC88B; NbExp=3; IntAct=EBI-743272, EBI-347573; CC O75604; Q96MT8-3: CEP63; NbExp=3; IntAct=EBI-743272, EBI-11522539; CC O75604; Q8NHQ1: CEP70; NbExp=3; IntAct=EBI-743272, EBI-739624; CC O75604; Q9BSW2: CRACR2A; NbExp=3; IntAct=EBI-743272, EBI-739773; CC O75604; Q8N4Y2-3: CRACR2B; NbExp=3; IntAct=EBI-743272, EBI-11982645; CC O75604; Q8WTU0: DDI1; NbExp=3; IntAct=EBI-743272, EBI-748248; CC O75604; O75140-2: DEPDC5; NbExp=3; IntAct=EBI-743272, EBI-12366971; CC O75604; Q9NRI5-2: DISC1; NbExp=3; IntAct=EBI-743272, EBI-11988027; CC O75604; Q8N9I9: DTX3; NbExp=3; IntAct=EBI-743272, EBI-2340258; CC O75604; Q9H596: DUSP21; NbExp=3; IntAct=EBI-743272, EBI-7357329; CC O75604; Q8WWB3: DYDC1; NbExp=3; IntAct=EBI-743272, EBI-740680; CC O75604; Q5JST6: EFHC2; NbExp=3; IntAct=EBI-743272, EBI-2349927; CC O75604; Q9NRA8: EIF4ENIF1; NbExp=3; IntAct=EBI-743272, EBI-301024; CC O75604; O00471: EXOC5; NbExp=3; IntAct=EBI-743272, EBI-949824; CC O75604; Q96B26: EXOSC8; NbExp=3; IntAct=EBI-743272, EBI-371922; CC O75604; P57678: GEMIN4; NbExp=3; IntAct=EBI-743272, EBI-356700; CC O75604; Q08379: GOLGA2; NbExp=6; IntAct=EBI-743272, EBI-618309; CC O75604; Q9NYA3: GOLGA6A; NbExp=3; IntAct=EBI-743272, EBI-11163335; CC O75604; A6NEM1: GOLGA6L9; NbExp=3; IntAct=EBI-743272, EBI-5916454; CC O75604; Q6PI77: GPRASP3; NbExp=3; IntAct=EBI-743272, EBI-11519926; CC O75604; Q14451-3: GRB7; NbExp=3; IntAct=EBI-743272, EBI-11991632; CC O75604; Q4V328: GRIPAP1; NbExp=3; IntAct=EBI-743272, EBI-717919; CC O75604; Q9NSC5: HOMER3; NbExp=6; IntAct=EBI-743272, EBI-748420; CC O75604; Q9UJC3: HOOK1; NbExp=3; IntAct=EBI-743272, EBI-746704; CC O75604; Q96ED9-2: HOOK2; NbExp=3; IntAct=EBI-743272, EBI-10961706; CC O75604; Q8IYA8: IHO1; NbExp=3; IntAct=EBI-743272, EBI-8638439; CC O75604; Q9UKT9: IKZF3; NbExp=3; IntAct=EBI-743272, EBI-747204; CC O75604; Q5TA45: INTS11; NbExp=3; IntAct=EBI-743272, EBI-748258; CC O75604; Q96N16: JAKMIP1; NbExp=3; IntAct=EBI-743272, EBI-2680803; CC O75604; O75564-2: JRK; NbExp=3; IntAct=EBI-743272, EBI-17181882; CC O75604; Q674X7-2: KAZN; NbExp=3; IntAct=EBI-743272, EBI-12024294; CC O75604; Q9BVG8: KIFC3; NbExp=3; IntAct=EBI-743272, EBI-2125614; CC O75604; Q9BVG8-5: KIFC3; NbExp=3; IntAct=EBI-743272, EBI-14069005; CC O75604; P19012: KRT15; NbExp=5; IntAct=EBI-743272, EBI-739566; CC O75604; Q7Z3Y8: KRT27; NbExp=3; IntAct=EBI-743272, EBI-3044087; CC O75604; Q15323: KRT31; NbExp=3; IntAct=EBI-743272, EBI-948001; CC O75604; Q14525: KRT33B; NbExp=3; IntAct=EBI-743272, EBI-1049638; CC O75604; O76011: KRT34; NbExp=3; IntAct=EBI-743272, EBI-1047093; CC O75604; Q92764: KRT35; NbExp=3; IntAct=EBI-743272, EBI-1058674; CC O75604; Q6A162: KRT40; NbExp=6; IntAct=EBI-743272, EBI-10171697; CC O75604; Q9UBR4-2: LHX3; NbExp=3; IntAct=EBI-743272, EBI-12039345; CC O75604; Q969G2: LHX4; NbExp=4; IntAct=EBI-743272, EBI-2865388; CC O75604; Q03252: LMNB2; NbExp=3; IntAct=EBI-743272, EBI-2830427; CC O75604; Q9BRK4: LZTS2; NbExp=6; IntAct=EBI-743272, EBI-741037; CC O75604; Q00987: MDM2; NbExp=4; IntAct=EBI-743272, EBI-389668; CC O75604; Q9UJV3-2: MID2; NbExp=3; IntAct=EBI-743272, EBI-10172526; CC O75604; Q5VZ52: MORN5; NbExp=3; IntAct=EBI-743272, EBI-12835568; CC O75604; Q13084: MRPL28; NbExp=3; IntAct=EBI-743272, EBI-723426; CC O75604; Q5JR59: MTUS2; NbExp=3; IntAct=EBI-743272, EBI-742948; CC O75604; Q5JR59-3: MTUS2; NbExp=3; IntAct=EBI-743272, EBI-11522433; CC O75604; Q15742: NAB2; NbExp=3; IntAct=EBI-743272, EBI-8641936; CC O75604; Q9GZM8: NDEL1; NbExp=6; IntAct=EBI-743272, EBI-928842; CC O75604; I6L9F6: NEFL; NbExp=3; IntAct=EBI-743272, EBI-10178578; CC O75604; P07196: NEFL; NbExp=3; IntAct=EBI-743272, EBI-475646; CC O75604; O43482: OIP5; NbExp=3; IntAct=EBI-743272, EBI-536879; CC O75604; Q96CV9: OPTN; NbExp=3; IntAct=EBI-743272, EBI-748974; CC O75604; Q4G0R1: PIBF1; NbExp=3; IntAct=EBI-743272, EBI-14066006; CC O75604; Q9NRD5: PICK1; NbExp=3; IntAct=EBI-743272, EBI-79165; CC O75604; Q58EX7: PLEKHG4; NbExp=3; IntAct=EBI-743272, EBI-949255; CC O75604; Q8ND90: PNMA1; NbExp=3; IntAct=EBI-743272, EBI-302345; CC O75604; Q16633: POU2AF1; NbExp=3; IntAct=EBI-743272, EBI-943588; CC O75604; Q9GZV8: PRDM14; NbExp=3; IntAct=EBI-743272, EBI-3957793; CC O75604; Q6MZQ0: PRR5L; NbExp=3; IntAct=EBI-743272, EBI-1567866; CC O75604; Q15276: RABEP1; NbExp=3; IntAct=EBI-743272, EBI-447043; CC O75604; Q8HWS3: RFX6; NbExp=3; IntAct=EBI-743272, EBI-746118; CC O75604; Q59EK9-3: RUNDC3A; NbExp=3; IntAct=EBI-743272, EBI-11957366; CC O75604; P60903: S100A10; NbExp=3; IntAct=EBI-743272, EBI-717048; CC O75604; O14492-2: SH2B2; NbExp=3; IntAct=EBI-743272, EBI-19952306; CC O75604; O60504: SORBS3; NbExp=3; IntAct=EBI-743272, EBI-741237; CC O75604; Q99932-2: SPAG8; NbExp=3; IntAct=EBI-743272, EBI-11959123; CC O75604; A6NLX3: SPDYE4; NbExp=3; IntAct=EBI-743272, EBI-12047907; CC O75604; P51692: STAT5B; NbExp=3; IntAct=EBI-743272, EBI-1186119; CC O75604; Q86VP1: TAX1BP1; NbExp=3; IntAct=EBI-743272, EBI-529518; CC O75604; Q8WW24: TEKT4; NbExp=3; IntAct=EBI-743272, EBI-750487; CC O75604; Q9UBB9: TFIP11; NbExp=3; IntAct=EBI-743272, EBI-1105213; CC O75604; Q08117-2: TLE5; NbExp=5; IntAct=EBI-743272, EBI-11741437; CC O75604; Q03169: TNFAIP2; NbExp=3; IntAct=EBI-743272, EBI-7954198; CC O75604; Q13077: TRAF1; NbExp=3; IntAct=EBI-743272, EBI-359224; CC O75604; Q12933: TRAF2; NbExp=7; IntAct=EBI-743272, EBI-355744; CC O75604; Q9Y4K3: TRAF6; NbExp=3; IntAct=EBI-743272, EBI-359276; CC O75604; P36406: TRIM23; NbExp=3; IntAct=EBI-743272, EBI-740098; CC O75604; P14373: TRIM27; NbExp=6; IntAct=EBI-743272, EBI-719493; CC O75604; Q86XT4: TRIM50; NbExp=3; IntAct=EBI-743272, EBI-9867283; CC O75604; Q15654: TRIP6; NbExp=3; IntAct=EBI-743272, EBI-742327; CC O75604; Q8N6Y0: USHBP1; NbExp=3; IntAct=EBI-743272, EBI-739895; CC O75604; Q70EL1-9: USP54; NbExp=3; IntAct=EBI-743272, EBI-11975223; CC O75604; Q9UK41-2: VPS28; NbExp=3; IntAct=EBI-743272, EBI-12146727; CC O75604; Q8N1B4: VPS52; NbExp=6; IntAct=EBI-743272, EBI-2799833; CC O75604; O96006: ZBED1; NbExp=3; IntAct=EBI-743272, EBI-740037; CC O75604; Q9NZV7: ZIM2; NbExp=3; IntAct=EBI-743272, EBI-11962760; CC O75604; Q9UGI0: ZRANB1; NbExp=3; IntAct=EBI-743272, EBI-527853; CC O75604-3; P05067: APP; NbExp=3; IntAct=EBI-10696113, EBI-77613; CC O75604-3; P54253: ATXN1; NbExp=6; IntAct=EBI-10696113, EBI-930964; CC O75604-3; G5E9A7: DMWD; NbExp=3; IntAct=EBI-10696113, EBI-10976677; CC O75604-3; Q01658: DR1; NbExp=3; IntAct=EBI-10696113, EBI-750300; CC O75604-3; Q00403: GTF2B; NbExp=3; IntAct=EBI-10696113, EBI-389564; CC O75604-3; Q9Y5Q9: GTF3C3; NbExp=3; IntAct=EBI-10696113, EBI-1054873; CC O75604-3; P04792: HSPB1; NbExp=3; IntAct=EBI-10696113, EBI-352682; CC O75604-3; O43464: HTRA2; NbExp=3; IntAct=EBI-10696113, EBI-517086; CC O75604-3; P42858: HTT; NbExp=6; IntAct=EBI-10696113, EBI-466029; CC O75604-3; Q8WXH2: JPH3; NbExp=3; IntAct=EBI-10696113, EBI-1055254; CC O75604-3; O60333-2: KIF1B; NbExp=3; IntAct=EBI-10696113, EBI-10975473; CC O75604-3; D3DTS7: PMP22; NbExp=3; IntAct=EBI-10696113, EBI-25882629; CC O75604-3; O60260-5: PRKN; NbExp=3; IntAct=EBI-10696113, EBI-21251460; CC O75604-3; P60891: PRPS1; NbExp=3; IntAct=EBI-10696113, EBI-749195; CC O75604-3; Q9Y3C5: RNF11; NbExp=3; IntAct=EBI-10696113, EBI-396669; CC O75604-3; Q7Z333: SETX; NbExp=3; IntAct=EBI-10696113, EBI-1220123; CC O75604-3; P37840: SNCA; NbExp=3; IntAct=EBI-10696113, EBI-985879; CC O75604-3; P00441: SOD1; NbExp=3; IntAct=EBI-10696113, EBI-990792; CC O75604-3; Q7Z699: SPRED1; NbExp=3; IntAct=EBI-10696113, EBI-5235340; CC O75604-3; Q13148: TARDBP; NbExp=6; IntAct=EBI-10696113, EBI-372899; CC O75604-3; O76024: WFS1; NbExp=3; IntAct=EBI-10696113, EBI-720609; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:O88623}. CC Cytoplasm, perinuclear region {ECO:0000250|UniProtKB:O88623}. CC Note=Localizes in the spermatid head in late-elongating spermatids in CC the thin area between the outer acrosomal membrane and the plasma CC membrane. {ECO:0000250|UniProtKB:Q5U349}. CC -!- SUBCELLULAR LOCATION: [Isoform 4]: Nucleus CC {ECO:0000250|UniProtKB:Q5U349}. Membrane CC {ECO:0000250|UniProtKB:O88623}; Peripheral membrane protein CC {ECO:0000305}. Cytoplasm {ECO:0000250|UniProtKB:O88623}. CC Note=Predominantly expressed at membranes. CC {ECO:0000250|UniProtKB:O88623}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; Synonyms=USP2a, USP2-69; CC IsoId=O75604-1; Sequence=Displayed; CC Name=2; Synonyms=USP2b; CC IsoId=O75604-2; Sequence=VSP_005256, VSP_005257; CC Name=3; CC IsoId=O75604-3; Sequence=VSP_039559; CC Name=4; CC IsoId=O75604-4; Sequence=VSP_039560; CC -!- TISSUE SPECIFICITY: Expressed in mesangial cells of the kidney and in CC different types of glomerulonephritides (at protein level). CC {ECO:0000269|PubMed:20403044}. CC -!- INDUCTION: Down-regulated by cisplatin (at protein level). CC {ECO:0000269|PubMed:19838211}. CC -!- DOMAIN: The different N-terminus extensions of isoform 1 and isoform 4 CC determine their respective subcellular localization and differentiel CC effect on myoblast fusion and accumulation of muscle-specific proteins. CC The different N-terminus extensions of isoform 1 and isoform 4 are not CC essential for their catalytic activity. {ECO:0000250|UniProtKB:Q5U349}. CC -!- SIMILARITY: Belongs to the peptidase C19 family. USP2 subfamily. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF079564; AAC28392.1; -; mRNA. DR EMBL; AF440755; AAN65363.1; -; mRNA. DR EMBL; AK057225; BAB71388.1; -; mRNA. DR EMBL; AK292255; BAF84944.1; -; mRNA. DR EMBL; EF445044; ACA06096.1; -; Genomic_DNA. DR EMBL; EF445044; ACA06097.1; -; Genomic_DNA. DR EMBL; AP003396; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471065; EAW67484.1; -; Genomic_DNA. DR EMBL; CH471065; EAW67485.1; -; Genomic_DNA. DR EMBL; CH471065; EAW67486.1; -; Genomic_DNA. DR EMBL; BC002854; AAH02854.1; -; mRNA. DR EMBL; BC002955; AAH02955.1; -; mRNA. DR EMBL; BC041366; AAH41366.1; -; mRNA. DR CCDS; CCDS58189.1; -. [O75604-3] DR CCDS; CCDS8422.1; -. [O75604-1] DR CCDS; CCDS8423.1; -. [O75604-4] DR RefSeq; NP_001230688.1; NM_001243759.1. [O75604-3] DR RefSeq; NP_004196.4; NM_004205.4. [O75604-1] DR RefSeq; NP_741994.1; NM_171997.2. [O75604-4] DR RefSeq; XP_005271778.1; XM_005271721.4. [O75604-1] DR RefSeq; XP_005271779.1; XM_005271722.2. [O75604-1] DR PDB; 2HD5; X-ray; 1.85 A; A=258-605. DR PDB; 2IBI; X-ray; 2.20 A; A=251-605. DR PDB; 3NHE; X-ray; 1.26 A; A=258-605. DR PDB; 3V6C; X-ray; 1.70 A; A=258-605. DR PDB; 3V6E; X-ray; 2.10 A; A=258-605. DR PDB; 5XU8; X-ray; 1.81 A; A=258-605. DR PDB; 5XVE; X-ray; 1.24 A; A=258-605. DR PDB; 6DGF; X-ray; 2.34 A; A=250-605. DR PDBsum; 2HD5; -. DR PDBsum; 2IBI; -. DR PDBsum; 3NHE; -. DR PDBsum; 3V6C; -. DR PDBsum; 3V6E; -. DR PDBsum; 5XU8; -. DR PDBsum; 5XVE; -. DR PDBsum; 6DGF; -. DR AlphaFoldDB; O75604; -. DR SMR; O75604; -. DR BioGRID; 114553; 231. DR CORUM; O75604; -. DR DIP; DIP-29134N; -. DR IntAct; O75604; 138. DR MINT; O75604; -. DR STRING; 9606.ENSP00000260187; -. DR BindingDB; O75604; -. DR ChEMBL; CHEMBL1293227; -. DR MEROPS; C19.013; -. DR MoonDB; O75604; Predicted. DR GlyGen; O75604; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; O75604; -. DR PhosphoSitePlus; O75604; -. DR BioMuta; USP2; -. DR MassIVE; O75604; -. DR MaxQB; O75604; -. DR PaxDb; 9606-ENSP00000260187; -. DR PeptideAtlas; O75604; -. DR ProteomicsDB; 22761; -. DR ProteomicsDB; 50112; -. [O75604-1] DR ProteomicsDB; 50113; -. [O75604-2] DR ProteomicsDB; 50114; -. [O75604-3] DR ProteomicsDB; 50115; -. [O75604-4] DR Antibodypedia; 1707; 462 antibodies from 33 providers. DR DNASU; 9099; -. DR Ensembl; ENST00000260187.7; ENSP00000260187.2; ENSG00000036672.16. [O75604-1] DR Ensembl; ENST00000455332.6; ENSP00000407842.2; ENSG00000036672.16. [O75604-3] DR Ensembl; ENST00000525735.1; ENSP00000436952.1; ENSG00000036672.16. [O75604-4] DR GeneID; 9099; -. DR KEGG; hsa:9099; -. DR MANE-Select; ENST00000260187.7; ENSP00000260187.2; NM_004205.5; NP_004196.4. DR UCSC; uc001pwl.5; human. [O75604-1] DR AGR; HGNC:12618; -. DR CTD; 9099; -. DR DisGeNET; 9099; -. DR GeneCards; USP2; -. DR HGNC; HGNC:12618; USP2. DR HPA; ENSG00000036672; Tissue enhanced (skeletal). DR MIM; 604725; gene. DR neXtProt; NX_O75604; -. DR OpenTargets; ENSG00000036672; -. DR PharmGKB; PA37244; -. DR VEuPathDB; HostDB:ENSG00000036672; -. DR eggNOG; KOG1868; Eukaryota. DR GeneTree; ENSGT00940000161289; -. DR HOGENOM; CLU_008279_1_2_1; -. DR InParanoid; O75604; -. DR OMA; CMSCNLR; -. DR OrthoDB; 227085at2759; -. DR PhylomeDB; O75604; -. DR TreeFam; TF106277; -. DR PathwayCommons; O75604; -. DR Reactome; R-HSA-5357786; TNFR1-induced proapoptotic signaling. DR Reactome; R-HSA-5357905; Regulation of TNFR1 signaling. DR Reactome; R-HSA-5357956; TNFR1-induced NF-kappa-B signaling pathway. DR Reactome; R-HSA-5689880; Ub-specific processing proteases. DR Reactome; R-HSA-6804757; Regulation of TP53 Degradation. DR SignaLink; O75604; -. DR SIGNOR; O75604; -. DR BioGRID-ORCS; 9099; 13 hits in 1203 CRISPR screens. DR ChiTaRS; USP2; human. DR EvolutionaryTrace; O75604; -. DR GeneWiki; USP2; -. DR GenomeRNAi; 9099; -. DR Pharos; O75604; Tbio. DR PRO; PR:O75604; -. DR Proteomes; UP000005640; Chromosome 11. DR RNAct; O75604; Protein. DR Bgee; ENSG00000036672; Expressed in hindlimb stylopod muscle and 156 other cell types or tissues. DR ExpressionAtlas; O75604; baseline and differential. DR GO; GO:0005813; C:centrosome; IEA:Ensembl. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell. DR GO; GO:0030332; F:cyclin binding; IPI:UniProtKB. DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:FlyBase. DR GO; GO:0004197; F:cysteine-type endopeptidase activity; TAS:ProtInc. DR GO; GO:0042802; F:identical protein binding; IEA:Ensembl. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB. DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW. DR GO; GO:0048512; P:circadian behavior; ISS:UniProtKB. DR GO; GO:0032922; P:circadian regulation of gene expression; ISS:UniProtKB. DR GO; GO:0043153; P:entrainment of circadian clock by photoperiod; ISS:UniProtKB. DR GO; GO:0045475; P:locomotor rhythm; ISS:UniProtKB. DR GO; GO:0007517; P:muscle organ development; IEA:UniProtKB-KW. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:UniProtKB. DR GO; GO:0045931; P:positive regulation of mitotic cell cycle; IMP:UniProtKB. DR GO; GO:0016579; P:protein deubiquitination; IDA:UniProtKB. DR GO; GO:0050821; P:protein stabilization; IDA:UniProtKB. DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW. DR GO; GO:1901796; P:regulation of signal transduction by p53 class mediator; TAS:Reactome. DR CDD; cd02674; Peptidase_C19R; 1. DR Gene3D; 3.90.70.10; Cysteine proteinases; 1. DR InterPro; IPR038765; Papain-like_cys_pep_sf. DR InterPro; IPR001394; Peptidase_C19_UCH. DR InterPro; IPR018200; USP_CS. DR InterPro; IPR028889; USP_dom. DR PANTHER; PTHR21646; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE; 1. DR PANTHER; PTHR21646:SF17; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE 2; 1. DR Pfam; PF00443; UCH; 1. DR SUPFAM; SSF54001; Cysteine proteinases; 1. DR PROSITE; PS00972; USP_1; 1. DR PROSITE; PS00973; USP_2; 1. DR PROSITE; PS50235; USP_3; 1. DR Genevisible; O75604; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Biological rhythms; Cell cycle; KW Cytoplasm; Hydrolase; Membrane; Metal-binding; Myogenesis; Nucleus; KW Protease; Reference proteome; Thiol protease; Ubl conjugation pathway; KW Zinc. FT CHAIN 1..605 FT /note="Ubiquitin carboxyl-terminal hydrolase 2" FT /id="PRO_0000080616" FT DOMAIN 267..599 FT /note="USP" FT REGION 1..200 FT /note="Necessary for interaction with MDM4" FT /evidence="ECO:0000269|PubMed:19838211" FT REGION 71..107 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 237..264 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 403..503 FT /note="Necessary for interaction with MDM4" FT /evidence="ECO:0000269|PubMed:19838211" FT COMPBIAS 244..264 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 276 FT /note="Nucleophile" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10092, FT ECO:0000255|PROSITE-ProRule:PRU10093" FT ACT_SITE 557 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10092, FT ECO:0000255|PROSITE-ProRule:PRU10093" FT BINDING 425 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000269|PubMed:16905103" FT BINDING 428 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000269|PubMed:16905103" FT BINDING 476 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000269|PubMed:16905103" FT BINDING 479 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000269|PubMed:16905103" FT VAR_SEQ 1..258 FT /note="MSQLSSTLKRYTESARYTDAHYAKSGYGAYTPSSYGANLAASLLEKEKLGFK FT PVPTSSFLTRPRTYGPSSLLDYDRGRPLLRPDITGGGKRAESQTRGTERPLGSGLSGGS FT GFPYGVTNNCLSYLPINAYDQGVTLTQKLDSQSDLARDFSSLRTSDSYRIDPRNLGRSP FT MLARTRKELCTLQGLYQTASCPEYLVDYLENYGRKGSASQVPSQAPPSRVPEIISPTYR FT PIGRYTLWETGKGQAPGPSRSSSPGRDGM -> MLVPGSTRPYSKKRQ (in FT isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_039559" FT VAR_SEQ 1..258 FT /note="MSQLSSTLKRYTESARYTDAHYAKSGYGAYTPSSYGANLAASLLEKEKLGFK FT PVPTSSFLTRPRTYGPSSLLDYDRGRPLLRPDITGGGKRAESQTRGTERPLGSGLSGGS FT GFPYGVTNNCLSYLPINAYDQGVTLTQKLDSQSDLARDFSSLRTSDSYRIDPRNLGRSP FT MLARTRKELCTLQGLYQTASCPEYLVDYLENYGRKGSASQVPSQAPPSRVPEIISPTYR FT PIGRYTLWETGKGQAPGPSRSSSPGRDGM -> MRTSYTVTLPEDPPAAPFPALAKELR FT PRSPLSPSLLLSTFVGLLLNKAK (in isoform 4)" FT /evidence="ECO:0000303|PubMed:14702039, ECO:0000303|Ref.2" FT /id="VSP_039560" FT VAR_SEQ 1..252 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|Ref.1" FT /id="VSP_005256" FT VAR_SEQ 253..258 FT /note="PGRDGM -> MLNKAK (in isoform 2)" FT /evidence="ECO:0000303|Ref.1" FT /id="VSP_005257" FT VARIANT 174 FT /note="R -> Q (in dbSNP:rs33929148)" FT /id="VAR_051519" FT VARIANT 383 FT /note="N -> S (in dbSNP:rs45533837)" FT /id="VAR_051520" FT MUTAGEN 276 FT /note="C->A: Loss of enzymatic activity. Increases the FT steady-state level of CCND1." FT /evidence="ECO:0000269|PubMed:19917254" FT MUTAGEN 549 FT /note="H->A: Loss of enzymatic activity. Increases the FT steady-state level of MDM2 and MDM4 that leads to FT attenuation of MDM2-mediated degradation of p53/TP53 and FT MDM4. Increases the level of p53/TP53 and MDM4 ubiquitin FT conjugates." FT /evidence="ECO:0000269|PubMed:17290220, FT ECO:0000269|PubMed:19838211" FT CONFLICT 421 FT /note="S -> G (in Ref. 3; BAB71388)" FT /evidence="ECO:0000305" FT CONFLICT 501 FT /note="H -> R (in Ref. 3; BAB71388)" FT /evidence="ECO:0000305" FT CONFLICT 594 FT /note="L -> H (in Ref. 1; AAC28392)" FT /evidence="ECO:0000305" FT CONFLICT 602..605 FT /note="PSRM -> TSPI (in Ref. 1; AAC28392)" FT /evidence="ECO:0000305" FT STRAND 272..274 FT /evidence="ECO:0007829|PDB:3V6E" FT HELIX 276..286 FT /evidence="ECO:0007829|PDB:5XVE" FT HELIX 289..296 FT /evidence="ECO:0007829|PDB:5XVE" FT HELIX 299..302 FT /evidence="ECO:0007829|PDB:5XVE" FT HELIX 312..325 FT /evidence="ECO:0007829|PDB:5XVE" FT HELIX 337..346 FT /evidence="ECO:0007829|PDB:5XVE" FT HELIX 348..350 FT /evidence="ECO:0007829|PDB:5XVE" FT STRAND 351..353 FT /evidence="ECO:0007829|PDB:3NHE" FT HELIX 358..373 FT /evidence="ECO:0007829|PDB:5XVE" FT HELIX 392..404 FT /evidence="ECO:0007829|PDB:5XVE" FT HELIX 410..415 FT /evidence="ECO:0007829|PDB:5XVE" FT STRAND 417..425 FT /evidence="ECO:0007829|PDB:5XVE" FT TURN 426..428 FT /evidence="ECO:0007829|PDB:5XVE" FT STRAND 431..443 FT /evidence="ECO:0007829|PDB:5XVE" FT STRAND 450..454 FT /evidence="ECO:0007829|PDB:5XVE" FT HELIX 455..463 FT /evidence="ECO:0007829|PDB:5XVE" FT STRAND 466..468 FT /evidence="ECO:0007829|PDB:5XVE" FT HELIX 470..472 FT /evidence="ECO:0007829|PDB:5XVE" FT TURN 477..480 FT /evidence="ECO:0007829|PDB:5XVE" FT STRAND 485..493 FT /evidence="ECO:0007829|PDB:5XVE" FT STRAND 496..502 FT /evidence="ECO:0007829|PDB:5XVE" FT STRAND 505..508 FT /evidence="ECO:0007829|PDB:6DGF" FT STRAND 509..511 FT /evidence="ECO:0007829|PDB:5XU8" FT STRAND 518..520 FT /evidence="ECO:0007829|PDB:6DGF" FT HELIX 529..531 FT /evidence="ECO:0007829|PDB:5XVE" FT STRAND 532..534 FT /evidence="ECO:0007829|PDB:5XU8" FT STRAND 540..551 FT /evidence="ECO:0007829|PDB:5XVE" FT STRAND 553..555 FT /evidence="ECO:0007829|PDB:3V6C" FT STRAND 556..563 FT /evidence="ECO:0007829|PDB:5XVE" FT TURN 565..567 FT /evidence="ECO:0007829|PDB:5XVE" FT STRAND 570..574 FT /evidence="ECO:0007829|PDB:5XVE" FT STRAND 577..581 FT /evidence="ECO:0007829|PDB:5XVE" FT HELIX 583..585 FT /evidence="ECO:0007829|PDB:5XVE" FT STRAND 591..598 FT /evidence="ECO:0007829|PDB:5XVE" FT CONFLICT O75604-3:10 FT /note="Y -> S (in Ref. 7; AAH41366)" FT /evidence="ECO:0000305" SQ SEQUENCE 605 AA; 68072 MW; AFF4DA9344D21812 CRC64; MSQLSSTLKR YTESARYTDA HYAKSGYGAY TPSSYGANLA ASLLEKEKLG FKPVPTSSFL TRPRTYGPSS LLDYDRGRPL LRPDITGGGK RAESQTRGTE RPLGSGLSGG SGFPYGVTNN CLSYLPINAY DQGVTLTQKL DSQSDLARDF SSLRTSDSYR IDPRNLGRSP MLARTRKELC TLQGLYQTAS CPEYLVDYLE NYGRKGSASQ VPSQAPPSRV PEIISPTYRP IGRYTLWETG KGQAPGPSRS SSPGRDGMNS KSAQGLAGLR NLGNTCFMNS ILQCLSNTRE LRDYCLQRLY MRDLHHGSNA HTALVEEFAK LIQTIWTSSP NDVVSPSEFK TQIQRYAPRF VGYNQQDAQE FLRFLLDGLH NEVNRVTLRP KSNPENLDHL PDDEKGRQMW RKYLEREDSR IGDLFVGQLK SSLTCTDCGY CSTVFDPFWD LSLPIAKRGY PEVTLMDCMR LFTKEDVLDG DEKPTCCRCR GRKRCIKKFS IQRFPKILVL HLKRFSESRI RTSKLTTFVN FPLRDLDLRE FASENTNHAV YNLYAVSNHS GTTMGGHYTA YCRSPGTGEW HTFNDSSVTP MSSSQVRTSD AYLLFYELAS PPSRM //