Modulation of Wnt–β-catenin signaling with antibodies: therapeutic opportunities and challenges

O'Brien, Siobhan; Chidiac, Rony; Angers, Stéphane

doi:10.1016/j.tips.2023.03.008

Cited by 13 publications

(8 citation statements)

References 71 publications

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“…Our experiments indicated that overexpressing ZBED3 reinstates the tumor-suppressive effects observed upon NSUN5 knockdown in Huh7 and Hep 3B cells. Additionally, since GSEA revealed that NSUN5 plays a role in the Wnt signaling pathway, where ZBED3 serves as a crucial mediator, we assessed the expression levels of key signaling molecules, such as β-catenin, c-Myc, and AXIN1 [ 37 , 38 ]. Consequently, we observed a close association between NSUN5-associated tumorigenesis and the Wnt/β-catenin pathway.…”

Section: Discussionmentioning

confidence: 99%

RNA 5-methylcytosine writer NSUN5 promotes hepatocellular carcinoma cell proliferation via a ZBED3-dependent mechanism

Gu,

Li,

Gao

et al. 2024

Oncogene

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Hepatocellular carcinoma (HCC) is one of the leading contributors to cancer-related mortality worldwide. Nop2/Sun domain family member 5 (NSUN5), a conserved RNA 5-methylcytosine methyltransferase, is conventionally recognized as oncogenic. However, its role in HCC development remains unknown. In this study, we observed a remarkable upregulation of NSUN5 expression in both tumor tissues from patients with HCC, establishing a correlation with unfavorable clinical outcomes. NSUN5 knockdown and overexpression significantly inhibited and promoted HCC cell proliferation, respectively. Additionally, employing a combination of methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RIP-seq techniques, we identified zinc finger BED domain-containing protein 3 (ZBED3) as a novel downstream target of NSUN5. Additionally, we found that the overexpression of ZBED3 counteracted the tumor-suppressing effect of NSUN5 knockdown and simultaneously reversed the inhibition of the Wnt/β-catenin signaling pathway. In summary, we elucidated the oncogenic role of NSUN5 in HCC development and identified the ZBED3/Wnt/β-catenin signaling pathway as its downstream target. This study provides a novel therapeutic target for further development in HCC treatment.

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Section: Discussionmentioning

confidence: 99%

RNA 5-methylcytosine writer NSUN5 promotes hepatocellular carcinoma cell proliferation via a ZBED3-dependent mechanism

Gu,

Li,

Gao

et al. 2024

Oncogene

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“…With 10 different Fzd subtypes and 19 different Wnts, along with Norrin, in the human genome, exquisite spatial and temporal signaling specificity is achieved through differential expression patterns (Nusse and Varmus, 1992) and pairwise affinities (Dijksterhuis et al, 2015) of the receptors and ligands. Specificity is also achieved through the expression of accessory proteins or co-receptors that modulate the expression levels, activity, or localization of core pathway components (Cruciat and Niehrs, 2013;Schulte, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, the tetraspanin Tspan12 is required for Norrin-directed retinal angiogenesis and maintenance of the BRB (Junge et al, 2009). Mutations in Norrin, Fzd4, LRP5, β -catenin, and Tspan12 are associated with inherited diseases of the retinal vasculature, most notably Familial Exudative Vitreoretinopathy (FEVR) (Jiao et al, 2004; Nikopoulos et al, 2010; Panagiotou et al, 2017; Poulter et al, 2010; Robitaille et al, 2002; Shastry et al, 1997; Toomes et al, 2004), and therapeutic targeting of Norrin/ β -catenin signaling shows promise for modulating the BRB and BBB (Chidiac et al, 2021; Ding et al, 2023; Nguyen et al, 2022; O’Brien et al, 2023; Phoenix et al, 2016). However, the mechanism by which Tspan12 promotes Norrin signaling is unclear.…”

Section: Introductionmentioning

confidence: 99%

The co-receptor Tspan12 directly captures Norrin to promote ligand-specific β-catenin signaling

Bruguera,

Mahoney,

Weis

2024

Preprint

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Wnt/β-catenin signaling directs animal development and tissue renewal in a tightly controlled, cell- and tissue-specific manner. In the central nervous system, the atypical ligand Norrin controls angiogenesis and maintenance of the blood-brain barrier and blood-retina barrier through the Wnt/β-catenin pathway. Like Wnt, Norrin activates signaling by binding and heterodimerizing the receptors Frizzled (Fzd) and Low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6), leading to membrane recruitment of the intracellular transducer Dishevelled (Dvl); this ultimately results in the stabilization of the transcriptional coactivator β-catenin. Unlike Wnt, the cysteine-knot ligand Norrin only signals through Fzd4 and additionally requires the co-receptor Tspan12; however, the mechanism underlying Tspan12-mediated signal enhancement is unclear. It has been proposed that Tspan12 integrates into the Norrin-Fzd4 complex to enhance Norrin-Fzd4 affinity or otherwise allosterically modulate Fzd4 signaling. Here, we measure direct, high-affinity binding between purified Norrin and Tspan12 in a lipid environment and use AlphaFold models to interrogate this interaction interface. We find that Tspan12 and Fzd4 can simultaneously bind Norrin and that a pre-formed Tspan12/Fzd4 heterodimer, as well as cells co-expressing Tspan12 and Fzd4, more efficiently capture low concentrations of Norrin than Fzd4 alone. We also show that Tspan12 competes with both heparan sulfate proteoglycans and LRP6 for Norrin binding and that Tspan12 does not impact Fzd4-Dvl affinity in the presence or absence of Norrin. Our findings suggest that Tspan12 does not allosterically enhance Fzd4 binding to Norrin or Dvl, but instead functions to directly capture Norrin upstream of signaling.

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“…Furthermore, as inhibition of GSK3 occurs distally in the signaling pathway, it bypasses normal regulatory mechanisms in place to achieve efficient patterning. The recent development of synthetic growth factors that selectively target receptors to activate signaling holds the potential to enhance DA neuron differentiation methods by providing a more precise and controlled activation of Wnt/β-catenin signaling ( O'Brien et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Exploiting spatiotemporal regulation of FZD5 during neural patterning for efficient ventral midbrain specification

Yang,

Chidiac,

Russo

et al. 2024

Development

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The Wnt/β-catenin signaling governs anterior-posterior neural patterning during development. Current hPSC differentiation protocols utilize a GSK3 inhibitor to activate Wnt signaling to promote posterior neural fate specification. However, GSK3 is a pleiotropic kinase involved in multiple signaling pathways and since GSK3 inhibition occurs downstream in the signaling cascade, it bypasses potential opportunities for achieving specificity or regulation at the receptor level. Additionally, the specific roles of individual FZD receptors in anterior-posterior patterning are poorly understood. Here, we characterized the cell surface expression of FZD receptors in neural progenitor cells with different regional identity. Our data reveals unique upregulation of FZD5 expression in anterior neural progenitors, and the expression is downregulated as cells adopt a posterior fate. This spatial regulation of FZD expression constitutes a novel regulatory mechanism adjusting the levels of β-catenin signaling along the anterior-posterior axis and possibly contribute to midbrain-hindbrain boundary formation. Stimulation of Wnt/β-catenin signaling in hPSC with a tetravalent antibody, which selectively triggers FZD5 and LRP6 clustering, leads to midbrain progenitor differentiation and give rise to functional dopaminergic neurons in vitro and in vivo.

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Modulation of Wnt–β-catenin signaling with antibodies: therapeutic opportunities and challenges

Cited by 13 publications

References 71 publications

RNA 5-methylcytosine writer NSUN5 promotes hepatocellular carcinoma cell proliferation via a ZBED3-dependent mechanism

RNA 5-methylcytosine writer NSUN5 promotes hepatocellular carcinoma cell proliferation via a ZBED3-dependent mechanism

The co-receptor Tspan12 directly captures Norrin to promote ligand-specific β-catenin signaling

Exploiting spatiotemporal regulation of FZD5 during neural patterning for efficient ventral midbrain specification

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