UBP6_HUMAN
ID UBP6_HUMAN Reviewed; 1406 AA.
AC P35125; Q15634; Q86WP6; Q8IWT4;
DT 01-FEB-1994, integrated into UniProtKB/Swiss-Prot.
DT 19-JUL-2004, sequence version 2.
DT 03-AUG-2022, entry version 179.
DE RecName: Full=Ubiquitin carboxyl-terminal hydrolase 6;
DE EC=3.4.19.12;
DE AltName: Full=Deubiquitinating enzyme 6;
DE AltName: Full=Proto-oncogene TRE-2;
DE AltName: Full=Ubiquitin thioesterase 6;
DE AltName: Full=Ubiquitin-specific-processing protease 6;
GN Name=USP6; Synonyms=HRP1, TRE2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3), TISSUE SPECIFICITY, AND
RP VARIANTS ARG-475 AND GLN-912.
RC TISSUE=Ewing sarcoma;
RX PubMed=1565468;
RA Nakamura T., Hillova J., Mariage-Samson R., Onno M., Huebner K.,
RA Cannizzaro L.A., Boghosian-Sell L., Croce C.M., Hill M.;
RT "A novel transcriptional unit of the tre oncogene widely expressed in human
RT cancer cells.";
RL Oncogene 7:733-741(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), ALTERNATIVE SPLICING,
RP TISSUE SPECIFICITY, AND DISCUSSION OF TRE2 EVOLUTION.
RX PubMed=12604796; DOI=10.1073/pnas.0437015100;
RA Paulding C.A., Ruvolo M., Haber D.A.;
RT "The Tre2 (USP6) oncogene is a hominoid-specific gene.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:2507-2511(2003).
RN [3]
RP CHARACTERIZATION.
RX PubMed=8247125; DOI=10.1038/366313a0;
RA Papa F.R., Hochstrasser M.;
RT "The yeast DOA4 gene encodes a deubiquitinating enzyme related to a product
RT of the human tre-2 oncogene.";
RL Nature 366:313-319(1993).
RN [4]
RP MUTAGENESIS OF THR-150 AND ARG-187.
RX PubMed=14521938; DOI=10.1016/j.bbrc.2003.09.051;
RA Bizimungu C., De Neve N., Burny A., Bach S., Bontemps F., Portetelle D.,
RA Vandenbol M.;
RT "Expression in a RabGAP yeast mutant of two human homologues, one of which
RT is an oncogene.";
RL Biochem. Biophys. Res. Commun. 310:498-504(2003).
RN [5]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH RAC1 AND CDC42.
RX PubMed=12612085; DOI=10.1128/mcb.23.6.2151-2161.2003;
RA Masuda-Robens J.M., Kutney S.N., Qi H., Chou M.M.;
RT "The TRE17 oncogene encodes a component of a novel effector pathway for Rho
RT GTPases Cdc42 and Rac1 and stimulates actin remodeling.";
RL Mol. Cell. Biol. 23:2151-2161(2003).
RN [6]
RP CHROMOSOMAL TRANSLOCATION WITH CDH11.
RX PubMed=15026324; DOI=10.1158/0008-5472.can-03-2827;
RA Oliveira A.M., Hsi B.L., Weremowicz S., Rosenberg A.E., Dal Cin P.,
RA Joseph N., Bridge J.A., Perez-Atayde A.R., Fletcher J.A.;
RT "USP6 (Tre2) fusion oncogenes in aneurysmal bone cyst.";
RL Cancer Res. 64:1920-1923(2004).
RN [7]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH ARF6.
RX PubMed=15509780; DOI=10.1128/mcb.24.22.9752-9762.2004;
RA Martinu L., Masuda-Robens J.M., Robertson S.E., Santy L.C., Casanova J.E.,
RA Chou M.M.;
RT "The TBC (Tre-2/Bub2/Cdc16) domain protein TRE17 regulates plasma membrane-
RT endosomal trafficking through activation of Arf6.";
RL Mol. Cell. Biol. 24:9752-9762(2004).
RN [8]
RP FUNCTION, INTERACTION WITH CALMODULIN, UBIQUITINATION, AND MUTAGENESIS OF
RP CYS-541.
RX PubMed=16127172; DOI=10.1074/jbc.m505220200;
RA Shen C., Ye Y., Robertson S.E., Lau A.W., Mak D.O., Chou M.M.;
RT "Calcium/calmodulin regulates ubiquitination of the ubiquitin-specific
RT protease TRE17/USP6.";
RL J. Biol. Chem. 280:35967-35973(2005).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [10]
RP FUNCTION.
RX PubMed=20418905; DOI=10.1038/onc.2010.116;
RA Ye Y., Pringle L.M., Lau A.W., Riquelme D.N., Wang H., Jiang T., Lev D.,
RA Welman A., Blobel G.A., Oliveira A.M., Chou M.M.;
RT "TRE17/USP6 oncogene translocated in aneurysmal bone cyst induces matrix
RT metalloproteinase production via activation of NF-kappaB.";
RL Oncogene 29:3619-3629(2010).
CC -!- FUNCTION: Deubiquitinase with an ATP-independent isopeptidase activity,
CC cleaving at the C-terminus of the ubiquitin moiety. Catalyzes its own
CC deubiquitination. In vitro, isoform 2, but not isoform 3, shows
CC deubiquitinating activity. Promotes plasma membrane localization of
CC ARF6 and selectively regulates ARF6-dependent endocytic protein
CC trafficking. Is able to initiate tumorigenesis by inducing the
CC production of matrix metalloproteinases following NF-kappa-B
CC activation. {ECO:0000269|PubMed:15509780, ECO:0000269|PubMed:16127172,
CC ECO:0000269|PubMed:20418905}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide
CC and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-
CC residue protein attached to proteins as an intracellular targeting
CC signal).; EC=3.4.19.12;
CC -!- SUBUNIT: Interacts with RAC1 and CDC42. Interacts (via Rab-GAP TBC
CC domain) with ARF6. Interacts with calmodulin (CALM1, CALM2 and/or
CC CALM3); the interaction is calcium-dependent.
CC {ECO:0000269|PubMed:12612085, ECO:0000269|PubMed:15509780,
CC ECO:0000269|PubMed:16127172}.
CC -!- INTERACTION:
CC P35125-3; Q8N8A2: ANKRD44; NbExp=4; IntAct=EBI-954590, EBI-1245329;
CC P35125-3; P10916: MYL2; NbExp=5; IntAct=EBI-954590, EBI-725770;
CC -!- SUBCELLULAR LOCATION: Cell membrane. Cytoplasm. Endosome.
CC Note=Localizes to the plasma membrane and to filamentous structures
CC within the cell corresponding to ARF6 regulated tubular endosomes.
CC Activation of RAC1 and CDC42 can direct the relocalization of USP6 to
CC the plasma membrane in a manner that depends on the integrity of the
CC actin cytoskeleton.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P35125-1; Sequence=Displayed;
CC Name=2; Synonyms=213(ORF2);
CC IsoId=P35125-2; Sequence=VSP_010878, VSP_010879;
CC Name=3; Synonyms=210(ORF1), oncTre210p;
CC IsoId=P35125-3; Sequence=VSP_010880, VSP_010881;
CC -!- TISSUE SPECIFICITY: Testis specific. Expressed in various cancer cell
CC lines. {ECO:0000269|PubMed:12604796, ECO:0000269|PubMed:1565468}.
CC -!- DOMAIN: The Rab-GAP TBC domain lacks GTPase activator activity but is
CC necessary for interaction with ARF6.
CC -!- PTM: Monubiquitinated; ubiquitination is calmodulin and calcium
CC dependent. {ECO:0000269|PubMed:16127172}.
CC -!- DISEASE: Note=A chromosomal aberration involving USP6 is a common
CC genetic feature of aneurysmal bone cyst, a benign osseous neoplasm.
CC Translocation t(16;17)(q22;p13) with CDH11. The translocation generates
CC a fusion gene in which the strong CDH11 promoter is fused to the entire
CC USP6 coding sequence, resulting in USP6 transcriptional up-regulation
CC (PubMed:15026324). {ECO:0000269|PubMed:15026324}.
CC -!- MISCELLANEOUS: The USP6 gene only exists in the primate lineage.
CC -!- MISCELLANEOUS: [Isoform 3]: Was shown to be tumorigenic in transfected
CC mice and seems not to act as GTPase activating protein. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the peptidase C19 family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/USP6ID530ch17p13.html";
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DR EMBL; X63546; CAA45108.1; -; mRNA.
DR EMBL; X63547; CAA45111.1; -; mRNA.
DR EMBL; AY143550; AAN38838.1; -; mRNA.
DR EMBL; AY163314; AAO21348.1; -; Genomic_DNA.
DR CCDS; CCDS11069.2; -. [P35125-1]
DR PIR; S57867; S57867.
DR PIR; S57868; S22158.
DR PIR; S57874; S22155.
DR RefSeq; NP_001291213.1; NM_001304284.1. [P35125-1]
DR RefSeq; NP_004496.2; NM_004505.3. [P35125-1]
DR RefSeq; XP_011522352.1; XM_011524050.1. [P35125-1]
DR RefSeq; XP_011522353.1; XM_011524051.2. [P35125-1]
DR RefSeq; XP_011522354.1; XM_011524052.2. [P35125-1]
DR RefSeq; XP_011522355.1; XM_011524053.2. [P35125-1]
DR RefSeq; XP_011522356.1; XM_011524054.2. [P35125-1]
DR RefSeq; XP_011522357.1; XM_011524055.2. [P35125-1]
DR RefSeq; XP_011522358.1; XM_011524056.2. [P35125-1]
DR RefSeq; XP_011522361.1; XM_011524059.2. [P35125-3]
DR RefSeq; XP_016880779.1; XM_017025290.1. [P35125-1]
DR AlphaFoldDB; P35125; -.
DR SMR; P35125; -.
DR BioGRID; 114552; 26.
DR IntAct; P35125; 6.
DR STRING; 9606.ENSP00000460380; -.
DR BindingDB; P35125; -.
DR ChEMBL; CHEMBL4630817; -.
DR MEROPS; C19.009; -.
DR MEROPS; C19.044; -.
DR iPTMnet; P35125; -.
DR PhosphoSitePlus; P35125; -.
DR BioMuta; USP6; -.
DR DMDM; 50403738; -.
DR EPD; P35125; -.
DR jPOST; P35125; -.
DR MassIVE; P35125; -.
DR MaxQB; P35125; -.
DR PaxDb; P35125; -.
DR PeptideAtlas; P35125; -.
DR PRIDE; P35125; -.
DR ProteomicsDB; 54980; -. [P35125-1]
DR ProteomicsDB; 54981; -. [P35125-2]
DR ProteomicsDB; 54982; -. [P35125-3]
DR Antibodypedia; 11505; 222 antibodies from 29 providers.
DR DNASU; 9098; -.
DR Ensembl; ENST00000250066.6; ENSP00000250066.6; ENSG00000129204.17. [P35125-1]
DR Ensembl; ENST00000572949.5; ENSP00000461581.1; ENSG00000129204.17. [P35125-3]
DR Ensembl; ENST00000574788.6; ENSP00000460380.1; ENSG00000129204.17. [P35125-1]
DR GeneID; 9098; -.
DR KEGG; hsa:9098; -.
DR MANE-Select; ENST00000574788.6; ENSP00000460380.1; NM_001304284.2; NP_001291213.1.
DR UCSC; uc002gau.2; human. [P35125-1]
DR CTD; 9098; -.
DR DisGeNET; 9098; -.
DR GeneCards; USP6; -.
DR HGNC; HGNC:12629; USP6.
DR HPA; ENSG00000129204; Group enriched (skeletal muscle, testis).
DR MalaCards; USP6; -.
DR MIM; 604334; gene.
DR neXtProt; NX_P35125; -.
DR OpenTargets; ENSG00000129204; -.
DR Orphanet; 477742; Nodular fasciitis.
DR PharmGKB; PA37254; -.
DR VEuPathDB; HostDB:ENSG00000129204; -.
DR eggNOG; KOG1102; Eukaryota.
DR eggNOG; KOG1870; Eukaryota.
DR GeneTree; ENSGT00940000155797; -.
DR HOGENOM; CLU_005123_0_0_1; -.
DR InParanoid; P35125; -.
DR OrthoDB; 1283205at2759; -.
DR PhylomeDB; P35125; -.
DR TreeFam; TF324190; -.
DR PathwayCommons; P35125; -.
DR SignaLink; P35125; -.
DR SIGNOR; P35125; -.
DR BioGRID-ORCS; 9098; 16 hits in 1074 CRISPR screens.
DR ChiTaRS; USP6; human.
DR GeneWiki; USP6; -.
DR GenomeRNAi; 9098; -.
DR Pharos; P35125; Tbio.
DR PRO; PR:P35125; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; P35125; protein.
DR Bgee; ENSG00000129204; Expressed in Brodmann (1909) area 23 and 197 other tissues.
DR ExpressionAtlas; P35125; baseline and differential.
DR Genevisible; P35125; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005764; C:lysosome; TAS:ProtInc.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0055037; C:recycling endosome; IDA:UniProtKB.
DR GO; GO:0005516; F:calmodulin binding; IEA:UniProtKB-KW.
DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:UniProtKB.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; TAS:UniProtKB.
DR GO; GO:0005096; F:GTPase activator activity; IBA:GO_Central.
DR GO; GO:0003676; F:nucleic acid binding; TAS:ProtInc.
DR GO; GO:0090630; P:activation of GTPase activity; IBA:GO_Central.
DR GO; GO:0016579; P:protein deubiquitination; IDA:UniProtKB.
DR GO; GO:0036211; P:protein modification process; NAS:UniProtKB.
DR GO; GO:0060627; P:regulation of vesicle-mediated transport; IDA:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IEA:InterPro.
DR InterPro; IPR038765; Papain-like_cys_pep_sf.
DR InterPro; IPR001394; Peptidase_C19_UCH.
DR InterPro; IPR000195; Rab-GTPase-TBC_dom.
DR InterPro; IPR035969; Rab-GTPase_TBC_sf.
DR InterPro; IPR018200; USP_CS.
DR InterPro; IPR028889; USP_dom.
DR Pfam; PF00566; RabGAP-TBC; 1.
DR Pfam; PF00443; UCH; 1.
DR SMART; SM00164; TBC; 1.
DR SUPFAM; SSF47923; SSF47923; 2.
DR SUPFAM; SSF54001; SSF54001; 1.
DR PROSITE; PS50086; TBC_RABGAP; 1.
DR PROSITE; PS00972; USP_1; 1.
DR PROSITE; PS00973; USP_2; 1.
DR PROSITE; PS50235; USP_3; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Calmodulin-binding; Cell membrane;
KW Chromosomal rearrangement; Cytoplasm; Endosome; Hydrolase; Membrane;
KW Protease; Proto-oncogene; Reference proteome; Thiol protease;
KW Ubl conjugation; Ubl conjugation pathway.
FT CHAIN 1..1406
FT /note="Ubiquitin carboxyl-terminal hydrolase 6"
FT /id="PRO_0000080625"
FT DOMAIN 100..292
FT /note="Rab-GAP TBC"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00163"
FT DOMAIN 532..1369
FT /note="USP"
FT REGION 348..380
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1120..1231
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1384..1406
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1132..1148
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1152..1201
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1213..1228
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1385..1400
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 541
FT /note="Nucleophile"
FT ACT_SITE 1328
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10092,
FT ECO:0000255|PROSITE-ProRule:PRU10093"
FT VAR_SEQ 1..317
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:1565468"
FT /id="VSP_010878"
FT VAR_SEQ 318..359
FT /note="GLWARLRNQFFDTWAMNDDTVLKHLRASTKKLTRKQGDLPPP -> MPQRLP
FT HARQHTPLPLGSADYRRVVSVRPQGPHRDPKDSRDA (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:1565468"
FT /id="VSP_010879"
FT VAR_SEQ 774..786
FT /note="NFPQDNQKVQLSV -> ISPLHHLQMECSP (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:1565468"
FT /id="VSP_010880"
FT VAR_SEQ 787..1406
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:1565468"
FT /id="VSP_010881"
FT VARIANT 475
FT /note="W -> R (in dbSNP:rs8073787)"
FT /evidence="ECO:0000269|PubMed:1565468"
FT /id="VAR_051522"
FT VARIANT 525
FT /note="V -> I (in dbSNP:rs2304449)"
FT /id="VAR_059749"
FT VARIANT 912
FT /note="R -> Q (in dbSNP:rs9899177)"
FT /evidence="ECO:0000269|PubMed:1565468"
FT /id="VAR_051523"
FT MUTAGEN 150
FT /note="T->R: Does not restore GAP activity in yeast
FT complementation assay."
FT /evidence="ECO:0000269|PubMed:14521938"
FT MUTAGEN 187
FT /note="R->Q: Does not restore GAP activity in yeast
FT complementation assay."
FT /evidence="ECO:0000269|PubMed:14521938"
FT MUTAGEN 541
FT /note="C->S: Loss of enzyme activity."
FT /evidence="ECO:0000269|PubMed:16127172"
FT CONFLICT 963
FT /note="N -> I (in Ref. 1; CAA45111)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1406 AA; 158658 MW; D3A6822CEB441DB3 CRC64;
MDMVENADSL QAQERKDILM KYDKGHRAGL PEDKGPEPVG INSSIDRFGI LHETELPPVT
AREAKKIRRE MTRTSKWMEM LGEWETYKHS SKLIDRVYKG IPMNIRGPVW SVLLNIQEIK
LKNPGRYQIM KERGKRSSEH IHHIDLDVRT TLRNHVFFRD RYGAKQRELF YILLAYSEYN
PEVGYCRDLS HITALFLLYL PEEDAFWALV QLLASERHSL PGFHSPNGGT VQGLQDQQEH
VVPKSQPKTM WHQDKEGLCG QCASLGCLLR NLIDGISLGL TLRLWDVYLV EGEQVLMPIT
SIALKVQQKR LMKTSRCGLW ARLRNQFFDT WAMNDDTVLK HLRASTKKLT RKQGDLPPPA
KREQGSLAPR PVPASRGGKT LCKGYRQAPP GPPAQFQRPI CSASPPWASR FSTPCPGGAV
REDTYPVGTQ GVPSLALAQG GPQGSWRFLE WKSMPRLPTD LDIGGPWFPH YDFEWSCWVR
AISQEDQLAT CWQAEHCGEV HNKDMSWPEE MSFTANSSKI DRQKVPTEKG ATGLSNLGNT
CFMNSSIQCV SNTQPLTQYF ISGRHLYELN RTNPIGMKGH MAKCYGDLVQ ELWSGTQKSV
APLKLRRTIA KYAPKFDGFQ QQDSQELLAF LLDGLHEDLN RVHEKPYVEL KDSDGRPDWE
VAAEAWDNHL RRNRSIIVDL FHGQLRSQVK CKTCGHISVR FDPFNFLSLP LPMDSYMDLE
ITVIKLDGTT PVRYGLRLNM DEKYTGLKKQ LRDLCGLNSE QILLAEVHDS NIKNFPQDNQ
KVQLSVSGFL CAFEIPVPSS PISASSPTQI DFSSSPSTNG MFTLTTNGDL PKPIFIPNGM
PNTVVPCGTE KNFTNGMVNG HMPSLPDSPF TGYIIAVHRK MMRTELYFLS PQENRPSLFG
MPLIVPCTVH TRKKDLYDAV WIQVSWLARP LPPQEASIHA QDRDNCMGYQ YPFTLRVVQK
DGNSCAWCPQ YRFCRGCKID CGEDRAFIGN AYIAVDWHPT ALHLRYQTSQ ERVVDKHESV
EQSRRAQAEP INLDSCLRAF TSEEELGESE MYYCSKCKTH CLATKKLDLW RLPPFLIIHL
KRFQFVNDQW IKSQKIVRFL RESFDPSAFL VPRDPALCQH KPLTPQGDEL SKPRILAREV
KKVDAQSSAG KEDMLLSKSP SSLSANISSS PKGSPSSSRK SGTSCPSSKN SSPNSSPRTL
GRSKGRLRLP QIGSKNKPSS SKKNLDASKE NGAGQICELA DALSRGHMRG GSQPELVTPQ
DHEVALANGF LYEHEACGNG CGDGYSNGQL GNHSEEDSTD DQREDTHIKP IYNLYAISCH
SGILSGGHYI TYAKNPNCKW YCYNDSSCEE LHPDEIDTDS AYILFYEQQG IDYAQFLPKI
DGKKMADTSS TDEDSESDYE KYSMLQ
