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P35125 (UBP6_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 121. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Ubiquitin carboxyl-terminal hydrolase 6

EC=3.4.19.12
Alternative name(s):
Deubiquitinating enzyme 6
Proto-oncogene TRE-2
Ubiquitin thioesterase 6
Ubiquitin-specific-processing protease 6
Gene names
Name:USP6
Synonyms:HRP1, TRE2
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1406 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

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. Ref.7 Ref.8 Ref.10

Catalytic activity

Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).

Subunit structure

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. Ref.5 Ref.7 Ref.8

Subcellular location

Cell membrane. Cytoplasm. Endosome. Note: Localizes to the plasma membrane and to filamentous structures within the cell corresponding to ARF6 regulated tubular endosomes. Activation of RAC1 and CDC42 can direct the relocalization of USP6 to the plasma membrane in a manner that depends on the integrity of the actin cytoskeleton. Ref.5 Ref.7

Tissue specificity

Testis specific. Expressed in various cancer cell lines. Ref.1 Ref.2

Domain

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

Post-translational modification

Monubiquitinated; ubiquitination is calmodulin and calcium dependent.

Involvement in disease

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.

Miscellaneous

The USP6 gene only exists in the primate lineage.

Sequence similarities

Belongs to the peptidase C19 family.

Contains 1 Rab-GAP TBC domain.

Contains 1 USP domain.

Ontologies

Keywords
   Biological processUbl conjugation pathway
   Cellular componentCell membrane
Cytoplasm
Endosome
Membrane
   Coding sequence diversityAlternative splicing
Chromosomal rearrangement
Polymorphism
   DiseaseProto-oncogene
   LigandCalmodulin-binding
   Molecular functionHydrolase
Protease
Thiol protease
   PTMUbl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcellular protein modification process

Non-traceable author statement PubMed 9827704. Source: UniProtKB

protein deubiquitination

Inferred from direct assay Ref.8. Source: UniProtKB

regulation of vesicle-mediated transport

Inferred from direct assay Ref.7. Source: UniProtKB

ubiquitin-dependent protein catabolic process

Inferred from electronic annotation. Source: InterPro

   Cellular_componentcytoplasm

Inferred from direct assay Ref.5. Source: UniProtKB

lysosome

Traceable author statement PubMed 9827704. Source: ProtInc

plasma membrane

Inferred from direct assay Ref.5. Source: UniProtKB

recycling endosome

Inferred from direct assay Ref.7. Source: UniProtKB

   Molecular_functionRab GTPase activator activity

Inferred from electronic annotation. Source: InterPro

calmodulin binding

Inferred from physical interaction Ref.8. Source: UniProtKB

cysteine-type endopeptidase activity

Traceable author statement PubMed 9827704. Source: UniProtKB

nucleic acid binding

Traceable author statement Ref.1. Source: ProtInc

protein binding

Inferred from physical interaction Ref.5Ref.7. Source: UniProtKB

ubiquitin-specific protease activity

Inferred from direct assay Ref.8. Source: UniProtKB

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

ANKRD44Q8N8A24EBI-954590,EBI-1245329
MYL2P109165EBI-954590,EBI-725770

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P35125-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: P35125-2)

Also known as: 213(ORF2);

The sequence of this isoform differs from the canonical sequence as follows:
     1-317: Missing.
     318-359: GLWARLRNQF...TRKQGDLPPP → MPQRLPHARQ...HRDPKDSRDA
Isoform 3 (identifier: P35125-3)

Also known as: 210(ORF1); oncTre210p;

The sequence of this isoform differs from the canonical sequence as follows:
     774-786: NFPQDNQKVQLSV → ISPLHHLQMECSP
     787-1406: Missing.
Note: Was shown to be tumorigenic in transfected mice and seems not to act as GTPase activating protein.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 14061406Ubiquitin carboxyl-terminal hydrolase 6
PRO_0000080625

Regions

Domain100 – 292193Rab-GAP TBC
Domain532 – 1369838USP

Sites

Active site5411Nucleophile
Active site13281Proton acceptor By similarity

Natural variations

Alternative sequence1 – 317317Missing in isoform 2.
VSP_010878
Alternative sequence318 – 35942GLWAR…DLPPP → MPQRLPHARQHTPLPLGSAD YRRVVSVRPQGPHRDPKDSR DA in isoform 2.
VSP_010879
Alternative sequence774 – 78613NFPQD…VQLSV → ISPLHHLQMECSP in isoform 3.
VSP_010880
Alternative sequence787 – 1406620Missing in isoform 3.
VSP_010881
Natural variant4751W → R. Ref.1
Corresponds to variant rs8073787 [ dbSNP | Ensembl ].
VAR_051522
Natural variant5251V → I.
Corresponds to variant rs2304449 [ dbSNP | Ensembl ].
VAR_059749
Natural variant9121R → Q. Ref.1
Corresponds to variant rs9899177 [ dbSNP | Ensembl ].
VAR_051523
Natural variant13301I → V.
Corresponds to variant rs1053611 [ dbSNP | Ensembl ].
VAR_051524

Experimental info

Mutagenesis1501T → R: Does not restore GAP activity in yeast complementation assay. Ref.4
Mutagenesis1871R → Q: Does not restore GAP activity in yeast complementation assay. Ref.4
Mutagenesis5411C → S: Loss of enzyme activity. Ref.8
Sequence conflict9631N → I in CAA45111. Ref.1

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified July 19, 2004. Version 2.
Checksum: D3A6822CEB441DB3

FASTA1,406158,658
        10         20         30         40         50         60 
MDMVENADSL QAQERKDILM KYDKGHRAGL PEDKGPEPVG INSSIDRFGI LHETELPPVT 

        70         80         90        100        110        120 
AREAKKIRRE MTRTSKWMEM LGEWETYKHS SKLIDRVYKG IPMNIRGPVW SVLLNIQEIK 

       130        140        150        160        170        180 
LKNPGRYQIM KERGKRSSEH IHHIDLDVRT TLRNHVFFRD RYGAKQRELF YILLAYSEYN 

       190        200        210        220        230        240 
PEVGYCRDLS HITALFLLYL PEEDAFWALV QLLASERHSL PGFHSPNGGT VQGLQDQQEH 

       250        260        270        280        290        300 
VVPKSQPKTM WHQDKEGLCG QCASLGCLLR NLIDGISLGL TLRLWDVYLV EGEQVLMPIT 

       310        320        330        340        350        360 
SIALKVQQKR LMKTSRCGLW ARLRNQFFDT WAMNDDTVLK HLRASTKKLT RKQGDLPPPA 

       370        380        390        400        410        420 
KREQGSLAPR PVPASRGGKT LCKGYRQAPP GPPAQFQRPI CSASPPWASR FSTPCPGGAV 

       430        440        450        460        470        480 
REDTYPVGTQ GVPSLALAQG GPQGSWRFLE WKSMPRLPTD LDIGGPWFPH YDFEWSCWVR 

       490        500        510        520        530        540 
AISQEDQLAT CWQAEHCGEV HNKDMSWPEE MSFTANSSKI DRQKVPTEKG ATGLSNLGNT 

       550        560        570        580        590        600 
CFMNSSIQCV SNTQPLTQYF ISGRHLYELN RTNPIGMKGH MAKCYGDLVQ ELWSGTQKSV 

       610        620        630        640        650        660 
APLKLRRTIA KYAPKFDGFQ QQDSQELLAF LLDGLHEDLN RVHEKPYVEL KDSDGRPDWE 

       670        680        690        700        710        720 
VAAEAWDNHL RRNRSIIVDL FHGQLRSQVK CKTCGHISVR FDPFNFLSLP LPMDSYMDLE 

       730        740        750        760        770        780 
ITVIKLDGTT PVRYGLRLNM DEKYTGLKKQ LRDLCGLNSE QILLAEVHDS NIKNFPQDNQ 

       790        800        810        820        830        840 
KVQLSVSGFL CAFEIPVPSS PISASSPTQI DFSSSPSTNG MFTLTTNGDL PKPIFIPNGM 

       850        860        870        880        890        900 
PNTVVPCGTE KNFTNGMVNG HMPSLPDSPF TGYIIAVHRK MMRTELYFLS PQENRPSLFG 

       910        920        930        940        950        960 
MPLIVPCTVH TRKKDLYDAV WIQVSWLARP LPPQEASIHA QDRDNCMGYQ YPFTLRVVQK 

       970        980        990       1000       1010       1020 
DGNSCAWCPQ YRFCRGCKID CGEDRAFIGN AYIAVDWHPT ALHLRYQTSQ ERVVDKHESV 

      1030       1040       1050       1060       1070       1080 
EQSRRAQAEP INLDSCLRAF TSEEELGESE MYYCSKCKTH CLATKKLDLW RLPPFLIIHL 

      1090       1100       1110       1120       1130       1140 
KRFQFVNDQW IKSQKIVRFL RESFDPSAFL VPRDPALCQH KPLTPQGDEL SKPRILAREV 

      1150       1160       1170       1180       1190       1200 
KKVDAQSSAG KEDMLLSKSP SSLSANISSS PKGSPSSSRK SGTSCPSSKN SSPNSSPRTL 

      1210       1220       1230       1240       1250       1260 
GRSKGRLRLP QIGSKNKPSS SKKNLDASKE NGAGQICELA DALSRGHMRG GSQPELVTPQ 

      1270       1280       1290       1300       1310       1320 
DHEVALANGF LYEHEACGNG CGDGYSNGQL GNHSEEDSTD DQREDTHIKP IYNLYAISCH 

      1330       1340       1350       1360       1370       1380 
SGILSGGHYI TYAKNPNCKW YCYNDSSCEE LHPDEIDTDS AYILFYEQQG IDYAQFLPKI 

      1390       1400 
DGKKMADTSS TDEDSESDYE KYSMLQ 

« Hide

Isoform 2 (213(ORF2)) [UniParc].

Checksum: A660606208ABD9EB
Show »

FASTA1,089121,943
Isoform 3 (210(ORF1)) (oncTre210p) [UniParc].

Checksum: 6D5D93D2CE65D879
Show »

FASTA78689,577

References

« Hide 'large scale' references
[1]"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 L.A., Boghosian-Sell L., Croce C.M., Hill M.
Oncogene 7:733-741(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3), TISSUE SPECIFICITY, VARIANTS ARG-475 AND GLN-912.
Tissue: Ewing sarcoma.
[2]"The Tre2 (USP6) oncogene is a hominoid-specific gene."
Paulding C.A., Ruvolo M., Haber D.A.
Proc. Natl. Acad. Sci. U.S.A. 100:2507-2511(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), ALTERNATIVE SPLICING, TISSUE SPECIFICITY, DISCUSSION OF TRE2 EVOLUTION.
[3]"The yeast DOA4 gene encodes a deubiquitinating enzyme related to a product of the human tre-2 oncogene."
Papa F.R., Hochstrasser M.
Nature 366:313-319(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: CHARACTERIZATION.
[4]"Expression in a RabGAP yeast mutant of two human homologues, one of which is an oncogene."
Bizimungu C., De Neve N., Burny A., Bach S., Bontemps F., Portetelle D., Vandenbol M.
Biochem. Biophys. Res. Commun. 310:498-504(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF THR-150 AND ARG-187.
[5]"The TRE17 oncogene encodes a component of a novel effector pathway for Rho GTPases Cdc42 and Rac1 and stimulates actin remodeling."
Masuda-Robens J.M., Kutney S.N., Qi H., Chou M.M.
Mol. Cell. Biol. 23:2151-2161(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, INTERACTION WITH RAC1 AND CDC42.
[6]"USP6 (Tre2) fusion oncogenes in aneurysmal bone cyst."
Oliveira A.M., Hsi B.L., Weremowicz S., Rosenberg A.E., Dal Cin P., Joseph N., Bridge J.A., Perez-Atayde A.R., Fletcher J.A.
Cancer Res. 64:1920-1923(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: CHROMOSOMAL TRANSLOCATION WITH CDH11.
[7]"The TBC (Tre-2/Bub2/Cdc16) domain protein TRE17 regulates plasma membrane-endosomal trafficking through activation of Arf6."
Martinu L., Masuda-Robens J.M., Robertson S.E., Santy L.C., Casanova J.E., Chou M.M.
Mol. Cell. Biol. 24:9752-9762(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH ARF6.
[8]"Calcium/calmodulin regulates ubiquitination of the ubiquitin-specific protease TRE17/USP6."
Shen C., Ye Y., Robertson S.E., Lau A.W., Mak D.O., Chou M.M.
J. Biol. Chem. 280:35967-35973(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH CALMODULIN, UBIQUITINATION, MUTAGENESIS OF CYS-541.
[9]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[10]"TRE17/USP6 oncogene translocated in aneurysmal bone cyst induces matrix metalloproteinase production via activation of NF-kappaB."
Ye Y., Pringle L.M., Lau A.W., Riquelme D.N., Wang H., Jiang T., Lev D., Welman A., Blobel G.A., Oliveira A.M., Chou M.M.
Oncogene 29:3619-3629(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X63546 mRNA. Translation: CAA45108.1.
X63547 mRNA. Translation: CAA45111.1.
AY143550 mRNA. Translation: AAN38838.1.
AY163314 Genomic DNA. Translation: AAO21348.1.
CCDSCCDS11069.2. [P35125-1]
PIRS57867.
S22158. S57868.
S22155. S57874.
RefSeqNP_004496.2. NM_004505.2.
XP_005256902.1. XM_005256845.2.
UniGeneHs.448851.

3D structure databases

ProteinModelPortalP35125.
SMRP35125. Positions 72-341, 528-713, 1031-1110, 1311-1367.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid114552. 12 interactions.
IntActP35125. 5 interactions.
MINTMINT-2865848.
STRING9606.ENSP00000250066.

Protein family/group databases

MEROPSC19.009.

PTM databases

PhosphoSiteP35125.

Polymorphism databases

DMDM50403738.

Proteomic databases

MaxQBP35125.
PaxDbP35125.
PRIDEP35125.

Protocols and materials databases

DNASU9098.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000250066; ENSP00000250066; ENSG00000129204. [P35125-1]
ENST00000304328; ENSP00000305473; ENSG00000129204. [P35125-2]
ENST00000332776; ENSP00000328010; ENSG00000129204. [P35125-3]
ENST00000572949; ENSP00000461581; ENSG00000129204. [P35125-3]
ENST00000574788; ENSP00000460380; ENSG00000129204. [P35125-1]
GeneID9098.
KEGGhsa:9098.
UCSCuc002gau.1. human. [P35125-1]
uc010ckz.1. human. [P35125-2]

Organism-specific databases

CTD9098.
GeneCardsGC17P005019.
H-InvDBHIX0202554.
HGNCHGNC:12629. USP6.
HPAHPA011742.
MIM604334. gene.
neXtProtNX_P35125.
PharmGKBPA37254.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG5210.
HOGENOMHOG000154762.
InParanoidP35125.
KOK11837.
OMAHDSNIKN.
OrthoDBEOG7PP55V.
PhylomeDBP35125.
TreeFamTF324190.

Gene expression databases

ArrayExpressP35125.
BgeeP35125.
CleanExHS_USP6.
GenevestigatorP35125.

Family and domain databases

InterProIPR018200. Pept_C19ubi-hydrolase_C_CS.
IPR001394. Peptidase_C19_UCH.
IPR000195. Rab-GTPase-TBC_dom.
IPR028889. UCH/PAN2.
[Graphical view]
PfamPF00566. RabGAP-TBC. 1 hit.
PF00443. UCH. 1 hit.
[Graphical view]
SMARTSM00164. TBC. 1 hit.
[Graphical view]
SUPFAMSSF47923. SSF47923. 2 hits.
PROSITEPS50086. TBC_RABGAP. 1 hit.
PS00972. USP_1. 1 hit.
PS00973. USP_2. 1 hit.
PS50235. USP_3. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSUSP6. human.
GeneWikiUSP6.
GenomeRNAi9098.
NextBio34099.
PROP35125.
SOURCESearch...

Entry information

Entry nameUBP6_HUMAN
AccessionPrimary (citable) accession number: P35125
Secondary accession number(s): Q15634, Q86WP6, Q8IWT4
Entry history
Integrated into UniProtKB/Swiss-Prot: February 1, 1994
Last sequence update: July 19, 2004
Last modified: July 9, 2014
This is version 121 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Peptidase families

Classification of peptidase families and list of entries

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 17

Human chromosome 17: entries, gene names and cross-references to MIM