USP6

Last updated
USP6
Identifiers
Aliases USP6 , HRP1, TRE17, TRE2, TRESMCR, Tre-2, USP6-short, ubiquitin specific peptidase 6
External IDs OMIM: 604334 HomoloGene: 136783 GeneCards: USP6
Orthologs
SpeciesHumanMouse
Entrez

9098

n/a

Ensembl

ENSG00000129204

n/a

UniProt

P35125

n/a

RefSeq (mRNA)

NM_001304284
NM_004505
NM_005152

n/a

RefSeq (protein)

NP_001291213
NP_004496

n/a

Location (UCSC) Chr 17: 5.12 – 5.18 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

Ubiquitin carboxyl-terminal hydrolase 6 (USB6), also termed TRE17 and Tre-2, is a deubiquitinating enzyme [3] that in humans is encoded by the hominid (i.e. found only in primates) USP6 gene [4] [5] [6] located at band 13.2 on the short (i.e. "p") arm of chromosome 17 (notated as 17p13.2). [7] Deubiquitinating enzymes (DUBs) are enzymes that act within cells to remove ubiquitins from various functionally important proteins. Ubiquitin enzymes add ubiquitin to these proteins and thereby regulate their cellular location, alter their activity, and/or promote their degradation. By deubiquitinating these proteins, DUBs counter the effects of the ubiquinating enzymes and contribute to regulating the actions of the targeted proteins. [8] In normal adult tissues, USP6 is highly expressed in testicle tissue, modestly expressed in ovarian tissue, and absent or minimally expressed in other tissues. [9] It is also highly expressed in fetal brain tissue. The specific functions of USP6 are poorly defined primarily because its presence is restricted to primates: there are no available animal models to determine the effects of its deletion, although some studies suggest that UPSP6 contributes to normal brain development. [7] In all events, USP6 has gained wide interest because of its abnormally increased expression by the neoplastic cells in various tumors derived from mesenchymal tissue.

The USP6 gene associated with tumors is part of a fusion gene. Fusion genes are abnormal and potentially tumor-inducing genes formed by mergers between parts of two different genes as a result of large scale gene mutations such as chromosomal translocations, interstitial deletions, or inversions. For example, the USP6-COL1A1 fusion gene is formed by a translocation between part of the USP6 gene located at band 13.2 on the p arm of chromosome 17 and the COL1A1 gene located at band 21.33 on the q arm of this same chromosome. [10] The USP6 gene has been documented to fuse with any one of scores of other genes and in doing so (as tested in many cases) create a fusion gene that is overproduced and contains high levels of deubiquitinating activity. [11] Studies suggest that USP6-containing fusion genes cause or at least contribute to tumor development by inappropriately activating multiple cell signaling pathways including the Wnt signaling pathway, one of the JAK-STAT signaling pathways (i.e. the Jak1-STAT3 pathway), the c-Jun signaling pathway, [12] and the NF-κB signaling pathway. [13] All of these pathways, when inappropriately activated, have been implicated in promoting the development of tumors and cancers. [12] The World Health Organization, 2021, classification of Tumors of Soft Tissue suggests that USP6-containing fusion protein-associated tumors are typically benign and usually self-limited in their growth. [12] Furthermore, high levels of USP6 activity may act to suppress rather than promote tumor development in Ewing sarcoma, a tumor which has USP-containing fusion genes in ~1/3 of cases. [3]

Tumor types that are associated with USP6-containing fusion genes and appear to promote their development and/or growth include:

Related Research Articles

<span class="mw-page-title-main">Deubiquitinating enzyme</span>

Deubiquitinating enzymes (DUBs), also known as deubiquitinating peptidases, deubiquitinating isopeptidases, deubiquitinases, ubiquitin proteases, ubiquitin hydrolases, or ubiquitin isopeptidases, are a large group of proteases that cleave ubiquitin from proteins. Ubiquitin is attached to proteins in order to regulate the degradation of proteins via the proteasome and lysosome; coordinate the cellular localisation of proteins; activate and inactivate proteins; and modulate protein-protein interactions. DUBs can reverse these effects by cleaving the peptide or isopeptide bond between ubiquitin and its substrate protein. In humans there are nearly 100 DUB genes, which can be classified into two main classes: cysteine proteases and metalloproteases. The cysteine proteases comprise ubiquitin-specific proteases (USPs), ubiquitin C-terminal hydrolases (UCHs), Machado-Josephin domain proteases (MJDs) and ovarian tumour proteases (OTU). The metalloprotease group contains only the Jab1/Mov34/Mpr1 Pad1 N-terminal+ (MPN+) (JAMM) domain proteases.

<span class="mw-page-title-main">Nodular fasciitis</span> Medical condition

Nodular fasciitis (NF) is a benign, soft tissue tumor composed of myofibroblasts that typically occurs in subcutaneous tissue, fascia, and/or muscles. The literature sometimes titles rare NF variants according to their tissue locations. The most frequently used and important of these are cranial fasciitis and intravascular fasciitis. In 2020, the World Health Organization classified nodular fasciitis as in the category of benign fibroblastic/myofibroblastic tumors. NF is the most common of the benign fibroblastic proliferative tumors of soft tissue.

<span class="mw-page-title-main">Aneurysmal bone cyst</span> Medical condition

Aneurysmal bone cyst (ABC) is a non-cancerous bone tumor composed of multiple varying sizes of spaces in a bone which are filled with blood. The term is a misnomer, as the lesion is neither an aneurysm nor a cyst. It generally presents with pain and swelling in the affected bone. Pressure on neighbouring tissues may cause compression effects such as neurological symptoms.

<span class="mw-page-title-main">GDF3</span> Protein-coding gene in humans

Growth differentiation factor-3 (GDF3), also known as Vg-related gene 2 (Vgr-2) is protein that in humans is encoded by the GDF3 gene. GDF3 belongs to the transforming growth factor beta (TGF-β) superfamily. It has high similarity to other TGF-β superfamily members including Vg1 and GDF1.

<span class="mw-page-title-main">UBE2I</span> Protein-coding gene in the species Homo sapiens

SUMO-conjugating enzyme UBC9 is an enzyme that in humans is encoded by the UBE2I gene. It is also sometimes referred to as "ubiquitin conjugating enzyme E2I" or "ubiquitin carrier protein 9", even though these names do not accurately describe its function.

<span class="mw-page-title-main">CDC34</span> Protein-coding gene in the species Homo sapiens

CDC34 is a gene that in humans encodes the protein Ubiquitin-conjugating enzyme E2 R1. This protein is a member of the ubiquitin-conjugating enzyme family, which catalyzes the covalent attachment of ubiquitin to other proteins.

<span class="mw-page-title-main">TOPORS</span> Protein-coding gene in the species Homo sapiens

E3 ubiquitin-protein ligase Topors is an enzyme that in humans is encoded by the TOPORS gene.

<span class="mw-page-title-main">LATS1</span> Protein-coding gene in the species Homo sapiens

Large tumor suppressor kinase 1 (LATS1) is an enzyme that in humans is encoded by the LATS1 gene.

<span class="mw-page-title-main">PDGFC</span> Protein-coding gene in the species Homo sapiens

Platelet-derived growth factor C, also known as PDGF-C, is a 345-amino acid protein that in humans is encoded by the PDGFC gene. Platelet-derived growth factors are important in connective tissue growth, survival and function, and consist of disulphide-linked dimers involving two polypeptide chains, PDGF-A and PDGF-B. PDGF-C is a member of the PDGF/VEGF family of growth factors with a unique two-domain structure and expression pattern. PDGF-C was not previously identified with PDGF-A and PDGF-B, possibly because it may be that it is synthesized and secreted as a latent growth factor, requiring proteolytic removal of the N-terminal CUB domain for receptor binding and activation.

<span class="mw-page-title-main">UBE2V1</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-conjugating enzyme E2 variant 1 is a protein that in humans is encoded by the UBE2V1 gene.

<span class="mw-page-title-main">UBE2B</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-conjugating enzyme E2 B is a protein that in humans is encoded by the UBE2B gene.

<span class="mw-page-title-main">FANCL</span> Protein-coding gene in the species Homo sapiens

E3 ubiquitin-protein ligase FANCL is an enzyme that in humans is encoded by the FANCL gene.

<span class="mw-page-title-main">USP16</span> Protein-coding gene in the species Homo sapiens

Ubiquitin carboxyl-terminal hydrolase 16 is an enzyme that in humans is encoded by the USP16 gene.

<span class="mw-page-title-main">USP4</span> Protein-coding gene in the species Homo sapiens

Ubiquitin specific protease 4 (USP4) is an enzyme that cleaves ubiquitin from a number of protein substrates. Prior to the standardization of nomenclature USP4 was known as UNP, and was one of the first deubiquitinating enzymes to be identified in mammals. In the mouse and human the USP4 protein is encoded by a gene containing 22 exons.

<span class="mw-page-title-main">UCHL3</span> Enzyme in humans encoded by the UCHL3 gene

Ubiquitin carboxyl-terminal hydrolase isozyme L3 is an enzyme that in humans is encoded by the UCHL3 gene.

<span class="mw-page-title-main">NUAK1</span> Protein-coding gene in the species Homo sapiens

NUAK family SNF1-like kinase 1 also known as AMPK-related protein kinase 5 (ARK5) is an enzyme that in humans is encoded by the NUAK1 gene.

<span class="mw-page-title-main">USP2</span> Protein-coding gene in the species Homo sapiens

Ubiquitin carboxyl-terminal hydrolase 2 is an enzyme that in humans is encoded by the USP2 gene.

<span class="mw-page-title-main">USP13</span> Protein-coding gene in the species Homo sapiens

Ubiquitin carboxyl-terminal hydrolase 13 is an enzyme that in humans is encoded by the USP13 gene.

<span class="mw-page-title-main">Proliferative fasciitis and proliferative myositis</span> Medical condition

Proliferative fasciitis and proliferative myositis (PF/PM) are rare benign soft tissue lesions that increase in size over several weeks and often regress over the ensuing 1–3 months. The lesions in PF/PM are typically obvious tumors or swellings. Historically, many studies had grouped the two descriptive forms of PF/PM as similar disorders with the exception that proliferative fasciitis occurs in subcutaneous tissues while proliferative myositis occurs in muscle tissues. In 2020, the World Health Organization agreed with this view and defined these lesions as virtually identical disorders termed proliferative fasciitis/proliferative myositis or proliferative fasciitis and proliferative myositis. The Organization also classified them as one of the various forms of the fibroblastic and myofibroblastic tumors.

The PPP6R3 gene is located at band 13.2 on the long arm of chromosome 11 and is expressed in all tissues tested in humans. It encodes protein phosphatase 6 regulatory subunit 3 (PP6RS3). Also termed serine/threonine-protein phosphatase 6 regulatory subunit 3, PP6RS3 is the function-regulating subunit of protein phosphatase 6 (PPP6C). PPP6C is a component of a signaling pathway that regulates various cell functions including cell division, the repair of damaged DNA, inflammatory responses, messenger mRNA splicing, and the stability of chromosomes.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000129204 - Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. 1 2 Henrich IC, Jain K, Young R, Quick L, Lindsay JM, Park DH, Oliveira AM, Blobel GA, Chou MM (April 2021). "Ubiquitin-Specific Protease 6 Functions as a Tumor Suppressor in Ewing Sarcoma through Immune Activation". Cancer Research. 81 (8): 2171–2183. doi:10.1158/0008-5472.CAN-20-1458. PMC   8137534 . PMID   33558334.
  4. ↑ Puente XS, Sanchez LM, Overall CM, Lopez-Otin C (Jul 2003). "Human and mouse proteases: a comparative genomic approach". Nat Rev Genet. 4 (7): 544–58. doi:10.1038/nrg1111. PMID   12838346. S2CID   2856065.
  5. ↑ Hoogendijk JE, Hensels GW, Gabreels-Festen AA, Gabreels FJ, Janssen EA, de Jonghe P, Martin JJ, van Broeckhoven C, Valentijn LJ, Baas F, et al. (May 1992). "De-novo mutation in hereditary motor and sensory neuropathy type I". Lancet. 339 (8801): 1081–2. doi:10.1016/0140-6736(92)90668-S. PMID   1349106. S2CID   35908066.
  6. ↑ "Entrez Gene: USP6 ubiquitin specific peptidase 6 (Tre-2 oncogene)".
  7. 1 2 Oliveira AM, Chou MM (January 2012). "The TRE17/USP6 oncogene: a riddle wrapped in a mystery inside an enigma". Frontiers in Bioscience (Scholar Edition). 4 (1): 321–34. doi: 10.2741/271 . PMID   22202063.
  8. ↑ Snyder NA, Silva GM (August 2021). "Deubiquitinating enzymes (DUBs): regulation, homeostasis, and oxidative stress response". The Journal of Biological Chemistry. 297 (3): 101077. doi: 10.1016/j.jbc.2021.101077 . PMC   8424594 . PMID   34391779.
  9. ↑ "USP6 ubiquitin specific peptidase 6 [Homo sapiens (Human)] - Gene - NCBI".
  10. ↑ Stražar K, Šekoranja D, Matjašič A, Zupan A, Snoj Ž, Martinčič D, Pižem J (June 2021). "Intraarticular nodular fasciitis-detection of USP6 gene fusions in three cases by targeted RNA sequencing". Virchows Archiv. 478 (6): 1117–1124. doi:10.1007/s00428-020-02991-6. ISSN   0945-6317. PMID   33404853. S2CID   230783712.
  11. ↑ Legrand M, Jourdan ML, Tallet A, Collin C, Audard V, Larousserie F, Aubert S, Gomez-Brouchet A, Bouvier C, de Pinieux G (July 2021). "Novel partners of USP6 gene in a spectrum of bone and soft tissue lesions". Virchows Archiv. 479 (1): 147–156. doi:10.1007/s00428-021-03047-z. PMID   33558945. S2CID   231850082.
  12. 1 2 3 Nakayama S, Nishio J, Aoki M, Koga K, Nabeshima K, Yamamoto T (2021). "Ubiquitin-specific Peptidase 6 (USP6)-associated Fibroblastic/Myofibroblastic Tumors: Evolving Concepts". Cancer Genomics & Proteomics. 18 (2): 93–101. doi:10.21873/cgp.20244. PMC   7943209 . PMID   33608306.
  13. ↑ Ye Y, Pringle LM, Lau AW, et al. (June 2010). "TRE17/USP6 oncogene translocated in aneurysmal bone cyst induces matrix metalloproteinase production via activation of NFκB". Oncogene. 29 (25): 3619–29. doi:10.1038/onc.2010.116. PMC   2892027 . PMID   20418905.
  14. 1 2 Agaram NP, LeLoarer FV, Zhang L, Hwang S, Athanasian EA, Hameed M, Antonescu CR (June 2014). "USP6 gene rearrangements occur preferentially in giant cell reparative granulomas of the hands and feet but not in gnathic location". Human Pathology. 45 (6): 1147–52. doi:10.1016/j.humpath.2014.01.020. PMC   4225080 . PMID   24742829.
  15. 1 2 Baumhoer D, Amary F, Flanagan AM (February 2019). "An update of molecular pathology of bone tumors. Lessons learned from investigating samples by next generation sequencing". Genes, Chromosomes & Cancer. 58 (2): 88–99. doi:10.1002/gcc.22699. PMID   30582658. S2CID   58637942.
  16. ↑ Hiemcke-Jiwa LS, van Gorp JM, Fisher C, Creytens D, van Diest PJ, Flucke U (December 2020). "USP6-Associated Neoplasms: A Rapidly Expanding Family of Lesions". International Journal of Surgical Pathology. 28 (8): 816–825. doi: 10.1177/1066896920938878 . PMID   32635781. S2CID   220413896.
  17. ↑ Sbaraglia M, Bellan E, Dei Tos AP (April 2021). "The 2020 WHO Classification of Soft Tissue Tumours: news and perspectives". Pathologica. 113 (2): 70–84. doi:10.32074/1591-951X-213. PMC   8167394 . PMID   33179614.
  18. ↑ Bekers EM, Eijkelenboom A, Grünberg K, Roverts RC, de Rooy JW, van der Geest IC, van Gorp JM, Creytens D, Flucke U (June 2018). "Myositis ossificans - Another condition with USP6 rearrangement, providing evidence of a relationship with nodular fasciitis and aneurysmal bone cyst". Annals of Diagnostic Pathology. 34: 56–59. doi:10.1016/j.anndiagpath.2018.01.006. hdl: 1854/LU-8559797 . PMID   29661729. S2CID   4957974.

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