USP6

Summary

USP6 (ubiquitin specific peptidase 6, HGNC:12629) is a protein-coding gene on chromosome 17p13.2, encoding Ubiquitin carboxyl-terminal hydrolase 6 (P35125). Deubiquitinase with an ATP-independent isopeptidase activity, cleaving at the C-terminus of the ubiquitin moiety.

Enables cysteine-type deubiquitinase activity. Involved in protein deubiquitination and regulation of postsynaptic neurotransmitter receptor internalization. Located in plasma membrane and recycling endosome. Is active in glutamatergic synapse and postsynaptic density, intracellular component.

Source: NCBI Gene 9098 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 228 total
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 8 cancer types
• MANE Select transcript: NM_001304284

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12629
Approved symbol	USP6
Name	ubiquitin specific peptidase 6
Location	17p13.2
Locus type	gene with protein product
Status	Approved
Aliases	Tre-2, TRE17, Tre2
Ensembl gene	ENSG00000129204
Ensembl biotype	protein_coding
OMIM	604334
Entrez	9098

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 2 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000250066, ENST00000357482, ENST00000572429, ENST00000572949, ENST00000574788, ENST00000575709

RefSeq mRNA: 2 — MANE Select: NM_001304284 NM_001304284, NM_004505

CCDS: CCDS11069

Canonical transcript exons

ENST00000574788 — 38 exons

Exon	Start	End
ENSE00001526356	5129936	5130089
ENSE00001526357	5128952	5129133
ENSE00001526358	5127504	5127639
ENSE00001526359	5124566	5125272
ENSE00001526361	5121375	5121750
ENSE00001526365	5118200	5118290
ENSE00001526367	5116032	5116740
ENSE00002340729	5125821	5125938
ENSE00002415016	5120627	5120788
ENSE00002632023	5172805	5174991
ENSE00003463309	5135808	5135928
ENSE00003464154	5147083	5147194
ENSE00003473238	5135234	5135282
ENSE00003477368	5130367	5130439
ENSE00003480259	5161528	5161614
ENSE00003499938	5137651	5137750
ENSE00003502383	5138121	5138273
ENSE00003517420	5141425	5141499
ENSE00003518796	5132910	5132990
ENSE00003523578	5170479	5170915
ENSE00003526924	5162884	5163004
ENSE00003527829	5148556	5148767
ENSE00003554601	5136640	5136734
ENSE00003556001	5132396	5132435
ENSE00003582137	5142397	5142502
ENSE00003603578	5133887	5133996
ENSE00003628546	5133443	5133550
ENSE00003632108	5146023	5146174
ENSE00003639777	5145405	5145579
ENSE00003656408	5171587	5171679
ENSE00003663235	5144690	5144863
ENSE00003668439	5130602	5130684
ENSE00003672603	5137121	5137186
ENSE00003682447	5139255	5139674
ENSE00003687782	5142003	5142141
ENSE00003688569	5167932	5168123
ENSE00003688746	5168767	5169055
ENSE00003691798	5155422	5155606

Expression profiles

Bgee: expression breadth ubiquitous, 264 present calls, max score 94.98.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1219 / max 77.1409, expressed in 17 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
159017	0.1025	14
159019	0.0195	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	94.98	gold quality
sperm	CL:0000019	94.54	gold quality
male germ cell	CL:0000015	93.90	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	91.07	silver quality
CA1 field of hippocampus	UBERON:0003881	91.04	gold quality
inferior olivary complex	UBERON:0002127	90.99	silver quality
gluteal muscle	UBERON:0002000	90.98	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	90.83	gold quality
biceps brachii	UBERON:0001507	90.78	gold quality
middle temporal gyrus	UBERON:0002771	90.04	gold quality
subthalamic nucleus	UBERON:0001906	89.26	gold quality
endothelial cell	CL:0000115	88.65	silver quality
postcentral gyrus	UBERON:0002581	88.26	gold quality
inferior vagus X ganglion	UBERON:0005363	88.26	gold quality
medulla oblongata	UBERON:0001896	88.25	gold quality
parietal lobe	UBERON:0001872	88.11	gold quality
superior vestibular nucleus	UBERON:0007227	87.75	gold quality
buccal mucosa cell	CL:0002336	87.65	gold quality
vastus lateralis	UBERON:0001379	86.93	gold quality
pons	UBERON:0000988	86.74	gold quality
entorhinal cortex	UBERON:0002728	86.60	gold quality
visceral pleura	UBERON:0002401	86.43	gold quality
ventral tegmental area	UBERON:0002691	86.40	gold quality
dorsal plus ventral thalamus	UBERON:0001897	86.30	silver quality
substantia nigra pars reticulata	UBERON:0001966	85.91	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	85.82	gold quality
orbitofrontal cortex	UBERON:0004167	85.75	silver quality
skeletal muscle tissue	UBERON:0001134	85.27	gold quality
cranial nerve II	UBERON:0000941	85.20	gold quality
mucosa of paranasal sinus	UBERON:0005030	85.04	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.84
E-MTAB-6058	no	92.77

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
MMP10	Activation
MMP9	Activation

miRNA regulators (miRDB)

150 targeting USP6, 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-5692A	100.00	74.40	6850
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-433-3P	99.98	69.37	1203
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787

Literature-anchored findings (GeneRIF, showing 40)

• TRE17 coprecipitated specifically with the active forms of Cdc42 and Rac1 in vivo. TRE17 is part of a novel effector complex for Cdc42 and Rac1, potentially contributing to their effects on actin remodeling. (PMID:12612085)
• Complementation tests in yeasts indicate that Tre2 codes for a nonfunctional RabGAP. (PMID:14521938)
• Deregulated USP6 transcription is associated with aneurysmal bone cyst (PMID:15026324)
• primary aneurysmal bone cysts are mesenchymal neoplasms exhibiting USP6 and/or CDH11 oncogenic rearrangements (PMID:15509545)
• TRE17 associates directly with Arf6 in its GDP- but not GTP-bound state. (PMID:15509780)
• Tre2 oncogene seems to encode a nonfunctional Rab GAP. As regions flanking the TBC domain may be crucial for catalytic activity (PMID:16099424)
• Ca2+/CaM has a role in regulating ubiquitination through direct interaction with TRE17 (PMID:16127172)
• The lack of secondary structure of the region flanking the TBC domain in TRE2 may explain why this region plays a role in the lack of GAP activity, even when a potentially functional TBC domain is present. (PMID:17701273)
• No USP6 rearrangements were found in cherubism or brown tumors. USP6 rearrangements were identified in 2 patients with myositis ossificans. (PMID:18265974)
• TRE17 is sufficient to initiate tumorigenesis, identify MMPs as novel TRE17 effectors that likely contribute to aneurysmal bone cyst pathogenesis. (PMID:20418905)
• It was shown that TRE17 activates the classical NF-kappa B pathway through an atypical mechanism that does not involve IkappaB degradation. Optimal activation of NF-kappa B by TRE17 required both catalytic subunits of IkappaB kinase. (PMID:22081069)
• manipulating USP6 expression levels alters the ability of cells to migrate and to divide. Cell proliferation and progression through cytokinesis depend on USP6 expression (PMID:22188517)
• identification of a USP6 gene rearrangement is helpful in making a diagnosis of nodular fasciitis. (PMID:23748914)
• we discuss the clinicopathologic features, molecular pathology, and pathogenesis of ABC and nodular fasciitis in relation to USP6 (PMID:23769422)
• 8 of the 9 giant cell reparative granulomas from hands and feet showed rearrangements of the USP6 gene compared with none of 8 gnathic lesions (PMID:24742829)
• TRE17/USP6 regulates ubiquitylation and trafficking of cargo proteins that enter cells by clathrin-independent endocytosis (PMID:25179595)
• Molecular analyses revealed the presence and amplification of the novel PPPR6-USP6 gene fusion, which resulted in USP6 mRNA transcriptional upregulation. These findings further support the oncogenic role of the USP6 protease in mesenchymal neoplasia and expand the biologic potential of Nodular fasciitis (PMID:27113271)
• Report the presence of USP6 rearrangements in a subset of cellular fibroma of tendon sheath. (PMID:27125357)
• the deubiquitylase ubiquitin-specific protease 6 (USP6) as a potent activator of Wnt signaling. USP6 enhances Wnt signaling by deubiquitylating Fzds, thereby increasing their cell-surface abundance. (PMID:27162353)
• USP6 fluorescence in-situ hybridization is a useful ancillary test in cases where nodular fasciitis is a potential diagnostic consideration. (PMID:27271298)
• our studies highlight Jak1 as the first identified substrate for USP6, and they offer a mechanistic rationale for the clinical investigation of Jak and STAT3 inhibitors as therapeutics for the treatment of bone and soft tissue tumors along with other neoplasms driven by USP6 overexpression (PMID:27440725)
• we identified seven novel fusion partners for USP6 in nodular fasciitis, highlighting the importance of USP6 expression and promoter-swapping fusions in the etiology of this neoplasm (PMID:28752842)
• USP6 is an enzyme that deubiquitinates c-Jun and regulates its downstream cellular functions.USP6 regulates the stability of the c-Jun protein in an enzyme activity-dependent manner. (PMID:29061731)
• Case Report: paranasal mass diagnosed as USP6-rearranged solid aneurysmal bone cyst, mimicking giant cell reparative granuloma, giant cell tumor of bone, and brown tumor. (PMID:29217425)
• None of the genitourinary pseudosarcomatous myofibroblastic proliferations was found to harbour USP6 (0/12), ROS1 (0/8) or ETV6 (0/7) rearrangements (PMID:29617048)
• Four out of six cases harbored COL1A1 rearrangement (Fig. 1) indicating COL1A1-USP6 fusions in a subset of myositis ossificans (PMID:29980413)
• Study reveals high USP6 expression in Ewing sarcoma tumors. USP6 expression is also associated with an IFN signature in primary Ewing sarcoma tumors. (PMID:30131449)
• USP6 promotes the invasion and metastasis of colon cancer. (PMID:30297112)
• USP6 Gene Rearrangement by FISH Analysis in Cranial Fasciitis: A Report of Three Cases. (PMID:30758758)
• We conclude that oncogenic activation of USP6 via USP9X promoter exchange represents a novel driver of primary ABC formation. (PMID:30767316)
• study confirmed the collagen type I alpha 1 chain-ubiquitin specific peptidase 6 rearrangement in 5/7 cases of myositis ossificans and found the same abnormality in 4/5 of fibro-osseous pseudotumor of digits (PMID:30946936)
• Recurrent and novel USP6 fusions in cranial fasciitis identified by targeted RNA sequencing. (PMID:31827231)
• USP6 positively modulates GluN1 expression in transfected cells, and USP6 down-regulation impedes focal GluN1 distribution at postsynaptic densities and impairs synaptic function in neurons derived from human embryonic stem cells. (PMID:31841517)
• Novel ASAP1-USP6, FAT1-USP6, SAR1A-USP6, and TNC-USP6 fusions in primary aneurysmal bone cyst. (PMID:32011035)
• Myositis ossificans-like soft tissue aneurysmal bone cyst: a clinical, radiological, and pathological study of seven cases with COL1A1-USP6 fusion and a novel ANGPTL2-USP6 fusion. (PMID:32157177)
• Benign infiltrative myofibroblastic neoplasms of childhood with USP6 gene rearrangement. (PMID:32583473)
• USP6-Associated Neoplasms: A Rapidly Expanding Family of Lesions. (PMID:32635781)
• Characterization of novel USP6 gene rearrangements in a subset of so-called cellular fibroma of tendon sheath. (PMID:32661296)
• Intraarticular nodular fasciitis-detection of USP6 gene fusions in three cases by targeted RNA sequencing. (PMID:33404853)
• Ubiquitin-Specific Protease 6 Functions as a Tumor Suppressor in Ewing Sarcoma through Immune Activation. (PMID:33558334)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	usp32	ENSDARG00000061895
mus_musculus	Usp32	ENSMUSG00000000804
rattus_norvegicus	Usp32	ENSRNOG00000027711

Paralogs (71): USP2 (ENSG00000036672), 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), 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 6 — P35125 (reviewed: P35125)

Alternative names: Deubiquitinating enzyme 6, Proto-oncogene TRE-2, RN-tre, Ubiquitin thioesterase 6, Ubiquitin-specific-processing protease 6

All UniProt accessions (2): P35125, Q15635

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinase with an ATP-independent isopeptidase activity, cleaving at the C-terminus of the ubiquitin moiety. Catalyzes its own deubiquitination. In vitro, isoform 2, but not isoform 3, shows deubiquitinating activity. Promotes plasma membrane localization of ARF6 and selectively regulates ARF6-dependent endocytic protein trafficking. Is able to initiate tumorigenesis by inducing the production of matrix metalloproteinases following NF-kappa-B activation. May act as a GTPase-activating protein for RAB3A.

Subunit / interactions. Interacts with RAC1 and CDC42. Interacts (via Rab-GAP TBC domain) with ARF6. Interacts with calmodulin (CALM1, CALM2 and/or CALM3); the interaction is calcium-dependent.

Subcellular location. Cell membrane. Cytoplasm. Endosome.

Tissue specificity. Testis specific. Expressed in various cancer cell lines.

Post-translational modifications. Monubiquitinated; ubiquitination is calmodulin and calcium dependent.

Disease relevance. A chromosomal aberration involving USP6 is a common genetic feature of aneurysmal bone cyst, a benign osseous neoplasm. Translocation t(16;17)(q22;p13) with CDH11. The translocation generates a fusion gene in which the strong CDH11 promoter is fused to the entire USP6 coding sequence, resulting in USP6 transcriptional up-regulation.

Domain organisation. The Rab-GAP TBC domain lacks GTPase activator activity but is necessary for interaction with ARF6.

Miscellaneous. The USP6 gene only exists in the primate lineage. Was shown to be tumorigenic in transfected mice and does not seem to act as GTPase activating protein.

Similarity. Belongs to the peptidase C19 family.

Isoforms (3)

UniProt ID	Names	Canonical?
P35125-1	1	yes
P35125-2	2, 213(ORF2)
P35125-3	3, 210(ORF1), oncTre210p

RefSeq proteins (2): NP_001291213, NP_004496 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000195	Rab-GAP-TBC_dom	Domain
IPR001394	Peptidase_C19_UCH	Domain
IPR018200	USP_CS	Conserved_site
IPR028889	USP	Domain
IPR035969	Rab-GAP_TBC_sf	Homologous_superfamily
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR050185	Ub_carboxyl-term_hydrolase	Family

Pfam: PF00443, PF00566

UniProt features (21 total): splice variant 4, sequence variant 3, mutagenesis site 3, region of interest 3, domain 2, compositionally biased region 2, active site 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35125-F1	66.79	0.27

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): 541 (nucleophile); 1328 (proton acceptor)

Mutagenesis-validated functional residues (3):

Position	Phenotype
150	does not restore gap activity in yeast complementation assay.
187	does not restore gap activity in yeast complementation assay.
541	loss of enzyme activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 134 (showing top): GGGACCA_MIR133A_MIR133B, WANG_CLIM2_TARGETS_UP, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GTGCCTT_MIR506, CAGCAGG_MIR370, AAACCAC_MIR140, GOBP_REGULATION_OF_RECEPTOR_INTERNALIZATION, GOBP_REGULATION_OF_RECEPTOR_MEDIATED_ENDOCYTOSIS, GOMF_CYSTEINE_TYPE_PEPTIDASE_ACTIVITY, GTGTTGA_MIR505, CAATGCA_MIR33, DACOSTA_UV_RESPONSE_VIA_ERCC3_COMMON_DN

GO Biological Process (5): proteolysis (GO:0006508), protein deubiquitination (GO:0016579), protein modification process (GO:0036211), regulation of vesicle-mediated transport (GO:0060627), regulation of postsynaptic neurotransmitter receptor internalization (GO:0099149)

GO Molecular Function (8): nucleic acid binding (GO:0003676), cysteine-type endopeptidase activity (GO:0004197), cysteine-type deubiquitinase activity (GO:0004843), calmodulin binding (GO:0005516), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787)

GO Cellular Component (9): cytoplasm (GO:0005737), lysosome (GO:0005764), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), recycling endosome (GO:0055037), glutamatergic synapse (GO:0098978), postsynaptic density, intracellular component (GO:0099092), endosome (GO:0005768), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	2
binding	2
cysteine-type peptidase activity	2
cellular anatomical structure	2
endomembrane system	2
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
macromolecule modification	1
vesicle-mediated transport	1
regulation of cellular process	1
regulation of transport	1
regulation of receptor internalization	1
regulation of biological quality	1
postsynaptic neurotransmitter receptor internalization	1
endopeptidase activity	1
deubiquitinase activity	1
protein binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
intracellular anatomical structure	1
lytic vacuole	1
cytoplasm	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
endosome	1
synapse	1
postsynaptic density	1
postsynaptic specialization, intracellular component	1
cytoplasmic vesicle	1

Protein interactions and networks

STRING

1552 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
USP6	CDC16	Q13042	987
USP6	TSC2	P49815	984
USP6	TSC1	Q92574	966
USP6	TBC1D7	Q9P0N9	956
USP6	TBC1D20	Q96BZ9	896
USP6	USP14	P54578	868
USP6	TBC1D25	Q3MII6	812
USP6	QTRT1	Q9BXR0	768
USP6	MYH9	P35579	673
USP6	TBC1D24	Q9ULP9	598
USP6	RASA1	P20936	582
USP6	TBC1D15	Q8TC07	577
USP6	RAB35	Q15286	573
USP6	RAB22A	Q9UL26	568
USP6	COL1A1	P02452	538

IntAct

7 interactions, top by confidence:

A	B	Type	Score
MDFI	USP6	psi-mi:“MI:0915”(physical association)	0.490
ANKRD44	USP6	psi-mi:“MI:0915”(physical association)	0.370
USP32		psi-mi:“MI:0914”(association)	0.350
DISC1	USP6	psi-mi:“MI:0915”(physical association)	0.000
ATXN7L3	USP6	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (40): USP6 (Affinity Capture-Western), EXOSC8 (Two-hybrid), USP6 (Reconstituted Complex), USP6 (Synthetic Lethality), JUN (Affinity Capture-Western), USP6 (Affinity Capture-Western), JUN (Biochemical Activity), JAK1 (Biochemical Activity), Jak1 (Affinity Capture-Western), USP6 (Reconstituted Complex), TFIP11 (Two-hybrid), USP6 (Affinity Capture-RNA), USP6 (Two-hybrid), USP6 (Two-hybrid), RIPPLY1 (Two-hybrid)

ESM2 similar proteins: A0A087WVF3, A0A087WXS9, A0A087X179, A0A087X1G2, A6NDS4, A6NER0, A6QPT6, B9A6J9, M3WHG5, O14771, O15482, O15553, O19110, O76081, P0C7X1, P0C7X3, P0C7X4, P35125, P48778, P48967, P79209, Q13670, Q15697, Q2TBC4, Q3T191, Q3UZD7, Q4R2Z8, Q5DRQ5, Q5SSQ6, Q5XFX8, Q69ZB3, Q6DHY5, Q6IPX1, Q6ZMN8, Q8BLR5, Q8BWA8, Q8IYF1, Q8IZP1, Q8JZW5, Q8N7G0

Diamond homologs: A0A087WVF3, A0A087WXS9, A0A087X179, A0A087X1G2, A2AWA9, A6H6A9, A6NDS4, A6NER0, B9A6J9, H2KZZ6, P0C7X1, P35125, Q2M2D7, Q5RAN1, Q5SVR0, Q66K14, Q6DHY5, Q6IPX1, Q80XC3, Q86UD7, Q8IZP1, Q92738, Q9UFV1, Q9Y3P9, A0A0R4IB93, A0JM59, A5PMR2, A5PN09, A6NNY8, A6QNM7, A7Z056, B1AY13, B1WBD7, D2HBJ8, D6RBM5, E1C213, E7F6T8, E9Q9U0, F6Z5C0, F8VPU6

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
USP6	up-regulates	ARF6	relocalization
USP6	“up-regulates quantity by expression”	MMP10	“transcriptional regulation”
USP6	“up-regulates quantity by expression”	MMP9	“transcriptional regulation”
USP6	up-regulates	NfKb-p65/p50
CDC42	up-regulates	USP6	relocalization
RAC1	up-regulates	USP6	relocalization

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 8 cancer types — AML, BCC, BRCA, COADREAD, HCC, LUSC, NBL, PRAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	194
Likely benign	11
Benign	7

Top pathogenic / likely-pathogenic (0)

SpliceAI

5405 predictions. Top by Δscore:

Variant	Effect	Δscore
17:5120762:G:GT	donor_gain	1.0000
17:5121751:G:GG	donor_gain	1.0000
17:5122975:A:AC	donor_gain	1.0000
17:5122976:C:CT	donor_gain	1.0000
17:5122976:CT:C	donor_gain	1.0000
17:5122976:CTG:C	donor_gain	1.0000
17:5122976:CTGCA:C	donor_gain	1.0000
17:5130682:GCA:G	donor_gain	1.0000
17:5130683:CA:C	donor_gain	1.0000
17:5130685:G:GG	donor_gain	1.0000
17:5133440:CA:C	acceptor_loss	1.0000
17:5133441:A:AC	acceptor_loss	1.0000
17:5133441:A:AG	acceptor_gain	1.0000
17:5133442:G:GA	acceptor_gain	1.0000
17:5133442:GC:G	acceptor_gain	1.0000
17:5133442:GCT:G	acceptor_gain	1.0000
17:5133442:GCTC:G	acceptor_gain	1.0000
17:5133546:ACCAG:A	donor_loss	1.0000
17:5133548:CAGGT:C	donor_loss	1.0000
17:5133550:GGTAT:G	donor_loss	1.0000
17:5133551:GTAT:G	donor_loss	1.0000
17:5133552:T:A	donor_loss	1.0000
17:5137746:GCAGA:G	donor_gain	1.0000
17:5137749:GA:G	donor_gain	1.0000
17:5138119:A:AG	acceptor_gain	1.0000
17:5138120:G:GG	acceptor_gain	1.0000
17:5138248:G:GT	donor_gain	1.0000
17:5138248:G:T	donor_gain	1.0000
17:5138269:CCCAG:C	donor_loss	1.0000
17:5138270:CCAG:C	donor_loss	1.0000

AlphaMissense

9314 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:5145513:T:C	F701L	0.996
17:5145515:T:A	F701L	0.996
17:5145515:T:G	F701L	0.996
17:5144825:G:C	D652H	0.992
17:5145405:G:C	A665P	0.989
17:5145514:T:C	F701S	0.989
17:5144826:A:T	D652V	0.988
17:5145522:T:C	F704L	0.988
17:5145524:C:A	F704L	0.988
17:5145524:C:G	F704L	0.988
17:5145417:C:G	H669D	0.987
17:5145418:A:C	H669P	0.987
17:5145453:T:C	F681L	0.986
17:5145455:C:A	F681L	0.986
17:5145455:C:G	F681L	0.986
17:5145483:T:A	C691S	0.985
17:5145484:G:C	C691S	0.985
17:5168013:T:C	F1040L	0.985
17:5168015:C:A	F1040L	0.985
17:5168015:C:G	F1040L	0.985
17:5142107:T:C	F560L	0.984
17:5142109:T:A	F560L	0.984
17:5142109:T:G	F560L	0.984
17:5144759:T:C	F630L	0.984
17:5144761:T:A	F630L	0.984
17:5144761:T:G	F630L	0.984
17:5145483:T:C	C691R	0.984
17:5144775:T:C	L635P	0.983
17:5144826:A:C	D652A	0.983
17:5142053:T:C	F542L	0.980

dbSNP variants (sampled 300 via entrez): RS1000079134 (17:5157724 A>C,G), RS1000102971 (17:5115688 T>C), RS1000107274 (17:5120735 A>C), RS1000132860 (17:5157331 C>T), RS1000164948 (17:5118270 A>G), RS1000177183 (17:5114524 G>A,C), RS1000204042 (17:5158964 G>C), RS1000295468 (17:5164407 C>A), RS1000407306 (17:5129345 G>A,C), RS1000542831 (17:5120359 C>T), RS1000620186 (17:5163009 GAATT>G), RS1000632334 (17:5169623 G>T), RS1000760273 (17:5128416 A>G), RS1000826438 (17:5129671 T>C), RS1000837558 (17:5175434 A>T)

Disease associations

OMIM: gene MIM:604334 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007540_10	PEG-asparaginase hypersensitivity without enzyme activity in childhood acute lymphoblastic leukaemia	5.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004881	asparaginase hypersensitivity

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630817 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Resveratrol	increases expression, affects cotreatment, decreases expression	2
Valproic Acid	increases expression, increases methylation	2
Antirheumatic Agents	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
methylmercuric chloride	increases expression	1
bisphenol A	affects cotreatment, decreases expression	1
sodium arsenite	affects expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
aflatoxin B2	increases methylation	1
perfluorooctane sulfonic acid	increases expression	1
perfluorohexanesulfonic acid	decreases expression	1
bisphenol S	affects cotreatment, decreases expression	1
Cacodylic Acid	increases expression	1
Copper	decreases expression, affects cotreatment	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Folic Acid	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Malathion	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Smoke	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Aflatoxin B1	decreases methylation	1
Copper Sulfate	increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4605976	Binding	Inhibition of human GST-tagged USP6 CD (529 to 1406 residues) expressed in Sf21 insect cells assessed as cleavage of Ubiquitin-Rhodamine110-glycine to Ubiquitin and Rhodamine110-glycine using Ubiquitin-Rhodamine110-glycine as substrate by f	Discovery of Potent, Selective, and Orally Bioavailable Inhibitors of USP7 with In Vivo Antitumor Activity. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4AB	USZ20-ESOS1	Cancer cell line	Male
CVCL_TX11	HAP1 USP6 (-) 1	Cancer cell line	Male
CVCL_TX12	HAP1 USP6 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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