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USP6 (ubiquitin specific protease 6 (Tre-2 oncogene))

Written2005-04Andre M Oliveira, Margaret Chou
Department of Pathology, Laboratory Medicine, Mayo Clinic, Mayo Foundation, 200 First Street SW, Rochester, MN 55905, USA

(Note : for Links provided by Atlas : click)


Alias (NCBI)TRE2
HGNC (Hugo) USP6
HGNC Alias symbTre-2
HGNC Alias nameubiquitin carboxyl-terminal hydrolase 6
 TBC1D3 and USP32 fusion
 Tre-2 oncogene
HGNC Previous nameHRP1
HGNC Previous nameubiquitin specific protease 6 (Tre-2 oncogene)
 TRE oncogene, Smith Magenis syndrome chromosome region
 ubiquitin specific peptidase 6 (Tre-2 oncogene)
LocusID (NCBI) 9098
Atlas_Id 530
Location 17p13.2  [Link to chromosome band 17p13]
Location_base_pair Starts at 5128809 and ends at 5174991 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping USP6.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CDH11 (16q21)::USP6 (17p13.2)CENPP (9q22.31)::USP6 (17p13.2)CNBP (3q21.3)::USP6 (17p13.2)
COL1A1 (17q21.33)::USP6 (17p13.2)LOC100130950 (17p13.2)::USP6 (17p13.2)MYH9 (22q12.3)::USP6 (17p13.2)
OMD (9q22.31)::USP6 (17p13.2)PPP6R3 (11q13.2)::USP6 (17p13.2)SS18 (18q11.2)::USP6 (17p13.2)
THRAP3 (1p34.3)::USP6 (17p13.2)USP6 (17p13.2)::CDH11 (16q21)USP6 (17p13.2)::CNBP (3q21.3)
USP6 (17p13.2)::COL1A1 (17q21.33)USP6 (17p13.2)::OMD (9q22.31)USP6 (17p13.2)::STPG1 (1p36.11)
USP6 (17p13.2)::THRAP3 (1p34.3)
Note The gene is the result of a recent evolutionary fusion of two other genes - (PRC17) on chromosome 17q12 and USP32 (NY-REN-60) on chromosome 17q22 (see below).


Description 30 exons spanning 47 kb of genomic DNA. Exons 1 to 14 are derived from the TBC1D3 (PRC17), and exons 15 to 30 are derived from the USP32 (NY-REN-60).
Transcription The gene is transcribed from telomere to centromere. The coding region starts on exon 2 but many splicing variants have been identified in the untranslated exon 1. There are at least two major transcripts with an approximate lenght of 8 kb.


Description USP6 encodes for a 1406 aminoacid protein containing two major domains: TBC (from TRE2-Bub2-Cdc16), which encodes a GTPase-activating protein of the Rab family of GTPases, and a UBP domain with a ubiquitin specific protease activity. A USP6 splicing variant, also known as 'onco-TRE17 or TRE17-onco', encodes a 786 aminoacid protein with a truncated UBP domain. See figure 1.
Expression Among normal tissues, USP6 seems to primarily expressed in testes.
Localisation Cytoplasmic protein.
Function USP6 function is still poorly understood but recent evidence has shown that USP6 is involved in endocytic trafficking. USP6 seems to operate in the same pathway controlled by Arf6 GTPase, which has been linked to mitogenic signaling and invasive behavior.
Homology While the N-terminal portion of USP6 is highly homologous to PRC17 (89% identity), the C-terminal end is highly homologous to USP32 (97% identity).

Implicated in

Disease Aneurysmal Bone Cyst or Aneurysmal Bone Tumor
Cytogenetics Rearrangements of 17p13 with different partner chromosomes.
Hybrid/Mutated Gene USP6 fusion genes are formed by juxtaposition of USP6 coding sequences to the promoter regions of several partner genes, which lead to USP6 transcriptional upregulation. There is no fusion protein.
  • THRAP3 -USP6 in t(1;17)(p34;p13)
  • ZNF9 -USP6 in t(3;17)(q21;p13)
  • OMD -USP6 in t(9;17)(q22;p13)
  • CDH11 -USP6 in t(16;17)(q22;p13)
  • COL1A1 -USP6 in t(17;17)(q12;p13)




    A rearranged transforming gene, tre, is made up of human sequences derived from chromosome regions 5q, 17q and 18q.
    Huebner K, Cannizzaro LA, Nakamura T, Hillova J, Mariage-Samson R, Hecht F, Hill M, Croce CM
    Oncogene. 1988 ; 3 (4) : 449-455.
    PMID 3274085
    The TBC (Tre-2/Bub2/Cdc16) domain protein TRE17 regulates plasma membrane-endosomal trafficking through activation of Arf6.
    Martinu L, Masuda-Robens JM, Robertson SE, Santy LC, Casanova JE, Chou MM
    Molecular and cellular biology. 2004 ; 24 (22) : 9752-9762.
    PMID 15509780
    Endocytosis of epidermal growth factor receptor regulated by Grb2-mediated recruitment of the Rab5 GTPase-activating protein RN-tre.
    Martinu L, Santiago-Walker A, Qi H, Chou MM
    The Journal of biological chemistry. 2002 ; 277 (52) : 50996-51002.
    PMID 12399475
    The TRE17 oncogene encodes a component of a novel effector pathway for Rho GTPases Cdc42 and Rac1 and stimulates actin remodeling.
    Masuda-Robens JM, Kutney SN, Qi H, Chou MM
    Molecular and cellular biology. 2003 ; 23 (6) : 2151-2161.
    PMID 12612085
    A novel transcriptional unit of the tre oncogene widely expressed in human cancer cells.
    Nakamura T, Hillova J, Mariage-Samson R, Onno M, Huebner K, Cannizzaro LA, Boghosian-Sell L, Croce CM, Hill M
    Oncogene. 1992 ; 7 (4) : 733-741.
    PMID 1565468
    Aneurysmal bone cyst variant translocations upregulate USP6 transcription by promoter swapping with the ZNF9, COL1A1, TRAP150, and OMD genes.
    Oliveira AM, Perez-Atayde AR, Dal Cin P, Gebhardt MC, Chen CJ, Neff JR, Demetri GD, Rosenberg AE, Bridge JA, Fletcher JA
    Oncogene. 2005 ; 24 (21) : 3419-3426.
    PMID 15735689
    The Tre2 (USP6) oncogene is a hominoid-specific gene.
    Paulding CA, Ruvolo M, Haber DA
    Proceedings of the National Academy of Sciences of the United States of America. 2003 ; 100 (5) : 2507-2511.
    PMID 12604796


    This paper should be referenced as such :
    Oliveira, AM ; Chou, M
    USP6 (ubiquitin specific protease 6 (Tre-2 oncogene))
    Atlas Genet Cytogenet Oncol Haematol. 2005;9(3):222-223.
    Free journal version : [ pdf ]   [ DOI ]

    External links


    HGNC (Hugo)USP6   12629
    Entrez_Gene (NCBI)USP6    ubiquitin specific peptidase 6
    AliasesHRP1; TRE17; TRE2; TRESMCR; 
    Tre-2; USP6-short
    GeneCards (Weizmann)USP6
    Ensembl hg19 (Hinxton)ENSG00000129204 [Gene_View]
    Ensembl hg38 (Hinxton)ENSG00000129204 [Gene_View]  ENSG00000129204 [Sequence]  chr17:5128809-5174991 [Contig_View]  USP6 [Vega]
    ICGC DataPortalENSG00000129204
    TCGA cBioPortalUSP6
    AceView (NCBI)USP6
    Genatlas (Paris)USP6
    SOURCE (Princeton)USP6
    Genetics Home Reference (NIH)USP6
    Genomic and cartography
    GoldenPath hg38 (UCSC)USP6  -     chr17:5128809-5174991 +  17p13.2   [Description]    (hg38-Dec_2013)
    GoldenPath hg19 (UCSC)USP6  -     17p13.2   [Description]    (hg19-Feb_2009)
    GoldenPathUSP6 - 17p13.2 [CytoView hg19]  USP6 - 17p13.2 [CytoView hg38]
    Genome Data Viewer NCBIUSP6 [Mapview hg19]  
    Gene and transcription
    Genbank (Entrez)AB449915 AY143550 BC029495 BX647719 DQ586847
    RefSeq transcript (Entrez)NM_001304284 NM_004505 NM_005152
    Consensus coding sequences : CCDS (NCBI)USP6
    Gene ExpressionUSP6 [ NCBI-GEO ]   USP6 [ EBI - ARRAY_EXPRESS ]   USP6 [ SEEK ]   USP6 [ MEM ]
    Gene Expression Viewer (FireBrowse)USP6 [ Firebrowse - Broad ]
    GenevisibleExpression of USP6 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
    BioGPS (Tissue expression)9098
    GTEX Portal (Tissue expression)USP6
    Human Protein AtlasENSG00000129204-USP6 [pathology]   [cell]   [tissue]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtP35125   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
    NextProtP35125  [Sequence]  [Exons]  [Medical]  [Publications]
    With graphics : InterProP35125
    Catalytic activity : Enzyme3.4.19.12 [ Enzyme-Expasy ] [ IntEnz-EBI ] [ BRENDA ] [ KEGG ]   [ MEROPS ]
    Domaine pattern : Prosite (Expaxy)TBC_RABGAP (PS50086)    USP_1 (PS00972)    USP_2 (PS00973)    USP_3 (PS50235)   
    Domains : Interpro (EBI)Papain-like_cys_pep_sf    Peptidase_C19_UCH    Rab-GTPase-TBC_dom    Rab-GTPase_TBC_sf    USP_CS    USP_dom   
    Domain families : Pfam (Sanger)RabGAP-TBC (PF00566)    UCH (PF00443)   
    Domain families : Pfam (NCBI)pfam00566    pfam00443   
    Domain families : Smart (EMBL)TBC (SM00164)  
    Conserved Domain (NCBI)USP6
    AlphaFold pdb e-kbP35125   
    Human Protein Atlas [tissue]ENSG00000129204-USP6 [tissue]
    Protein Interaction databases
    DIP (DOE-UCLA)P35125
    IntAct (EBI)P35125
    Ontologies - Pathways
    Ontology : AmiGOnucleic acid binding  cysteine-type endopeptidase activity  thiol-dependent deubiquitinase  GTPase activator activity  protein binding  calmodulin binding  cytoplasm  lysosome  plasma membrane  cellular protein modification process  ubiquitin-dependent protein catabolic process  intracellular protein transport  protein deubiquitination  recycling endosome  regulation of vesicle-mediated transport  activation of GTPase activity  
    Ontology : EGO-EBInucleic acid binding  cysteine-type endopeptidase activity  thiol-dependent deubiquitinase  GTPase activator activity  protein binding  calmodulin binding  cytoplasm  lysosome  plasma membrane  cellular protein modification process  ubiquitin-dependent protein catabolic process  intracellular protein transport  protein deubiquitination  recycling endosome  regulation of vesicle-mediated transport  activation of GTPase activity  
    NDEx NetworkUSP6
    Atlas of Cancer Signalling NetworkUSP6
    Wikipedia pathwaysUSP6
    Orthology - Evolution
    GeneTree (enSembl)ENSG00000129204
    Phylogenetic Trees/Animal Genes : TreeFamUSP6
    Homologs : HomoloGeneUSP6
    Homology/Alignments : Family Browser (UCSC)USP6
    Gene fusions - Rearrangements
    Fusion : MitelmanCDH11::USP6 [16q21/17p13.2]  
    Fusion : MitelmanCNBP::USP6 [3q21.3/17p13.2]  
    Fusion : MitelmanCOL1A1::USP6 [17q21.33/17p13.2]  
    Fusion : MitelmanMYH9::USP6 [22q12.3/17p13.2]  
    Fusion : MitelmanOMD::USP6 [9q22.31/17p13.2]  
    Fusion : MitelmanTHRAP3::USP6 [1p34.3/17p13.2]  
    Fusion : MitelmanUSP6::COL1A1 [17p13.2/17q21.33]  
    Fusion : COSMICTHRAP3 [1p34.3]  -  USP6 [17p13.2]  [fusion_1410]  [fusion_1411]  
    Fusion : FusionGDB3.4.19.12   
    Fusion : QuiverUSP6
    Polymorphisms : SNP and Copy number variants
    NCBI Variation ViewerUSP6 [hg38]
    dbSNP Single Nucleotide Polymorphism (NCBI)USP6
    Exome Variant ServerUSP6
    GNOMAD BrowserENSG00000129204
    Varsome BrowserUSP6
    ACMGUSP6 variants
    Genomic Variants (DGV)USP6 [DGVbeta]
    DECIPHERUSP6 [patients]   [syndromes]   [variants]   [genes]  
    CONAN: Copy Number AnalysisUSP6 
    ICGC Data PortalUSP6 
    TCGA Data PortalUSP6 
    Broad Tumor PortalUSP6
    OASIS PortalUSP6 [ Somatic mutations - Copy number]
    Cancer Gene: CensusUSP6 
    Somatic Mutations in Cancer : COSMICUSP6  [overview]  [genome browser]  [tissue]  [distribution]  
    Somatic Mutations in Cancer : COSMIC3DUSP6
    Mutations and Diseases : HGMDUSP6
    intOGen PortalUSP6
    LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
    DgiDB (Drug Gene Interaction Database)USP6
    DoCM (Curated mutations)USP6
    CIViC (Clinical Interpretations of Variants in Cancer)USP6
    NCG (London)USP6
    Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
    Genetic Testing Registry USP6
    NextProtP35125 [Medical]
    Target ValidationUSP6
    Huge Navigator USP6 [HugePedia]
    Clinical trials, drugs, therapy
    Protein Interactions : CTDUSP6
    Pharm GKB GenePA37254
    Clinical trialUSP6
    canSAR (ICR)USP6
    DataMed IndexUSP6
    PubMed61 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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    indexed on : Fri Oct 8 21:30:29 CEST 2021

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