Wnts as ligands: processing, secretion and reception

Mikels, Amanda; Nusse, Roel

doi:10.1038/sj.onc.1210053

Cited by 308 publications

(248 citation statements)

References 83 publications

(96 reference statements)

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“…In contrast, V2Nter enhanced CRT in this context (Figure 2a). Indeed, heparan sulfates attached to the 47-aa stretch common to the three C18 variants (Figure 1b) may locally increase Wnt concentration and thus CRT, as shown for C18 (Quelard et al, 2008) and for other heparan sulfate proteoglycans (Mikels and Nusse, 2006). Accordingly, the slope of the Wnt3a dose-response curve for V2Nter-HCT116 cells was steeper than that of the other cells, including Vector-HCT116 cells.…”

Section: Hct116 Colorectal Cancer Cells Stably Expressing V3ntermentioning

confidence: 88%

“…Interaction of Wnt ligands with the Frizzled receptors is enhanced by heparan sulfate glycosaminoglycans controlling Wnt diffusion at the cell surface (Mikels and Nusse, 2006) or inhibited by several families of extracellular antagonists (Kawano and Kypta, 2003;Bovolenta et al, 2008). Members of the Dickkopf (DKK) family antagonize canonical signaling by binding to LRP5/6, thus disrupting the Wnt-induced Frizzled-LRP5/6 complex (MacDonald et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Blocking Wnt signaling by SFRP-like molecules inhibits in vivo cell proliferation and tumor growth in cells carrying active β-catenin

et al. 2010

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Constitutive activation of Wnt/b-catenin signaling in cancer results from mutations in pathway components, which frequently coexist with autocrine Wnt signaling or epigenetic silencing of extracellular Wnt antagonists. Among the extracellular Wnt inhibitors, the secreted frizzled-related proteins (SFRPs) are decoy receptors that contain soluble Wnt-binding frizzled domains. In addition to SFRPs, other endogenous molecules harboring frizzled motifs bind to and inhibit Wnt signaling. One of such molecules is V3Nter, a soluble SFRP-like frizzled polypeptide that binds to Wnt3a and inhibits Wnt signaling and expression of the b-catenin target genes cyclin D1 and c-myc. V3Nter is derived from the cell surface extracellular matrix component collagen XVIII. Here, we used HCT116 human colon cancer cells carrying the DS45 activating mutation in one of the alleles of b-catenin to show that V3Nter and SFRP-1 decrease baseline and Wnt3a-induced b-catenin stabilization. Consequently, V3Nter reduces the growth of human colorectal cancer xenografts by specifically controlling cell proliferation and cell cycle progression, without affecting angiogenesis or apoptosis, as shown by decreased

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Section: Hct116 Colorectal Cancer Cells Stably Expressing V3ntermentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Blocking Wnt signaling by SFRP-like molecules inhibits in vivo cell proliferation and tumor growth in cells carrying active β-catenin

et al. 2010

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“…2C, we observed that both Wnt3 and FZD7 proteins were present in the tumor cells; peritumoral areas, however, revealed reduced expression. Following secretion, Wnt proteins are hydrophobic and found associated with the extracellular matrix as well as on the cell surface where activation of signaling takes place [24]. These results suggest that Wnt3 could stimulate FZD7 via autocrine or paracrine mechanisms(s) in HBV-related HCC.…”

Section: Expression Of Wnt3 Fzd7 and β-Catenin Target Genes In Humamentioning

confidence: 92%

Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/β-catenin signaling pathway in hepatocellular carcinoma cells

Kim¹,

Lee²,

Tsedensodnom³

et al. 2008

Journal of Hepatology

171

173

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Background/Aims-The canonical Wnt signaling is frequently activated in human hepatocellular carcinoma (HCC). We previously demonstrated that up-regulation of Frizzled-7 receptor (FZD7) in HCC was associated with nuclear accumulation of wild-type β-catenin. Here, we investigated Wnt ligand(s) that may activate the Wnt/β-catenin pathway through FZD7 in HCC cells. Results-In hepatitis B virus (HBV)-induced HCC, Wnt3 was upregulated in tumor and peritumoral tissues compared to normal liver and downstream β-catenin target genes were also increased in these samples. Activation of the Wnt/β-catenin pathway in FOCUS-Wnt3 cells was demonstrated by β-catenin accumulation, enhanced TCF transcriptional activity and proliferation rate. The activation of Wnt/β-catenin signaling in FOCUS-Wnt3 was abolished by a knockdown of FZD7 expression by siRNA. More important, a specific Wnt3-FZD7 interaction was observed by co-immunoprecipitation experiments, which suggest that the action of Wnt3 was mediated via FZD7. Methods-To identifyConclusions-These findings demonstrate a functional interaction between Wnt3 and FZD7 leading to activation of the Wnt/β-catenin signaling pathway in HCC cells and may play a role during hepatocarcinogenesis.

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“…During canonical signaling, secreted Wnt ligands bind to their Frizzled receptors to induce cytoplasmic accumulation and nuclear translocation of β-catenin (Clevers and Nusse, 2012;Mikels and Nusse, 2006), which is the key intracellular component of the transduction cascade. In the nucleus, β-catenin binds to the TCF/LEF transcription factors, triggering changes in chromatin conformation and gene transcription (Komiya and Habas, 2008;Valenta et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Localization of planarian β-CATENIN-1 reveals multiple roles during anterior-posterior regeneration and organogenesis

2016

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The β-catenin-dependent Wnt pathway exerts multiple contextdependent roles in embryonic and adult tissues. In planarians, β-catenin-1 is thought to specify posterior identities through the generation of an anteroposterior gradient. However, the existence of such a gradient has not been directly demonstrated. Here, we use a specific polyclonal antibody to demonstrate that nuclear β-CATENIN-1 exists as an anteroposterior gradient from the pre-pharyngeal region to the tail of the planarian Schmidtea polychroa. High levels in the posterior region steadily decrease towards the pre-pharyngeal region but then increase again in the head region. During regeneration, β-CATENIN-1 is nuclearized in both anterior and posterior blastemas, but the canonical WNT1 ligand only influences posterior nuclearization. Additionally, β-catenin-1 is required for proper anterior morphogenesis, consistent with the high levels of nuclear β-CATENIN-1 observed in this region. We further demonstrate that β-CATENIN-1 is abundant in developing and differentiated organs, and is particularly required for the specification of the germline. Altogether, our findings provide the first direct evidence of an anteroposterior nuclear β-CATENIN-1 gradient in adult planarians and uncover novel, context-dependent roles for β-catenin-1 during anterior regeneration and organogenesis.

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Wnts as ligands: processing, secretion and reception

Cited by 308 publications

References 83 publications

Blocking Wnt signaling by SFRP-like molecules inhibits in vivo cell proliferation and tumor growth in cells carrying active β-catenin

Blocking Wnt signaling by SFRP-like molecules inhibits in vivo cell proliferation and tumor growth in cells carrying active β-catenin

Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/β-catenin signaling pathway in hepatocellular carcinoma cells

Localization of planarian β-CATENIN-1 reveals multiple roles during anterior-posterior regeneration and organogenesis

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