The Ubiquitin-specific Protease 12 (USP12) Is a Negative Regulator of Notch Signaling Acting on Notch Receptor Trafficking toward Degradation

Moretti, Julien; Chastagner, Patricia; Liang, Chih-Chao; Cohn, Martin A.; Israël, Alain; Brou, Christel

doi:10.1074/jbc.m112.366807

Cited by 58 publications

(50 citation statements)

References 30 publications

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“…As expected, knockdown of CSL, the key DNA-binding subunit of the Notch-containing transcriptional complex (Bray, 2006), led to a significant reduction of Notch activation. By contrast, silencing of USP12, a negative regulator of Notch signaling (Moretti et al, 2012), significantly increased Notch activity (233% over siNT). Strikingly, knockdown of either b-arrestins or ARRDC1 also induced Notch reporter activity (161% and 127%, respectively) showing that ARRDC1 and b-arrestins are negative regulators of Notch signaling.…”

Section: Arrdc1 Cooperates With B-arrestins On Notch Signalingmentioning

confidence: 99%

“…OP9-Dll1 and U2OS-FL cell lines were described previously (Six et al, 2004;Moretti et al, 2012). Mouse embryonic fibroblast (MEF) cells isolated from b-arrestin 1 and b-arrestin 2 double-knockout (DKO) embryos and matched wild-type (WT) embryos were provided by Robert J. Lefkowitz (Duke University, Durham, NC).…”

Section: Cell Lines and Transfectionsmentioning

confidence: 99%

“…In mammals, non-activated Notch receptor is constitutively internalized and ubiquitylated by Itch/AIP4 E3 ubiquitin ligase in order to be processed for lysosomal degradation (Chastagner et al, 2008). Moreover, the deubiquitylating complex USP12/ UAF1 is recruited by Itch to Notch and allows Notch deubiquitylation, probably before its entry into the intralumenal vesicles of the multivesicular bodies (MVBs) (Moretti et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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α-arrestin 1 (ARRDC1) and β-arrestins cooperate to mediate Notch degradation in mammals

Puca

Chastagner

Meas-Yedid

et al. 2013

Journal of Cell Science

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SummaryNotch signaling is a conserved signaling pathway implicated in embryogenesis and adult tissue maintenance. Notch signaling strength is strictly regulated, notably by maintaining a controlled pool of functional receptor at the cell surface. Mammalian non-activated Notch receptor is internalized, ubiquitylated by the Itch E3 ubiquitin ligase and degraded in the lysosomes. Here, we show that b-arrestins are necessary for Itch-Notch interaction and for Itch-driven ubiquitylation and degradation of Notch. Interestingly, b-arrestins do not directly bind Itch but heterodimerize with a member of another subfamily of arrestins called ARRDC1 or a-arrestin 1, which harbors PPxY motifs that allow direct interaction with Itch. Cells transfected with ARRDC1 mutated in PPxY motifs show reduced Itchmediated Notch ubiquitylation and impaired lysosomal degradation of Notch, as observed in b-arrestin 2/2 or Itch 2/2 cells. Our data show for the first time that ARRDC1 and b-arrestins heterodimerize and cooperate in the same complex to promote non-activated Notch receptor degradation, thus acting as negative regulators of Notch signaling.

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Section: Arrdc1 Cooperates With B-arrestins On Notch Signalingmentioning

confidence: 99%

Section: Cell Lines and Transfectionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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α-arrestin 1 (ARRDC1) and β-arrestins cooperate to mediate Notch degradation in mammals

Puca

Chastagner

Meas-Yedid

et al. 2013

Journal of Cell Science

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“…Both USP12 and USP46 interact with other proteins for their activation, including WD40 repeat-containing proteins and Usp1-associated factor 1 (UAF1; Kee et al 2010). USP12 has also been implicated as a negative regulator of Notch signalling, an evolutionarily conserved pathway that has key roles in the determination of cell fate (Moretti et al 2012).…”

Section: Endocrine-related Cancermentioning

confidence: 99%

Histone H2B monoubiquitination: roles to play in human malignancy

Cole¹,

Clifton‐Bligh²,

Marsh³

2014

Endocrine-Related Cancer

116

120

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Ubiquitination has traditionally been viewed in the context of polyubiquitination that is essential for marking proteins for degradation via the proteasome. Recent discoveries have shed light on key cellular roles for monoubiquitination, including as a post-translational modification (PTM) of histones such as histone H2B. Monoubiquitination plays a significant role as one of the largest histone PTMs, alongside smaller, better-studied modifications such as methylation, acetylation and phosphorylation. Monoubiquitination of histone H2B at lysine 120 (H2Bub1) has been shown to have key roles in transcription, the DNA damage response and stem cell differentiation. The H2Bub1 enzymatic cascade involves E3 RING finger ubiquitin ligases, with the main E3 generally accepted to be the RNF20-RNF40 complex, and deubiquitinases including ubiquitin-specific protease 7 (USP7), USP22 and USP44. H2Bub1 has been shown to physically disrupt chromatin strands, fostering a more open chromatin structure accessible to transcription factors and DNA repair proteins. It also acts as a recruiting signal, actively attracting proteins with roles in transcription and DNA damage. H2Bub1 also appears to play central roles in histone cross-talk, influencing methylation events on histone H3, including H3K4 and H3K79. Most significantly, global levels of H2Bub1 are low to absent in advanced cancers including breast, colorectal, lung and parathyroid, marking H2Bub1 and the enzymes that regulate it as key molecules of interest as possible new therapeutic targets for the treatment of cancer. This review offers an overview of current knowledge regarding H2Bub1 and highlights links between dysregulation of H2Bub1-associated enzymes, stem cells and malignancy.

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“…Usp12 has three reported targets; histones H2B, H2A (23), and nonactivated Notch (24). Usp12 is highly homologous to Usp46 and Usp1, and its activity, similar to that of Usp46, is enhanced by binding to its cofactors Uaf-1 and WDR20, with Uaf-1 required for enzymatic activity of Usp12 (25)(26)(27).…”

mentioning

confidence: 99%

Deubiquitinating Enzyme Usp12 Is a Novel Co-activator of the Androgen Receptor

Burska¹,

Harle²,

Coffey

et al. 2013

Journal of Biological Chemistry

111

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Background: Androgen receptor (AR) is the principle therapeutic target in prostate cancer. Result: We have established that Usp12 deubiquitinates and stabilizes the AR resulting in increased transcriptional and proproliferative activity. Conclusion:We have identified Usp12 to be a novel positive regulator of AR. Significance: Usp12 presents a therapeutic target upstream of AR that could enable bypassing the limitations of therapeutics aimed specifically at AR.

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The Ubiquitin-specific Protease 12 (USP12) Is a Negative Regulator of Notch Signaling Acting on Notch Receptor Trafficking toward Degradation

Cited by 58 publications

References 30 publications

α-arrestin 1 (ARRDC1) and β-arrestins cooperate to mediate Notch degradation in mammals

α-arrestin 1 (ARRDC1) and β-arrestins cooperate to mediate Notch degradation in mammals

Histone H2B monoubiquitination: roles to play in human malignancy

Deubiquitinating Enzyme Usp12 Is a Novel Co-activator of the Androgen Receptor

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