Mechanism of USP7/HAUSP Activation by Its C-Terminal Ubiquitin-like Domain and Allosteric Regulation by GMP-Synthetase

Faesen, Alex C.; Dirac, Annette M.G.; Shanmugham, Anitha; Ovaa, Huib; Perrakis, Anastassis; Sixma, Titia K.

doi:10.1016/j.molcel.2011.06.034

Cited by 203 publications

(340 citation statements)

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“…[21][22][23][24] However, the ability of exogenous guanosine to fully revert all phenotypes caused by GMPS depletion in vitro (Figure 1) strongly suggests that guanylate biosynthetic function has the most important role in GMPS-dependent maintenance of invasive and tumorigenic phenotypes of melanoma cells.…”

Section: Discussionmentioning

confidence: 99%

“…[18][19][20] Mammalian GMPS has been the subject of several studies addressing its unconventional (GMP-unrelated) roles in the regulation of activity of ubiquitin-specific protease 7 (USP7). [21][22][23][24] However, because of the newly revealed importance of guanylate metabolism in control of melanoma cell invasion and tumorigenicity, 8 GMPS emerges as an attractive target for anti-cancer therapy.…”

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confidence: 99%

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Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity

et al. 2015

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Malignant melanoma possesses one of the highest metastatic potentials among human cancers. Acquisition of invasive phenotypes is a prerequisite for melanoma metastases. Elucidation of the molecular mechanisms underlying melanoma invasion will greatly enhance the design of novel agents for melanoma therapeutic intervention. Here, we report that guanosine monophosphate synthase (GMPS), an enzyme required for the de novo biosynthesis of GMP, has a major role in invasion and tumorigenicity of cells derived from either BRAF V600E or NRAS Q61R human metastatic melanomas. Moreover, GMPS levels are increased in metastatic human melanoma specimens compared with primary melanomas arguing that GMPS is an attractive candidate for anti-melanoma therapy. Accordingly, for the first time we demonstrate that angustmycin A, a nucleoside-analog inhibitor of GMPS produced by Streptomyces hygroscopius efficiently suppresses melanoma cell invasion in vitro and tumorigenicity in immunocompromised mice. Our data identify GMPS as a powerful driver of melanoma cell invasion and warrant further investigation of angustmycin A as a novel anti-melanoma agent.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity

et al. 2015

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“…The metabolic enzyme GMPS increases deubiquitylating activity of USP7 binding to a 'switching' loop close to the catalytic domain. 49 Daxx may bind USP7 in a similar manner to enhance its activity in mitosis. Alternatively, Daxx may recruit USP7 substrates.…”

Section: Discussionmentioning

confidence: 99%

USP7 and Daxx regulate mitosis progression and taxane sensitivity by affecting stability of Aurora-A kinase

et al. 2013

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A large number of patients are resistant to taxane-based chemotherapy. Functional mitotic checkpoints are essential for taxane sensitivity. Thus, mitotic regulators are potential markers for therapy response and could be targeted for anticancer therapy. In this study, we identified a novel function of ubiquitin (Ub)-specific processing protease-7 (USP7) that interacts and cooperates with protein death domain-associated protein (Daxx) in the regulation of mitosis and taxane resistance. Depletion of USP7 impairs mitotic progression, stabilizes cyclin B and reduces stability of the mitotic E3 Ub ligase, checkpoint with forkhead and Ring-finger (CHFR). Consequently, cells with depleted USP7 accumulate Aurora-A kinase, a CHFR substrate, thus elevating multipolar mitoses. We further show that these effects are independent of the USP7 substrate p53. Thus, USP7 and Daxx are necessary to regulate proper execution of mitosis, partially via regulation of CHFR and Aurora-A kinase stability. Results from colony formation assay, in silico analysis across the NCI60 platform and in breast cancer patients suggest that USP7 levels inversely correlate with response to taxanes, pointing at the USP7 protein as a potential predictive factor for taxane response in cancer patients. In addition, we demonstrated that inhibition of Aurora-A attenuates USP7-mediated taxane resistance, suggesting that combinatorial drug regimens of Taxol and Aurora-A inhibitors may improve the outcome of chemotherapy response in cancer patients resistant to taxane treatment. Finally, our study offers novel insights on USP7 inhibition as cancer therapy.

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“…However, the interaction between USP1 and UAF1 is itself regulated by CDK1-mediated serine phosphorylation of USP1 (267). The COOHterminal region of USP7 contains 5 Ubiquitin-like (Ubl) domains organized into 2-1-2 Ubl units, the last pair of which (HUBL-45) activate USP7 by 100-fold (66,71 (171,218).…”

Section: Regulation Of Dub Activitymentioning

confidence: 99%

Deubiquitylases From Genes to Organism

Clague

Barsukov

Coulson

et al. 2013

Physiological Reviews

356

380

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Ubiquitylation is a major posttranslational modification that controls most complex aspects of cell physiology. It is reversed through the action of a large family of deubiquitylating enzymes (DUBs) that are emerging as attractive therapeutic targets for a number of disease conditions. Here, we provide a comprehensive analysis of the complement of human DUBs, indicating structural motifs, typical cellular copy numbers, and tissue expression profiles. We discuss the means by which specificity is achieved and how DUB activity may be regulated. Generically DUB catalytic activity may be used to 1) maintain free ubiquitin levels, 2) rescue proteins from ubiquitin-mediated degradation, and 3) control the dynamics of ubiquitin-mediated signaling events. Functional roles of individual DUBs from each of five subfamilies in specific cellular processes are highlighted with an emphasis on those linked to pathological conditions where the association is supported by whole organism models. We then specifically consider the role of DUBs associated with protein degradative machineries and the influence of specific DUBs upon expression of receptors and channels at the plasma membrane.

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Mechanism of USP7/HAUSP Activation by Its C-Terminal Ubiquitin-like Domain and Allosteric Regulation by GMP-Synthetase

Cited by 203 publications

References 50 publications

Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity

Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity

USP7 and Daxx regulate mitosis progression and taxane sensitivity by affecting stability of Aurora-A kinase

Deubiquitylases From Genes to Organism

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