Trabid, a new positive regulator of Wnt-induced transcription with preference for binding and cleaving K63-linked ubiquitin chains

Tran, Hoanh; Hamada, Fumihiko; Schwarz-Romond, Thomas; Bienz, Mariann

doi:10.1101/gad.463208

Cited by 110 publications

(182 citation statements)

References 68 publications

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“…FuGENE 6 HD (Roche Applied Science) was used for plasmid transfection in RPE cells. Epitope-tagged Trabid, HectD1, APC, Tankyrase (TNKS1) and RNF146 constructs have been described (17,24,25). Recombinant mouse Wnt3a was purchased from R & D Systems.…”

Section: Methodsmentioning

confidence: 99%

“…Through its DUB activity, UBPY facilitates the recycling of ubiquitylated Frizzled receptors from endosomal compartments to the plasma membrane (23). Further downstream, Trabid is a DUB that appears to promote Wnt signaling in the nucleus, but its relevant target(s) in this compartment have not been identified (24). Interestingly, siRNA knockdown of Trabid caused accumulation of polyubiquitin chains on APC, implicating APC as an enzymatic target (24).…”

mentioning

confidence: 99%

“…Further downstream, Trabid is a DUB that appears to promote Wnt signaling in the nucleus, but its relevant target(s) in this compartment have not been identified (24). Interestingly, siRNA knockdown of Trabid caused accumulation of polyubiquitin chains on APC, implicating APC as an enzymatic target (24). We have established that APC is modified predominantly with Lys-63-linked polyubiquitin in cells, relative to Lys-11-and Lys-48-linked chains (14), but the functional significance of Lys-63 adducts on APC remains unclear.…”

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confidence: 99%

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HectD1 E3 Ligase Modifies Adenomatous Polyposis Coli (APC) with Polyubiquitin to Promote the APC-Axin Interaction

Tran

Bustos²,

Yeh³

et al. 2013

Journal of Biological Chemistry

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Section: Methodsmentioning

confidence: 99%

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HectD1 E3 Ligase Modifies Adenomatous Polyposis Coli (APC) with Polyubiquitin to Promote the APC-Axin Interaction

Tran

Bustos²,

Yeh³

et al. 2013

Journal of Biological Chemistry

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“…USP34 regulates AXIN1/2 stability and opposes its tankyrase (TNKS)-dependent ubiquitylation, hence functioning as a positive regulator of Wnt signaling (17). TRABID also positively regulates Wnt signaling by deubiquitylating adenomatous polyposis coli (APC) and regulating the stability of the β-catenin/ TCF transcription complex (18). USP47 and USP4 can directly regulate β-catenin deubiquitylation (19,20).…”

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confidence: 99%

USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds

Madan

Walker

Young

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The Wnt signaling pathways play pivotal roles in carcinogenesis. Modulation of the cell-surface abundance of Wnt receptors is emerging as an important mechanism for regulating sensitivity to Wnt ligands. Endocytosis and degradation of the Wnt receptors Frizzled (Fzd) and lipoprotein-related protein 6 (LRP6) are regulated by the E3 ubiquitin ligases zinc and ring finger 3 (ZNRF3) and ring finger protein 43 (RNF43), which are disrupted in cancer. In a genome-wide small interfering RNA screen, we identified the deubiquitylase ubiquitin-specific protease 6 (USP6) as a potent activator of Wnt signaling. USP6 enhances Wnt signaling by deubiquitylating Fzds, thereby increasing their cell-surface abundance. Chromosomal translocations in nodular fasciitis result in USP6 overexpression, leading to transcriptional activation of the Wnt/β-catenin pathway. Inhibition of Wnt signaling using Dickkopf-1 (DKK1) or a Porcupine (PORCN) inhibitor significantly decreased the growth of USP6-driven xenograft tumors, indicating that Wnt signaling is a key target of USP6 during tumorigenesis. Our study defines an additional route to ectopic Wnt pathway activation in human disease, and identifies a potential approach to modulate Wnt signaling for therapeutic benefit.

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“…Conversely, USP34 acts as a positive regulator of Wnt signaling by hindering b-catenin-dependent transcription (Lui et al, 2011). Furthermore, TRABID is a DUB critically involved in T-cell factor (TCF)-mediated transcription of Wnt genes that also shows the ability to deubiquitylate APC (Tran et al, 2008).…”

Section: Signaling Pathwaysmentioning

confidence: 99%

Deubiquitinases in cancer: new functions and therapeutic options

et al. 2011

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Deubiquitinases (DUBs) have fundamental roles in the ubiquitin system through their ability to specifically deconjugate ubiquitin from targeted proteins. The human genome encodes at least 98 DUBs, which can be grouped into 6 families, reflecting the need for specificity in their function. The activity of these enzymes affects the turnover rate, activation, recycling and localization of multiple proteins, which in turn is essential for cell homeostasis, protein stability and a wide range of signaling pathways. Consistent with this, altered DUB function has been related to several diseases, including cancer. Thus, multiple DUBs have been classified as oncogenes or tumor suppressors because of their regulatory functions on the activity of other proteins involved in tumor development. Therefore, recent studies have focused on pharmacological intervention on DUB activity as a rationale to search for novel anticancer drugs. This strategy may benefit from our current knowledge of the physiological regulatory mechanisms of these enzymes and the fact that growth of several tumors depends on the normal activity of certain DUBs. Further understanding of these processes may provide answers to multiple remaining questions on DUB functions and lead to the development of DUB-targeting strategies to expand the repertoire of molecular therapies against cancer.

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Trabid, a new positive regulator of Wnt-induced transcription with preference for binding and cleaving K63-linked ubiquitin chains

Abstract: [Keywords: Wnt pathway; ␤-catenin; APC tumour suppressor; deubiquitylation; K63-linked ubiquitin; NZF zinc finger; transcription] Supplemental material is available at http://www.genesdev.org.

Cited by 110 publications

References 68 publications

HectD1 E3 Ligase Modifies Adenomatous Polyposis Coli (APC) with Polyubiquitin to Promote the APC-Axin Interaction

HectD1 E3 Ligase Modifies Adenomatous Polyposis Coli (APC) with Polyubiquitin to Promote the APC-Axin Interaction

USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds

Deubiquitinases in cancer: new functions and therapeutic options

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