USP2

Summary

USP2 (ubiquitin specific peptidase 2, HGNC:12618) is a protein-coding gene on chromosome 11q23.3, encoding Ubiquitin carboxyl-terminal hydrolase 2 (O75604). Hydrolase that deubiquitinates polyubiquitinated target proteins such as MDM2, MDM4 and CCND1.

This gene encodes a member of the family of de-ubiquitinating enzymes, which belongs to the peptidase C19 superfamily. The encoded protein is a ubiquitin-specific protease which is required for TNF-alpha (tumor necrosis factor alpha) -induced NF-kB (nuclear factor kB) signaling. This protein deubiquitinates polyubiquitinated target proteins such as fatty acid synthase, murine double minute 2 (MDM2), MDM4/MDMX and cyclin D1. MDM2 and MDM4 are negative regulators of the p53 tumor suppressor and cyclin D1 is required for cell cycle G1/S transition. Multiple alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 9099 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Limited, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 89 total
• Druggable target: yes — 124 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004205

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12618
Approved symbol	USP2
Name	ubiquitin specific peptidase 2
Location	11q23.3
Locus type	gene with protein product
Status	Approved
Aliases	UBP41
Ensembl gene	ENSG00000036672
Ensembl biotype	protein_coding
OMIM	604725
Entrez	9099

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 2 retained_intron

ENST00000260187, ENST00000455332, ENST00000525189, ENST00000525735, ENST00000527843, ENST00000531070, ENST00000532613, ENST00000876643

RefSeq mRNA: 3 — MANE Select: NM_004205 NM_001243759, NM_004205, NM_171997

CCDS: CCDS58189, CCDS8422, CCDS8423

Canonical transcript exons

ENST00000260187 — 13 exons

Exon	Start	End
ENSE00000748555	119357981	119358061
ENSE00000796207	119357483	119357590
ENSE00000796208	119357187	119357307
ENSE00000930893	119357757	119357835
ENSE00001103488	119372707	119373521
ENSE00001206641	119381473	119381690
ENSE00001528116	119355215	119356922
ENSE00003482404	119358773	119358837
ENSE00003520403	119359537	119359660
ENSE00003604416	119360184	119360234
ENSE00003623976	119359231	119359342
ENSE00003631515	119359024	119359134
ENSE00003641240	119358149	119358252

Expression profiles

Bgee: expression breadth ubiquitous, 237 present calls, max score 97.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.5069 / max 257.4886, expressed in 1151 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
122713	5.2418	860
122719	0.8104	76
122721	0.3940	207
122720	0.3889	67
122722	0.3718	207
122724	0.3221	44
122718	0.2717	114
122723	0.1865	78
122717	0.1655	67
122714	0.1505	69

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	97.94	gold quality
gastrocnemius	UBERON:0001388	96.53	gold quality
left testis	UBERON:0004533	96.07	gold quality
sperm	CL:0000019	95.93	gold quality
apex of heart	UBERON:0002098	95.82	gold quality
right testis	UBERON:0004534	95.74	gold quality
secondary oocyte	CL:0000655	95.53	gold quality
muscle of leg	UBERON:0001383	95.34	gold quality
oocyte	CL:0000023	95.09	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	93.98	gold quality
heart left ventricle	UBERON:0002084	93.86	gold quality
cardiac ventricle	UBERON:0002082	93.62	gold quality
male germ cell	CL:0000015	93.55	gold quality
testis	UBERON:0000473	93.25	gold quality
right atrium auricular region	UBERON:0006631	93.22	gold quality
skeletal muscle organ	UBERON:0014892	92.22	gold quality
muscle organ	UBERON:0001630	92.21	gold quality
mucosa of transverse colon	UBERON:0004991	92.08	gold quality
metanephros cortex	UBERON:0010533	91.66	gold quality
cardiac atrium	UBERON:0002081	91.32	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.28	gold quality
heart	UBERON:0000948	89.85	gold quality
cerebellar hemisphere	UBERON:0002245	89.77	gold quality
cerebellar cortex	UBERON:0002129	89.71	gold quality
adenohypophysis	UBERON:0002196	89.17	gold quality
mucosa of stomach	UBERON:0001199	89.14	gold quality
cerebellum	UBERON:0002037	87.80	gold quality
right frontal lobe	UBERON:0002810	87.44	gold quality
caudate nucleus	UBERON:0001873	86.88	gold quality
adult mammalian kidney	UBERON:0000082	86.52	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-2983	no	1018.03
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CLOCK

miRNA regulators (miRDB)

61 targeting USP2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-3660	99.68	67.33	1149
HSA-MIR-4526	99.68	67.07	1136
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-4524A-5P	99.57	71.73	1193
HSA-MIR-4524B-5P	99.57	71.68	1195
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-548B-3P	99.38	67.26	1000

Literature-anchored findings (GeneRIF, showing 40)

• Overexpression of Ubp41 is sufficient to elicit all features of apoptosis in human cells. (PMID:12566314)
• the isopeptidase USP2a plays a critical role in prostate cancer cell survival (PMID:15050917)
• USP2a is a novel regulator of the p53 pathway that acts through its ability to selectively target Mdm2. (PMID:17290220)
• USP2 were over-expressed in ovarian serous cystadenocarcinoma tissues, suggesting that the activity of ubiquitin-proteasome system is obviously enhanced in ovarian cancer. (PMID:17553343)
• Data show that ectopic expression of wild-type USP2a but not a catalytic mutant prevents Mdm2-mediated degradation of MdmX. (PMID:19838211)
• Findings suggest that targeting USP2 is an effective approach to induce growth suppression in the cancer cells addicted to cyclin D1 expression. (PMID:19917254)
• USP2-69 was upregulated in mesangial cells during mesangial proliferative glomerulonephritides in vivo and in vitro, which may relate to the proliferation of mesangial cells. (PMID:20403044)
• Data indicate that CHIP and USP2 show antagonistic functions in the control of AIF-mediated cell death, and implicate the role of the enzymes as a switch for cells to live or die under stresses that cause truncated AIF release. (PMID:21293491)
• the data support the conclusion that Usp2-45 action on epithelial Na(+) channel is promoted by various interactions, including through binding to Nedd4-2 (PMID:21478478)
• our results implicate USP2 as a novel positive regulator of TNF-alpha-induced NF-kappaB signaling and show that its expression is altered in tumor cells. (PMID:21480224)
• Etiology of nodular fasciitis seems to involve USP6 transcriptional upregulation due to its fusion with a strong ectopic promoter (MYH9). (PMID:21826056)
• a novel mechanism for the role of USP2a in mediating the stability of Aurora-A. (PMID:21890637)
• De-ubiquitinating protease USP2a targets RIP1 and TRAF2 to mediate cell death by TNF. (PMID:22179575)
• USP2a loss attenuates proliferation and migration in T24 human bladder cancer cells. (PMID:22370483)
• we have demonstrated that USP2a plays a negative regulatory role in IL-1beta- and SeV-induced NF-kappaB activation. (PMID:22611252)
• TRAF2 inhibits USP2a effect on K48- but not on K63-linked ubiquitin chains. (PMID:22659130)
• USP2a potentially mediates circadian disruption by suppressing the CRY1 degradation during inflammation. (PMID:22669941)
• USP2a antagonizes EGFR endocytosis and thus amplifies signaling activity from the receptor. (PMID:22710717)
• USP2a plays an important role in TCR signaling by deSUMOylating TRAF6 and mediating TRAF6-MALT1 interaction (PMID:23264041)
• USP2 and its substrate, fatty acid synthase (FASN), are over-expressed in glioma tissue. (PMID:23416128)
• USP2a increases intracellular glutathione content, thus interfering with the oxidative cascade triggered by chemotherapeutic agents. (PMID:24071644)
• Loss of USP2a expression is associated with glioblastoma. (PMID:24445145)
• findings demonstrated that USP2b deubiquitinates K63-linked polyubiquitin chains from TBK1 to terminate TBK1 activation and negatively regulate IFN-beta signaling and antiviral immune response. (PMID:25070846)
• The present study showed that USP2 expression is associated with TNBC cell line’s invasiveness and poor survival of breast cancer patients and may serve as a prognostic biomarker and therapeutic target for TNBC (PMID:25687182)
• Data suggest up-regulation of ASAH1 (acid ceramidase) activity by androgen in androgen-sensitive prostate cancer cells (but not other cancer cells) is mainly due to prolonged stability of ASAH1 by androgen-stimulated induction of USP2 expression. (PMID:25888580)
• Modulation of USP-2 expression plays a crucial role in cell cycle regulation by leptin and adiponectin. (PMID:26033248)
• Our findings suggest that USP2a mRNA may be considered as a diagnostic marker candidate for bladder cancer, in particular, to stratify MIBC patients with a more invasive phenotype. (PMID:26250800)
• Identify USP2 as a novel regulator of lipoprotein clearance owing to its ability to control ubiquitylation-dependent degradation of the LDLR by IDOL. (PMID:26666640)
• Authors show here USP2 is expressed in quiescent and activated T-cells and its expression is 50% lower in CTCL cell lines (MyLa2000, SeAx and Hut-78) than in normal T-cells. (PMID:27351221)
• the deubiquitinase USP2a translocates into the nucleus and binds to pY701-STAT1, and inhibits K48-linked ubiquitination and degradation of pY701-STAT1 (PMID:27434509)
• Data show that ubiquitin variants (Ubvs) that bind to USP2 or USP21 contain a similar core functional epitope, or “hot spot,” consisting mainly of positions that are conserved as the wild type sequence, but also some positions that prefer mutant sequences. (PMID:27436899)
• The results show a connection between miR-125b and USP2 gene the etiology of psoriasis. They proceeded to show that modulation of nuclear factor kappa B-mediated inflammation is the likely mechanism through which this miRNA gene pair function (PMID:27479112)
• ML364 also caused a decrease in homologous recombination-mediated DNA repair. These effects by a small molecule inhibitor support a key role for USP2 as a regulator of cell cycle, DNA repair, and tumor cell growth. (PMID:27681596)
• Data suggest that ubiquitin (Ub) and neural precursor cell expressed developmentally down-regulated 8 (NEDD8) residues 4, 12, 14, and 72 serve as the molecular determinants for specific recognition by ubiquitin specific protease 2 protein (USP2). (PMID:28536428)
• In general, we collect and summarize the factors involved in the alternative splicing of USP2 in this review to further understand the mechanism behind the USP2’s alternative splicing (PMID:29230097)
• These findings have characterized an essential role of USP2a as a potential target for treatment of metastatic cancers. (PMID:29490279)
• USP2-mediated Twist/Bmi1 pathway represents a cell-intrinsic mechanism crucial for CSC regulation besides EMT and provides pre-clinical evidence that targeting USP2 is indeed a promising approach for anti-CSC therapy. (PMID:30918246)
• The deubiquitylase USP2 maintains ErbB2 abundance via counteracting endocytic degradation and represents a therapeutic target in ErbB2-positive breast cancer. (PMID:32327714)
• Ubiquitin-specific protease 2a promotes hepatocellular carcinoma progression via deubiquitination and stabilization of RAB1A. (PMID:33074477)
• Disulfiram and 6-Thioguanine synergistically inhibit the enzymatic activities of USP2 and USP21. (PMID:33582217)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	usp2a	ENSDARG00000020107
mus_musculus	Usp2	ENSMUSG00000032010
rattus_norvegicus	Usp2	ENSRNOG00000006663
caenorhabditis_elegans		WBGENE00019259

Paralogs (71): USP28 (ENSG00000048028), USP36 (ENSG00000055483), USP13 (ENSG00000058056), USP33 (ENSG00000077254), USP40 (ENSG00000085982), USP48 (ENSG00000090686), USP14 (ENSG00000101557), USP11 (ENSG00000102226), USP10 (ENSG00000103194), USP31 (ENSG00000103404), USP42 (ENSG00000106346), USP5 (ENSG00000111667), USP4 (ENSG00000114316), USP9Y (ENSG00000114374), USP34 (ENSG00000115464), USP35 (ENSG00000118369), USP45 (ENSG00000123552), USP22 (ENSG00000124422), USP9X (ENSG00000124486), USP6 (ENSG00000129204), USP29 (ENSG00000131864), USP26 (ENSG00000134588), USP30 (ENSG00000135093), USP15 (ENSG00000135655), USP37 (ENSG00000135913), USP44 (ENSG00000136014), USP20 (ENSG00000136878), USP8 (ENSG00000138592), USP3 (ENSG00000140455), USP21 (ENSG00000143258), USP43 (ENSG00000154914), USP25 (ENSG00000155313), USP16 (ENSG00000156256), USP24 (ENSG00000162402), USP1 (ENSG00000162607), USP49 (ENSG00000164663), USP38 (ENSG00000170185), USP50 (ENSG00000170236), USP47 (ENSG00000170242), USP32 (ENSG00000170832)

Protein

Protein identifiers

Ubiquitin carboxyl-terminal hydrolase 2 — O75604 (reviewed: O75604)

Alternative names: 41 kDa ubiquitin-specific protease, Deubiquitinating enzyme 2, Ubiquitin thioesterase 2, Ubiquitin-specific-processing protease 2

All UniProt accessions (3): E9PJ34, E9PSH6, O75604

UniProt curated annotations — full annotation on UniProt →

Function. Hydrolase that deubiquitinates polyubiquitinated target proteins such as MDM2, MDM4 and CCND1. Isoform 1 and isoform 4 possess both ubiquitin-specific peptidase and isopeptidase activities. Deubiquitinates MDM2 without reversing MDM2-mediated p53/TP53 ubiquitination and thus indirectly promotes p53/TP53 degradation and limits p53 activity. Has no deubiquitinase activity against p53/TP53. Prevents MDM2-mediated degradation of MDM4. Plays a role in the G1/S cell-cycle progression in normal and cancer cells. Regulates the circadian clock by modulating its intrinsic circadian rhythm and its capacity to respond to external cues. Associates with clock proteins and deubiquitinates core clock component PER1 but does not affect its overall stability. Regulates the nucleocytoplasmic shuttling and nuclear retention of PER1 and its repressive role on the clock transcription factors CLOCK and BMAL1. Plays a role in the regulation of myogenic differentiation of embryonic muscle cells. Circadian clock output effector that regulates Ca(2+) absorption in the small intestine. Probably functions by regulating protein levels of the membrane scaffold protein NHERF4 in a rhythmic manner, and is therefore likely to control Ca(2+) membrane permeability mediated by the Ca(2+) channel TRPV6 in the intestine.

Subunit / interactions. Homooligomer. Found in trimeric complex with MDM2 and MDM4 and USP2. Interacts with CCND1; the interaction is direct and promotes its stabilization by antagonizing ubiquitin-dependent degradation. Interacts (via N-terminus and C-terminus) with MDM2. Interacts with MDM4. Interacts with PER1. Interacts with KCNQ1; counteracts the NEDD4L-specific down-regulation of I(Ks) and restore plasma membrane localization of KCNQ1. Isoform 4: Interacts with NHERF4 and CLTC.

Subcellular location. Cytoplasm. Perinuclear region Nucleus. Membrane.

Tissue specificity. Expressed in mesangial cells of the kidney and in different types of glomerulonephritides (at protein level).

Activity regulation. Cleavage is inhibited by ubiquitin in a dosage-dependent manner. Cleavage is blocked by ubiquitin aldehyde.

Domain organisation. The different N-terminus extensions of isoform 1 and isoform 4 determine their respective subcellular localization and differential effect on myoblast fusion and accumulation of muscle-specific proteins. The different N-terminus extensions of isoform 1 and isoform 4 are not essential for their catalytic activity.

Induction. Down-regulated by cisplatin (at protein level).

Similarity. Belongs to the peptidase C19 family. USP2 subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
O75604-1	1, USP2a, USP2-69	yes
O75604-2	2, USP2b
O75604-3	3
O75604-4	4

RefSeq proteins (3): NP_001230688, NP_004196, NP_741994 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001394	Peptidase_C19_UCH	Domain
IPR018200	USP_CS	Conserved_site
IPR028889	USP	Domain
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR050185	Ub_carboxyl-term_hydrolase	Family

Pfam: PF00443

UniProt features (61 total): strand 18, helix 13, sequence conflict 5, binding site 4, splice variant 4, region of interest 4, turn 3, sequence variant 2, mutagenesis site 2, compositionally biased region 2, active site 2, chain 1, domain 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
5XVE	X-RAY DIFFRACTION	1.24
3NHE	X-RAY DIFFRACTION	1.26
3V6C	X-RAY DIFFRACTION	1.7
5XU8	X-RAY DIFFRACTION	1.81
2HD5	X-RAY DIFFRACTION	1.85
3V6E	X-RAY DIFFRACTION	2.1
2IBI	X-RAY DIFFRACTION	2.2
6DGF	X-RAY DIFFRACTION	2.34

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75604-F1	69.00	0.50

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 276 (nucleophile); 557 (proton acceptor)

Ligand- & substrate-binding residues (4): 425; 428; 476; 479

Mutagenesis-validated functional residues (2):

Position	Phenotype
276	loss of enzymatic activity. increases the steady-state level of ccnd1.
549	loss of enzymatic activity. increases the steady-state level of mdm2 and mdm4 that leads to attenuation of mdm2-mediated

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-5357786	TNFR1-induced proapoptotic signaling
R-HSA-5357905	Regulation of TNFR1 signaling
R-HSA-5357956	TNFR1-induced NF-kappa-B signaling pathway
R-HSA-5689880	Ub-specific processing proteases
R-HSA-6804757	Regulation of TP53 Degradation

MSigDB gene sets: 295 (showing top): GOBP_CIRCADIAN_RHYTHM, E2F_Q4_01, GOBP_BEHAVIOR, MODULE_169, CCAWYNNGAAR_UNKNOWN, KAAB_FAILED_HEART_ATRIUM_DN, GOBP_PHOTOPERIODISM, GCANCTGNY_MYOD_Q6, CMYB_01, SP3_Q3, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_POSITIVE_REGULATION_OF_MITOTIC_CELL_CYCLE, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, AREB6_01, CREBP1_Q2

GO Biological Process (12): negative regulation of transcription by RNA polymerase II (GO:0000122), proteolysis (GO:0006508), muscle organ development (GO:0007517), protein deubiquitination (GO:0016579), circadian regulation of gene expression (GO:0032922), entrainment of circadian clock by photoperiod (GO:0043153), locomotor rhythm (GO:0045475), positive regulation of mitotic cell cycle (GO:0045931), circadian behavior (GO:0048512), protein stabilization (GO:0050821), regulation of signal transduction by p53 class mediator (GO:1901796), rhythmic process (GO:0048511)

GO Molecular Function (10): cysteine-type endopeptidase activity (GO:0004197), cysteine-type deubiquitinase activity (GO:0004843), cyclin binding (GO:0030332), ubiquitin protein ligase binding (GO:0031625), identical protein binding (GO:0042802), metal ion binding (GO:0046872), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787)

GO Cellular Component (6): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), centrosome (GO:0005813), membrane (GO:0016020), perinuclear region of cytoplasm (GO:0048471), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
TNF signaling	3
Deubiquitination	1
Regulation of TP53 Expression and Degradation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
circadian rhythm	2
cysteine-type peptidase activity	2
protein binding	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
protein metabolic process	1
animal organ development	1
muscle structure development	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
regulation of gene expression	1
photoperiodism	1
entrainment of circadian clock	1
locomotory behavior	1
circadian behavior	1
mitotic cell cycle	1
regulation of mitotic cell cycle	1
positive regulation of cell cycle	1
rhythmic behavior	1
regulation of protein stability	1
signal transduction by p53 class mediator	1
regulation of intracellular signal transduction	1
biological_process	1
endopeptidase activity	1
deubiquitinase activity	1
ubiquitin-like protein ligase binding	1
cation binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
nuclear lumen	1
intracellular anatomical structure	1
centriole	1
microtubule organizing center	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1384 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
USP2	ZUP1	Q96AP4	783
USP2	USP14	P54578	770
USP2	USP28	Q96RU2	739
USP2	UCHL3	P15374	708
USP2	OTUB1	Q96FW1	704
USP2	USP25	Q9UHP3	686
USP2	STAMBP	O95630	675
USP2	OTUD3	Q5T2D3	662
USP2	OTULIN	Q96BN8	655
USP2	USP13	Q92995	644
USP2	USP5	P45974	639
USP2	UCHL5	Q9Y5K5	623
USP2	NEDD4L	Q96PU5	618
USP2	MDM2	Q00987	607
USP2	CYLD	Q9NQC7	607

IntAct

367 interactions, top by confidence:

A	B	Type	Score
USP2	TRAF2	psi-mi:“MI:0915”(physical association)	0.780
TRAF2	USP2	psi-mi:“MI:0915”(physical association)	0.780
USP2	HOMER3	psi-mi:“MI:0915”(physical association)	0.720
USP2	TRIM27	psi-mi:“MI:0915”(physical association)	0.720
GOLGA2	USP2	psi-mi:“MI:0915”(physical association)	0.720
KRT40	USP2	psi-mi:“MI:0915”(physical association)	0.720
VPS52	USP2	psi-mi:“MI:0915”(physical association)	0.720
USP2	LZTS2	psi-mi:“MI:0915”(physical association)	0.720
USP2	NDEL1	psi-mi:“MI:0915”(physical association)	0.720
USP2	KRT40	psi-mi:“MI:0915”(physical association)	0.720
USP2	VPS52	psi-mi:“MI:0915”(physical association)	0.720
NDEL1	USP2	psi-mi:“MI:0915”(physical association)	0.720
USP2	GOLGA2	psi-mi:“MI:0915”(physical association)	0.720
KRT15	USP2	psi-mi:“MI:0915”(physical association)	0.700
USP2	KRT15	psi-mi:“MI:0915”(physical association)	0.700
LHX4	USP2	psi-mi:“MI:0915”(physical association)	0.670
USP2	LHX4	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (377): UBC (Biochemical Activity), PLA2G2A (Biochemical Activity), ERBB2 (Biochemical Activity), USP2 (Two-hybrid), USP2 (Two-hybrid), USP2 (Two-hybrid), USP2 (Two-hybrid), USP2 (Two-hybrid), USP2 (Two-hybrid), USP2 (Two-hybrid), USP2 (Two-hybrid), PNMA1 (Two-hybrid), HOMER3 (Two-hybrid), MTUS2 (Two-hybrid), HOOK1 (Two-hybrid)

ESM2 similar proteins: A5D6R3, A6NHC0, G5EE56, O08529, O14815, O35350, O35920, O57429, O74442, O75604, O88623, P00789, P07384, P17655, P23298, P24723, P35750, P42680, P97571, Q07009, Q08881, Q1JPZ3, Q1RLL3, Q27970, Q27971, Q2KHV7, Q32NH8, Q4R6D3, Q4VSI4, Q5NVS7, Q5U349, Q64617, Q6A4J8, Q6P8X6, Q6QN14, Q6U7I1, Q78EJ9, Q84WC6, Q8BLR2, Q8IYJ1

Diamond homologs: A4FUN7, A5PMR2, A5PN09, A6H8I0, A6NNY8, A6QNM7, A6QR55, A7Z056, A8MUK1, B1AY15, B1WBD7, B2GUZ1, B2RQC2, C9JJH3, C9JLJ4, C9JPN9, C9JVI0, D3ZU96, D6R901, D6R9N7, D6RA61, D6RBM5, D6RBQ6, D6RCP7, D6RJB6, E1B9W9, F6Z5C0, M9PD06, O22207, O60079, O75604, O94966, P0C8Z3, P35123, P39538, P40818, P50102, P51784, Q09738, Q0WX57

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
TGFBR2	“up-regulates activity”	USP2	phosphorylation
USP2	“up-regulates activity”	TGFBR1	deubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 104 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
TNFR1-induced NF-kappa-B signaling pathway	5	26.7×	1e-04
Regulation of TNFR1 signaling	6	21.3×	1e-04
Formation of the cornified envelope	8	11.2×	1e-04
Regulation of PLK1 Activity at G2/M Transition	5	10.1×	3e-03
Keratinization	8	7.1×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
morphogenesis of an epithelium	7	24.8×	4e-06
intermediate filament organization	8	19.9×	4e-06
epithelial cell differentiation	7	12.7×	3e-04
regulation of apoptotic process	9	7.7×	4e-04
protein transport	10	4.5×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

89 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	77
Likely benign	6
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1615 predictions. Top by Δscore:

Variant	Effect	Δscore
11:119356921:CG:C	acceptor_gain	1.0000
11:119356923:C:CC	acceptor_gain	1.0000
11:119357304:TGGT:T	acceptor_gain	1.0000
11:119357308:C:CC	acceptor_gain	1.0000
11:119357481:A:AC	donor_gain	1.0000
11:119357482:C:CC	donor_gain	1.0000
11:119357482:CT:C	donor_gain	1.0000
11:119357482:CTG:C	donor_gain	1.0000
11:119357482:CTGGT:C	donor_gain	1.0000
11:119357623:CAA:C	acceptor_gain	1.0000
11:119357976:CTT:C	donor_loss	1.0000
11:119357978:TAC:T	donor_loss	1.0000
11:119357979:A:AC	donor_gain	1.0000
11:119357979:ACTGG:A	donor_gain	1.0000
11:119357980:C:CG	donor_gain	1.0000
11:119357980:CT:C	donor_gain	1.0000
11:119357980:CTG:C	donor_gain	1.0000
11:119357980:CTGG:C	donor_gain	1.0000
11:119357980:CTGGC:C	donor_gain	1.0000
11:119358058:CTCG:C	acceptor_gain	1.0000
11:119358059:TCG:T	acceptor_gain	1.0000
11:119358060:CG:C	acceptor_gain	1.0000
11:119358060:CGC:C	acceptor_gain	1.0000
11:119358061:GC:G	acceptor_loss	1.0000
11:119358062:C:CA	acceptor_loss	1.0000
11:119358062:C:CC	acceptor_gain	1.0000
11:119358144:CATA:C	donor_loss	1.0000
11:119358145:ATAC:A	donor_loss	1.0000
11:119358146:TA:T	donor_loss	1.0000
11:119358147:A:AT	donor_loss	1.0000

AlphaMissense

3915 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:119357193:T:A	D575V	1.000
11:119357193:T:C	D575G	1.000
11:119357193:T:G	D575A	1.000
11:119357194:C:G	D575H	1.000
11:119357207:C:A	W570C	1.000
11:119357207:C:G	W570C	1.000
11:119357209:A:G	W570R	1.000
11:119357209:A:T	W570R	1.000
11:119357238:G:T	A560D	1.000
11:119357239:C:G	A560P	1.000
11:119357246:G:C	H557Q	1.000
11:119357246:G:T	H557Q	1.000
11:119357265:C:T	G551E	1.000
11:119357270:G:C	H549Q	1.000
11:119357270:G:T	H549Q	1.000
11:119357272:G:C	H549D	1.000
11:119357550:C:A	K514N	1.000
11:119357550:C:G	K514N	1.000
11:119357577:G:C	F505L	1.000
11:119357577:G:T	F505L	1.000
11:119357579:A:G	F505L	1.000
11:119357797:C:A	K487N	1.000
11:119357797:C:G	K487N	1.000
11:119358234:A:G	L419P	1.000
11:119359242:A:C	F350L	1.000
11:119359242:A:T	F350L	1.000
11:119359244:A:G	F350L	1.000
11:119359272:C:A	K340N	1.000
11:119359272:C:G	K340N	1.000
11:119359655:G:C	F277L	1.000

dbSNP variants (sampled 300 via entrez): RS1000137380 (11:119363584 G>A), RS1000188796 (11:119363732 G>A,C), RS1000393885 (11:119382618 T>C), RS1000475276 (11:119382888 G>A,C), RS1000600849 (11:119376840 C>T), RS1000844996 (11:119364320 C>A,G), RS1000868926 (11:119357246 G>C), RS1000989560 (11:119381029 T>A,C), RS1001048591 (11:119369049 C>T), RS1001148041 (11:119374877 C>T), RS1001150561 (11:119376708 C>T), RS1001265086 (11:119376342 T>A), RS1001338302 (11:119380726 G>A), RS1001430953 (11:119370876 G>T), RS1001583521 (11:119358188 G>C)

Disease associations

OMIM: gene MIM:604725 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Limited	Autosomal recessive

Mondo (1): complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001791_15	Urate levels	2.000000e-06
GCST007733_18	Serum uric acid levels	5.000000e-08
GCST008971_79	Urate levels	3.000000e-13
GCST008972_10	Urate levels	3.000000e-15
GCST010002_199	Refractive error	3.000000e-34
GCST010637_33	Urate levels	6.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0004761	uric acid measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1293227 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

124 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 431,320 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1009	LEVODOPA	4	103,854
CHEMBL1014	CANDESARTAN CILEXETIL	4	11,194
CHEMBL1017	TELMISARTAN	4	27,457
CHEMBL104	CLOTRIMAZOLE	4	56,325
CHEMBL1072	BUMETANIDE	4	22,087
CHEMBL1113	AMOXAPINE	4	20,128
CHEMBL1117	IDARUBICIN	4	136,065
CHEMBL1200348	SULCONAZOLE NITRATE	4	3,129
CHEMBL1200467	HYDROXYZINE PAMOATE	4	7,357
CHEMBL1200471	PYRITHIONE ZINC	4	24,834
CHEMBL1200836	OXICONAZOLE NITRATE	4	3,245
CHEMBL1200883	THONZONIUM BROMIDE	4	1,098
CHEMBL1200938	METHYSERGIDE MALEATE	4	4
CHEMBL1201038	ACRISORCIN	4	1,956
CHEMBL1201049	ECONAZOLE NITRATE	4	3,918
CHEMBL1201119	LIOTHYRONINE SODIUM	4	3,058
CHEMBL1201154	PROCHLORPERAZINE EDISYLATE	4	1,206
CHEMBL1201171	PRAMOXINE HYDROCHLORIDE	4	2,783
CHEMBL1201322	THONZONIUM	4	34
CHEMBL1201323	BETAZOLE	4	1,588
CHEMBL1201356	METHYLERGONOVINE	4
CHEMBL1280	VERAPAMIL HYDROCHLORIDE	4
CHEMBL1410	NONOXYNOL 9	4
CHEMBL1417019	MITOXANTRONE HYDROCHLORIDE	4
CHEMBL1423	PIMOZIDE	4
CHEMBL1448187	FLUPHENAZINE HYDROCHLORIDE	4
CHEMBL1516474	TEGASEROD MALEATE	4
CHEMBL1517	OXYTETRACYCLINE	4
CHEMBL1519	TRANDOLAPRIL	4
CHEMBL1534	RIBOFLAVIN	4

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — C19: Ubiquitin-specific protease

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
ML364	Inhibition	5.28	pKd

Binding affinities (BindingDB)

3 measured of 17 human assays (19 total across all organisms); most potent 3 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
ML323	IC50	17 nM	US-9802904: Inhibitors of the USP1/UAF1 deubiquitinase complex and uses thereof
Acetyl Isogambogic Acid	IC50	11100 nM
Mangiferin	IC50	56600 nM

ChEMBL bioactivities

3401 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.20	Potency	6.3	nM	CHEMBL1395605
8.10	Potency	7.9	nM	CHEMBL1437213
7.80	Potency	15.8	nM	CHEMBL1323897
7.70	Potency	20	nM	CHEMBL1314723
7.50	Potency	31.6	nM	CHEMBL1608984
7.50	Potency	31.6	nM	CHEMBL1475207
7.40	Potency	39.8	nM	CHEMBL1394223
7.00	Potency	100	nM	CHEMBL1575586
6.90	Potency	125.9	nM	CHEMBL1367789
6.80	Potency	158.5	nM	CHEMBL1559404
6.80	Potency	158.5	nM	CHEMBL489943
6.70	Potency	199.5	nM	CHEMBL374632
6.70	Potency	199.5	nM	CHEMBL1465204
6.60	IC50	250	nM	CHEMBL5556193
6.60	Potency	251.2	nM	CHEMBL1558999
6.60	Potency	251.2	nM	CHEMBL1597805
6.60	Potency	251.2	nM	CHEMBL1306484
6.60	Potency	251.2	nM	CHEMBL1364519
6.60	Potency	251.2	nM	CHEMBL1338051
6.60	Potency	251.2	nM	CHEMBL1484120
6.60	Potency	251.2	nM	CHEMBL1474503
6.55	Potency	281.8	nM	CHEMBL1560196
6.50	Potency	316.2	nM	CHEMBL3197156
6.50	Potency	316.2	nM	IODOQUINOL
6.50	Potency	316.2	nM	CHEMBL1475686
6.50	Potency	316.2	nM	CHEMBL1524600
6.40	Potency	398.1	nM	CHEMBL1447663
6.40	Potency	398.1	nM	CHEMBL1379269
6.40	Potency	398.1	nM	CHEMBL1477247
6.40	Potency	398.1	nM	CHEMBL1593545
6.40	Potency	398.1	nM	CHEMBL1724937
6.35	Potency	446.7	nM	CHEMBL1583747
6.30	Potency	501.2	nM	CHEMBL1341658
6.30	Potency	501.2	nM	CHEMBL1361346
6.30	Potency	501.2	nM	CHEMBL576544
6.30	Potency	501.2	nM	CHEMBL416615
6.30	Potency	501.2	nM	CHEMBL1460582
6.30	Potency	501.2	nM	CHEMBL1471583
6.30	Potency	501.2	nM	CHEMBL1441649
6.30	Potency	501.2	nM	CHEMBL1304690
6.30	Potency	501.2	nM	ACRISORCIN
6.30	Potency	501.2	nM	CHEMBL1599155
6.30	Potency	501.2	nM	CHEMBL1325932
6.30	Potency	501.2	nM	CHEMBL1326155
6.30	Potency	501.2	nM	CHEMBL1515885
6.30	Potency	501.2	nM	CHEMBL1341609
6.30	Potency	501.2	nM	CHEMBL1487321
6.25	Potency	562.3	nM	CHEMBL1583734
6.20	Potency	631	nM	CHEMBL1558420
6.20	Potency	631	nM	CHEMBL1334796

PubChem BioAssay actives

35 with measured affinity, of 150 total; 30 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-(2-bromophenyl)-3-(6-fluoro-1,3-dioxo-4H-isoquinolin-2-yl)propanamide	2069636: Inhibition of USP2 (unknown origin) incubated for 20 mins followed by substrate addition by fluorescence based high-throughput assay	ic50	0.2500	uM
2,3-bis(butylsulfonylmethyl)benzo[g]quinoxaline-5,10-dione	2069640: Inhibition of USP2 (unknown origin) using Di-Ub IQF K48-4 as substrate preincubated for 10 mins followed by substrate addition by high-throughput assay	ic50	0.8000	uM
4-methoxy-2-[(4-phenylphenyl)sulfonylamino]-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzamide	2069590: Inhibition of USP2 (267 to 599 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) cells using ubiquitin-rhodamine-110 as substrate preincubated with compound for 30 mins followed by substrate addition measured after 30 mins by fluorometric assay	ic50	0.8000	uM
4-methoxy-2-[[4-(5-methylthiophen-2-yl)phenyl]sulfonylamino]-N-(4-phenyl-1,3-thiazol-2-yl)benzamide	2069590: Inhibition of USP2 (267 to 599 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) cells using ubiquitin-rhodamine-110 as substrate preincubated with compound for 30 mins followed by substrate addition measured after 30 mins by fluorometric assay	ic50	0.8900	uM
2-[(4-methylphenyl)sulfonylamino]-N-(4-phenyl-1,3-thiazol-2-yl)-4-(trifluoromethyl)benzamide	1930821: Inhibition of human USP2 using Di-Ub IQF as substrate incubated for 15 mins by K63-2 assay	ic50	1.1000	uM
2-[(4-phenylphenyl)sulfonylamino]-N-(5-phenyl-1,3,4-thiadiazol-2-yl)-4-(trifluoromethyl)benzamide	2069590: Inhibition of USP2 (267 to 599 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) cells using ubiquitin-rhodamine-110 as substrate preincubated with compound for 30 mins followed by substrate addition measured after 30 mins by fluorometric assay	ic50	1.3000	uM
N-(1,3-benzothiazol-2-yl)-2-[(4-phenylphenyl)sulfonylamino]-4-(trifluoromethyl)benzamide	2069590: Inhibition of USP2 (267 to 599 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) cells using ubiquitin-rhodamine-110 as substrate preincubated with compound for 30 mins followed by substrate addition measured after 30 mins by fluorometric assay	ic50	1.4000	uM
4-methoxy-N-(5-phenyl-1,3,4-thiadiazol-2-yl)-2-[[3-(trifluoromethyl)phenyl]sulfonylamino]benzamide	2069590: Inhibition of USP2 (267 to 599 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) cells using ubiquitin-rhodamine-110 as substrate preincubated with compound for 30 mins followed by substrate addition measured after 30 mins by fluorometric assay	ic50	1.5000	uM
2-[(4-phenylphenyl)sulfonylamino]-N-(4-phenyl-1,3-thiazol-2-yl)-4-(trifluoromethyl)benzamide	2069590: Inhibition of USP2 (267 to 599 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) cells using ubiquitin-rhodamine-110 as substrate preincubated with compound for 30 mins followed by substrate addition measured after 30 mins by fluorometric assay	ic50	1.6000	uM
2-[(4-bromophenyl)sulfonylamino]-4-methoxy-N-(4-phenyl-1,3-thiazol-2-yl)benzamide	2069590: Inhibition of USP2 (267 to 599 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) cells using ubiquitin-rhodamine-110 as substrate preincubated with compound for 30 mins followed by substrate addition measured after 30 mins by fluorometric assay	ic50	3.2000	uM
(4R)-4-[(5R,8R,9S,10S,13R,14S,17R)-3-methoxycarbonyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid	1802687: Di-UB K63-2 Hydrolysis Assay from Article 10.1016/j.chembiol.2017.03.002: “Lithocholic Acid Hydroxyamide Destabilizes Cyclin D1 and Induces G0/G1 Arrest by Inhibiting Deubiquitinase USP2a.”	ic50	3.3000	uM
2-(naphthalen-1-ylsulfonylamino)-N-(4-phenyl-1,3-thiazol-2-yl)-4-(trifluoromethyl)benzamide	2069590: Inhibition of USP2 (267 to 599 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) cells using ubiquitin-rhodamine-110 as substrate preincubated with compound for 30 mins followed by substrate addition measured after 30 mins by fluorometric assay	ic50	3.3000	uM
2-[[2-[(5-thiophen-2-yl-1,2-oxazol-3-yl)methoxy]acetyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide	1383944: Inhibition of human USP2a (258 to 605 residues) expressed in Escherichia coli BL21(DE3) using Ub-AMC as substrate incubated for 30 mins measured at 30 secs interval by fluorescence assay	ic50	3.3000	uM
4-methoxy-N-(4-phenyl-1,3-thiazol-2-yl)-2-[[2-(trifluoromethyl)phenyl]sulfonylamino]benzamide	2069590: Inhibition of USP2 (267 to 599 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) cells using ubiquitin-rhodamine-110 as substrate preincubated with compound for 30 mins followed by substrate addition measured after 30 mins by fluorometric assay	ic50	3.4000	uM
(4R)-N-hydroxy-4-[(3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanamide	1802687: Di-UB K63-2 Hydrolysis Assay from Article 10.1016/j.chembiol.2017.03.002: “Lithocholic Acid Hydroxyamide Destabilizes Cyclin D1 and Induces G0/G1 Arrest by Inhibiting Deubiquitinase USP2a.”	ic50	3.7000	uM
2-[2-chloro-6-fluoro-3-[(3R)-1-methylpyrrolidin-3-yl]oxyphenyl]benzo[f][1,3]benzoxazole-4,9-dione	1857650: Inhibition of USP2 (unknown origin) using Ub-Rho measured after 0.5 to 3 hrs	ic50	3.8000	uM
4-methoxy-N-(5-phenyl-1,3,4-thiadiazol-2-yl)-2-(pyridin-3-ylsulfonylamino)benzamide	2069590: Inhibition of USP2 (267 to 599 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) cells using ubiquitin-rhodamine-110 as substrate preincubated with compound for 30 mins followed by substrate addition measured after 30 mins by fluorometric assay	ic50	3.8000	uM
2-[(4-fluorophenyl)sulfonylamino]-4-methoxy-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzamide	2069590: Inhibition of USP2 (267 to 599 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) cells using ubiquitin-rhodamine-110 as substrate preincubated with compound for 30 mins followed by substrate addition measured after 30 mins by fluorometric assay	ic50	4.4000	uM
4-methoxy-2-[[4-(4-methyl-3-pyridinyl)phenyl]sulfonylamino]-N-(4-phenyl-1,3-thiazol-2-yl)benzamide	2069590: Inhibition of USP2 (267 to 599 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) cells using ubiquitin-rhodamine-110 as substrate preincubated with compound for 30 mins followed by substrate addition measured after 30 mins by fluorometric assay	ic50	4.6000	uM
2-pyridin-3-ylbenzo[f][1,3]benzoxazole-4,9-dione	1857650: Inhibition of USP2 (unknown origin) using Ub-Rho measured after 0.5 to 3 hrs	ic50	5.1000	uM
N-(4-phenyl-1,3-thiazol-2-yl)-2-(thiophen-2-ylsulfonylamino)-4-(trifluoromethyl)benzamide	2069590: Inhibition of USP2 (267 to 599 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) cells using ubiquitin-rhodamine-110 as substrate preincubated with compound for 30 mins followed by substrate addition measured after 30 mins by fluorometric assay	ic50	5.5000	uM
N-(5-phenyl-1,3,4-thiadiazol-2-yl)-2-(pyridin-3-ylsulfonylamino)-4-(trifluoromethyl)benzamide	2069590: Inhibition of USP2 (267 to 599 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) cells using ubiquitin-rhodamine-110 as substrate preincubated with compound for 30 mins followed by substrate addition measured after 30 mins by fluorometric assay	ic50	5.5000	uM
(4R)-4-[(3R,5R,8R,9S,10S,13R,14S,17R)-3-acetyloxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid	2069637: Inhibition of human USP2A (258 to 605 residues) expressed in Escherichia coli BL21 (DE3) using Ub-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence based assay	ic50	5.8000	uM
4-methoxy-N-(4-phenyl-1,3-thiazol-2-yl)-2-(thiophen-2-ylsulfonylamino)benzamide	2069590: Inhibition of USP2 (267 to 599 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) cells using ubiquitin-rhodamine-110 as substrate preincubated with compound for 30 mins followed by substrate addition measured after 30 mins by fluorometric assay	ic50	5.9000	uM
2-[2-chloro-5-[(3R)-1-methylpyrrolidin-3-yl]oxyphenyl]benzo[f][1,3]benzoxazole-4,9-dione	1857650: Inhibition of USP2 (unknown origin) using Ub-Rho measured after 0.5 to 3 hrs	ic50	6.2000	uM
4-methoxy-N-(4-phenyl-1,3-thiazol-2-yl)-2-(pyridin-3-ylsulfonylamino)benzamide	2069590: Inhibition of USP2 (267 to 599 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) cells using ubiquitin-rhodamine-110 as substrate preincubated with compound for 30 mins followed by substrate addition measured after 30 mins by fluorometric assay	ic50	6.4000	uM
(2,6-diamino-5-thiocyanato-3-pyridinyl) thiocyanate	1925871: Inhibition of USP2 (unknown origin)	ec50	7.2000	uM
(4R)-N-(cyanomethyl)-4-[(3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanamide	1802686: Ub-AMC-Hydrolysis Assay from Article 10.1016/j.chembiol.2017.03.002: “Lithocholic Acid Hydroxyamide Destabilizes Cyclin D1 and Induces G0/G1 Arrest by Inhibiting Deubiquitinase USP2a.”	ic50	7.4000	uM
2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide	1383944: Inhibition of human USP2a (258 to 605 residues) expressed in Escherichia coli BL21(DE3) using Ub-AMC as substrate incubated for 30 mins measured at 30 secs interval by fluorescence assay	ic50	8.7000	uM
(4R)-N-hydroxy-4-[(3R,5R,8R,9R,10S,13R,14R,17R)-3-hydroxy-8,10,13-trimethyl-1,2,3,4,5,6,7,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]pentanamide	1558721: Inhibition of USP2 (unknown origin) using Ub-AMC substrate	ic50	9.7000	uM

CTD chemical–gene interactions

48 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, decreases expression, increases expression	3
Valproic Acid	decreases expression, increases expression	3
Aflatoxin B1	affects expression, decreases methylation, increases expression	3
Air Pollutants	decreases expression, increases abundance, increases expression	2
Benzo(a)pyrene	increases methylation, affects methylation, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Smoke	increases abundance, increases expression	2
aristolochic acid I	increases expression	1
CB-5083	increases ubiquitination, decreases reaction, increases reaction	1
dicrotophos	increases expression	1
testosterone enanthate	affects expression	1
bisphenol A	decreases expression	1
arsenite	increases methylation	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
nickel sulfate	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
CGP 52608	increases reaction, affects binding	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
incobotulinumtoxinA	decreases expression	1
Sunitinib	decreases expression	1
Amiodarone	increases expression	1
Amphotericin B	increases expression	1
Arsenic	increases reaction, decreases reaction, increases ubiquitination	1
Atrazine	increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1

ChEMBL screening assays

49 unique, capped per target: 41 binding, 8 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1613927	Functional	PUBCHEM_BIOASSAY: qHTS Validation Assay for Inhibitors of Ubiquitin-specific Protease USP2a Using CHOP2 as the Reporter. (Class of assay: confirmatory) [Related pubchem assays: 2281 (Summary of qHTS Assay for Inhibitors of Ubiquitin-specifi	PubChem BioAssay data set
CHEMBL2163012	Binding	Inhibition of USP2 expressed in Escherichia coli BL21(DE3) by Ub-CHOP reporter assay	Selective Dual Inhibitors of the Cancer-Related Deubiquitylating Proteases USP7 and USP47. — ACS Med Chem Lett

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D9VI	Ubigene HEK293 USP2 KO	Transformed cell line	Female
CVCL_E0SL	Ubigene HeLa USP2 KO	Cancer cell line	Female
CVCL_TW70	HAP1 USP2 (-) 1	Cancer cell line	Male
CVCL_TW71	HAP1 USP2 (-) 2	Cancer cell line	Male
CVCL_XU89	HAP1 USP2 (-) 3	Cancer cell line	Male
CVCL_XU90	HAP1 USP2 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

2 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder