Identification, Functional Characterization, and Chromosomal Localization of USP15, a Novel Human Ubiquitin-Specific Protease Related to the UNP Oncoprotein, and a Systematic Nomenclature for Human Ubiquitin-Specific Proteases

Baker, Rohan T.; Wang, Xiaowen; Woollatt, Erica; White, Jonathan; Sutherland, Grant R.

doi:10.1006/geno.1999.5879

Cited by 67 publications

(53 citation statements)

References 46 publications

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“…A protein containing the T-ag NLS fused to ␤-galactosidase was used as a positive control, whereas ␤-galactosidase alone was used as a negative control. Recombinant IMP ␣ and ␤ were expressed as GST fusion proteins as previously (11). The results show that both NLS2-containing proteins have a higher affinity for the IMP ␣/␤ 1 heterodimer than for IMP ␣ or ␤ alone (Fig.…”

Section: Fig 2 Subcellular Localization Of Endogenous Usp4 In Variomentioning

confidence: 79%

“…These include the human tre-2/tre-17(USP6) proto-oncogene (9) and the mouse cytokine-inducible UBPs DUB-1 and DUB-2 (10). We have studied the mouse Unp gene (Usp4 in the systematic nomenclature) (11), which was originally identified as a proto-oncogene related to tre-2/tre-17/ USP6 (12,13). Unp/Usp4 was subsequently observed to contain the UBP Cys and His boxes (9,14) and since shown to have DUB activity (15,16).…”

mentioning

confidence: 99%

“…In contrast, cell fractionation studies by Frederick et al (17) using a different anti-peptide antibody showed it to be cytoplasmic. Both of these studies are clouded by the subsequent identification of a novel DUB termed USP15 (11,20), which is 61% identical to USP4. Since the antibody produced by Frederick et al (17) was raised against a peptide that is almost identical in the subsequently identified USP15, it seems likely that both USP4 and USP15 were being detected.…”

mentioning

confidence: 99%

“…Since the antibody produced by Frederick et al (17) was raised against a peptide that is almost identical in the subsequently identified USP15, it seems likely that both USP4 and USP15 were being detected. Both USP4 and USP15 contain putative nuclear localization signals (NLSs), with that of USP4 being very similar to that of p53 (11,13). Overexpression of transfected myc epitope-tagged USP4 in IMR90 cells revealed either whole-cell or cytoplasmic staining (17).…”

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confidence: 99%

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Nuclear-Cytoplasmic Shuttling of the Oncogenic Mouse UNP/USP4 Deubiquitylating Enzyme

Soboleva

Jans

Johnson-Saliba

et al. 2005

Journal of Biological Chemistry

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The oncogenic deubiquitylating enzyme (DUB) Unp/ Usp4, which binds to the retinoblastoma family of tumor suppressor proteins, was originally described as a nuclear protein. However, more recent studies have shown it to be cytoplasmic. In addition, analysis of its subcellular localization has been complicated by the existence of the paralog Usp15. In this study, we resolved this controversy by investigating the localization of exogenously expressed Usp4 (using red fluorescent proteinUsp4) and of endogenous Usp4 (using highly specific antibodies that can distinguish Usp4 from Usp15). We found that by inhibiting nuclear export with leptomycin B, both exogenous and endogenous Usp4 accumulate in the nucleus. Further, using a Rev-green fluorescent protein-based export assay, we confirmed the existence of a nuclear export signal ( 133 VEVYLLELKL 142 ) in Usp4. In addition, a functional nuclear import signal ( 766 QPQKKKK 772 ) was also identified, which was specifically recognized by importin ␣/␤. Finally, we show that the equilibrium of Usp4 subcellular localization varies between different cell types. Usp4 is thus the first DUB reported to have nucleocytoplasmic shuttling properties. The implications of this shuttling for its function as a DUB are discussed.

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Section: Fig 2 Subcellular Localization Of Endogenous Usp4 In Variomentioning

confidence: 79%

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confidence: 99%

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confidence: 99%

mentioning

confidence: 99%

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Nuclear-Cytoplasmic Shuttling of the Oncogenic Mouse UNP/USP4 Deubiquitylating Enzyme

Soboleva

Jans

Johnson-Saliba

et al. 2005

Journal of Biological Chemistry

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“…Ub-specific protease Y (UBPY) also designated as Ubspecific protease 8 (USP8), is a deubiqutinating enzyme that belongs to the Ub-specific protease (UBP) family of cysteine proteases (Naviglio et al, 1998;Baker et al, 1999). Previous in vitro experiments have shown that UBPY binds to the Src homology 3 (SH3) domain of STAM, a component of the Hrs-STAM endosomal sorting complex for ubiquitinated RTKs (Kato et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Epidermal Growth Factor Receptor Down-Regulation by UBPY-mediated Deubiquitination at Endosomes

Mizuno

Iura

Mukai

et al. 2005

MBoC

248

259

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Ligand-activated receptor tyrosine kinases undergo endocytosis and are transported via endosomes to lysosomes for degradation. This "receptor down-regulation" process is crucial to terminate the cell proliferation signals produced by activated receptors. During the process, ubiquitination of the receptors serves as a sorting signal for their trafficking from endosomes to lysosomes. Here, we describe the role of a deubiquitinating enzyme UBPY/USP8 in the down-regulation of epidermal growth factor (EGF) receptor (EGFR). Overexpression of UBPY reduced the ubiquitination level of EGFR and delayed its degradation in EGF-stimulated cells. Immunopurified UBPY deubiquitinated EGFR in vitro. In EGF-stimulated cells, UBPY underwent ubiquitination and bound to EGFR. Overexpression of Hrs or a dominant-negative mutant of SKD1, proteins that play roles in the endosomal sorting of ubiquitinated receptors, caused the accumulation of endogenous UBPY on exaggerated endosomes. A catalytically inactive UBPY mutant clearly localized on endosomes, where it overlapped with EGFR when cells were stimulated with EGF. Finally, depletion of endogenous UBPY by RNA interference resulted in elevated ubiquitination and accelerated degradation of EGF-activated EGFR. We conclude that UBPY negatively regulates the rate of EGFR down-regulation by deubiquitinating EGFR on endosomes.

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Deubiquitinating Enzymes, Cell Proliferation, and Cancer

Baker

2007

Protein Degradation Series

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Identification, Functional Characterization, and Chromosomal Localization of USP15, a Novel Human Ubiquitin-Specific Protease Related to the UNP Oncoprotein, and a Systematic Nomenclature for Human Ubiquitin-Specific Proteases

Cited by 67 publications

References 46 publications

Nuclear-Cytoplasmic Shuttling of the Oncogenic Mouse UNP/USP4 Deubiquitylating Enzyme

Nuclear-Cytoplasmic Shuttling of the Oncogenic Mouse UNP/USP4 Deubiquitylating Enzyme

Regulation of Epidermal Growth Factor Receptor Down-Regulation by UBPY-mediated Deubiquitination at Endosomes

Deubiquitinating Enzymes, Cell Proliferation, and Cancer

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