Loss of Tankyrase-Mediated Destruction of 3BP2 Is the Underlying Pathogenic Mechanism of Cherubism

Levaot, Noam; Voytyuk, Oleksandr; Dimitriou, Ioannis D.; Sircoulomb, Fabrice; Chandrakumar, Arun A.; Deckert, Marcel; Krzyzanowski, Paul M.; Scotter, Andrew J; Gu, Shengqing; Janmohamed, Salima; Cong, Feng; Simoncic, Paul D.; Ueki, Yasuyoshi; Rose, José La; Rottapel, Robert

doi:10.1016/j.cell.2011.10.045

Cited by 173 publications

(234 citation statements)

References 35 publications

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“…Interestingly, RNF146 displayed a diffuse localization and colocalization with any of these junctional markers was not enriched. This is consistent with the multifunctional role of RNF146 in targeting a broad range of cellular substrates Levaot et al, 2011;Li et al, 2015;Zhang et al, 2011).…”

Section: Knockdown Of Rnf146 Results In Mislocalization Of Pals1 and supporting

confidence: 86%

The RNF146/Tankyrase pathway maintains the junctional Crumbs complex through regulation of Angiomotin

Campbell

Samavarchi-Tehrani

Barrios‐Rodiles

et al. 2016

Journal of Cell Science

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The Crumbs complex is an important determinant of epithelial apicalbasal polarity that functions in regulation of tight junctions, resistance to epithelial-to-mesenchymal transitions and as a tumour suppressor. Although the functional role of the Crumbs complex is being elucidated, its regulation is poorly understood. Here, we show that suppression of RNF146, an E3 ubiquitin ligase that recognizes ADP-ribosylated substrates, and tankyrase, a poly(ADP-ribose) polymerase, disrupts the junctional Crumbs complex and disturbs the function of tight junctions. We show that RNF146 binds a number of polarity-associated proteins, in particular members of the angiomotin (AMOT) family. Accordingly, AMOT proteins are ADPribosylated by TNKS2, which drives ubiquitylation by RNF146 and subsequent degradation. Ablation of RNF146 or tankyrase, as well as overexpression of AMOT, led to the relocation of PALS1 (a Crumbs complex component) from the apical membrane to internal puncta, a phenotype that is rescued by AMOTL2 knockdown. We thus reveal a new function of RNF146 and tankyrase in stabilizing the Crumbs complex through downregulation of AMOT proteins at the apical membrane.

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Section: Knockdown Of Rnf146 Results In Mislocalization Of Pals1 and supporting

confidence: 86%

The RNF146/Tankyrase pathway maintains the junctional Crumbs complex through regulation of Angiomotin

Campbell

Samavarchi-Tehrani

Barrios‐Rodiles

et al. 2016

Journal of Cell Science

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“…Similarly, 3BP2 is substrate of ARTD5 and RNF146. Mutants in 3BP2, associated with cherubism, prevent the binding of ARTD5/6 and thus reduce PARylation, leading to increased protein stability 26,27 . These findings define PARylation as a signal to mediate K48-linked pUb.…”

Section: Discussionmentioning

confidence: 99%

Regulation of NF-κB signalling by the mono-ADP-ribosyltransferase ARTD10

et al. 2013

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Adenosine diphosphate-ribosylation is a post-translational modification mediated by intracellular and membrane-associated extracellular enzymes and many bacterial toxins. The intracellular enzymes modify their substrates either by poly-ADP-ribosylation, exemplified by ARTD1/PARP1, or by mono-ADP-ribosylation. The latter has been discovered only recently, and little is known about its physiological relevance. The founding member of mono-ADPribosyltransferases is ARTD10/PARP10. It possesses two ubiquitin-interaction motifs, a unique feature among ARTD/PARP enzymes. Here, we find that the ARTD10 ubiquitininteraction motifs bind to K63-linked poly-ubiquitin, a modification that is essential for NF-kB signalling. We therefore studied the role of ARTD10 in this pathway. ARTD10 inhibits the activation of NF-kB and downstream target genes in response to interleukin-1b and tumour necrosis factor-a, dependent on catalytic activity and poly-ubiquitin binding of ARTD10. Mechanistically ARTD10 interferes with poly-ubiquitination of NEMO, which interacts with and is a substrate of ARTD10. Our findings identify a novel regulator of NF-kB signalling and provide evidence for cross-talk between K63-linked poly-ubiquitination and mono-ADPribosylation.

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“…Tankyrase also PARylates and promotes the degradation of 3BP2, a component of a multiprotein signaling complex, through RNF146-mediated ubiquitylation. Interestingly, mutations in Sh3bp2, the gene encoding 3BP2, uncouple 3BP2 from tankyrase-mediated degradation, resulting in (1) the stabilization of 3BP2, (2) the subsequent hyperactivation of cellular signaling pathways, and (3) cherubism, a syndrome characterized by inflammatory destructive lesions, resulting in symmetrical deformities of the facial bones (Guettler et al 2011;Levaot et al 2011). The intriguing link between PARP-mediated PARylation and E3 ligasedependent ubiquitylation is likely to be a key component in the function of PARP family members in various other physiological and pathological processes.…”

Section: Regulating Parp-1 Through Post-translational Modificationsmentioning

confidence: 99%

On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1

Luo¹,

Kraus²

2012

Genes Dev.

603

602

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Cellular stress responses are mediated through a series of regulatory processes that occur at the genomic, transcriptional, post-transcriptional, translational, and posttranslational levels. These responses require a complex network of sensors and effectors from multiple signaling pathways, including the abundant and ubiquitous nuclear enzyme poly(ADP-ribose) (PAR) polymerase-1 (PARP-1). PARP-1 functions at the center of cellular stress responses, where it processes diverse signals and, in response, directs cells to specific fates (e.g., DNA repair vs. cell death) based on the type and strength of the stress stimulus. Many of PARP-1's functions in stress response pathways are mediated by its regulated synthesis of PAR, a negatively charged polymer, using NAD + as a donor of ADP-ribose units. Thus, PARP-1's functions are intimately tied to nuclear NAD + metabolism and the broader metabolic profile of the cell. Recent studies in cell and animal models have highlighted the roles of PARP-1 and PAR in the response to a wide variety of extrinsic and intrinsic stress signals, including those initiated by oxidative, nitrosative, genotoxic, oncogenic, thermal, inflammatory, and metabolic stresses. These responses underlie pathological conditions, including cancer, inflammation-related diseases, and metabolic dysregulation. The development of PARP inhibitors is being pursued as a therapeutic approach to these conditions. In this review, we highlight the newest findings about PARP-1's role in stress responses in the context of the historical data.Poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) is the most abundant and ubiquitous member of a family of 17 related mammalian proteins. Studies over the past two decades, complemented by some exciting recent reports, have begun to crystallize a clearer view of one of the most robust and consistent functions of PARP-1 across biological systems: as a stress sensor and a stress response mediator. In this review, we highlight the newest findings in this area in the context of the historical data. We did not attempt to provide a comprehensive review, but rather opted to focus on key findings that have clarified the role of PARP-1 (and related PARPs) in stress responses. The reader is directed to a variety of other excellent reviews that cover other aspects of PARP-1 biology (D

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Loss of Tankyrase-Mediated Destruction of 3BP2 Is the Underlying Pathogenic Mechanism of Cherubism

Cited by 173 publications

References 35 publications

The RNF146/Tankyrase pathway maintains the junctional Crumbs complex through regulation of Angiomotin

The RNF146/Tankyrase pathway maintains the junctional Crumbs complex through regulation of Angiomotin

Regulation of NF-κB signalling by the mono-ADP-ribosyltransferase ARTD10

On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1

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