WNT secretion and signalling in human disease

Herr, Patrick; Hausmann, George; Basler, Konrad

doi:10.1016/j.molmed.2012.06.008

Cited by 141 publications

(105 citation statements)

References 109 publications

(102 reference statements)

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“…In humans, loss-of-function (LoF) mutations in the PORCN gene cause focal dermal hypoplasia, an X-linked dominant disorder associated with a variety of congenital abnormalities in both heterozygotes and those individuals with mosaicism for the PORCN gene. This phenotype is consistent with the role of the Wnt signaling pathway during embryogenesis and development (15).…”

supporting

confidence: 89%

“…Specific Wnt secretion inhibitors should be active in the Wnt coculture assay but not the HH coculture or Wnt3A CM assays. These compounds were further characterized to elucidate their potential targets, including the two known dedicated nodes required for Wnt secretion: Wntless, a 7-pass transmembrane protein that is responsible for Wnt intracellular trafficking, and PORCN (3,15).…”

Section: Resultsmentioning

confidence: 99%

“…Wnt pathway signaling activity is dependent on Wnt ligand. During the biosynthesis of Wnt ligands, Wnt undergoes posttranslational acylation (palmitoylation) that is mediated by Porcupine (PORCN), a membrane bound Oacyltransferase (3,15). PORCN is specific and dedicated to Wnt posttranslational acylation, which is required for subsequent Wnt secretion (16).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974

Pan

Hsieh

et al. 2013

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

685

620

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Wnt signaling is one of the key oncogenic pathways in multiple cancers, and targeting this pathway is an attractive therapeutic approach. However, therapeutic success has been limited because of the lack of therapeutic agents for targets in the Wnt pathway and the lack of a defined patient population that would be sensitive to a Wnt inhibitor. We developed a screen for small molecules that block Wnt secretion. This effort led to the discovery of LGK974, a potent and specific small-molecule Porcupine (PORCN) inhibitor. PORCN is a membrane-bound O-acyltransferase that is required for and dedicated to palmitoylation of Wnt ligands, a necessary step in the processing of Wnt ligand secretion. We show that LGK974 potently inhibits Wnt signaling in vitro and in vivo, including reduction of the Wnt-dependent LRP6 phosphorylation and the expression of Wnt target genes, such as AXIN2.LGK974 is potent and efficacious in multiple tumor models at well-tolerated doses in vivo, including murine and rat mechanistic breast cancer models driven by MMTV-Wnt1 and a human head and neck squamous cell carcinoma model (HN30). We also show that head and neck cancer cell lines with loss-of-function mutations in the Notch signaling pathway have a high response rate to LGK974. Together, these findings provide both a strategy and tools for targeting Wntdriven cancers through the inhibition of PORCN.Wnt inhibition | β-catenin | HNSCC

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supporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974

Pan

Hsieh

et al. 2013

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

685

620

View full text Add to dashboard Cite

show abstract

“…Mutations in a number of WNT pathway genes have now been associated with a variety of tumour types (e.g. Axin loss-of-4 function and constitutively activating ctnnb1 mutations; (Herr, et al 2012). …”

Section: Wnt Signaling In Cancermentioning

confidence: 99%

WNT Signaling in Cutaneous Squamous Cell Carcinoma: A Future Treatment Strategy?

Sherwood

Leigh

2016

Journal of Investigative Dermatology

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The molecular mechanisms underlying cutaneous squamous cell carcinoma are less well established than other common skin cancers, but recent evidence has highlighted a potentially critical role for WNT signaling in both the development and progression of cSCC.WNT pathways are aberrantly regulated in multiple tumour types (albeit in a context-dependent manner) and this has stimulated the development of WNT inhibitory compounds for cancer treatment. In this review, we examine existing evidence for a role of WNT signaling in cSCC and discuss if WNT inhibition represents a realistic therapeutic strategy for the future.2

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“…Aberrant regulation of the Wnt signaling pathway has been suggested to be involved in tumorigenesis (12). Three intracellular pathways are known to induce Wnt signaling: i) The Wnt-β-catenin signaling pathway, in which Wnt signaling alters transcription, and it is referred to as 'canonical' Wnt signaling (13); ii) the Wnt-Ca 2+ signaling pathway; and iii) the Wnt-c-Jun N-terminal kinase signaling pathway, which do not involve the nucleus or transcription, but rather drive cytoplasmic changes involving the actin cytoskeleton and intracellular calcium stores.…”

Section: Introductionmentioning

confidence: 99%

Low expression of secreted frizzled-related protein 2 and nuclear accumulation of β-catenin in aggressive nonfunctioning pituitary adenoma

Bai

Hong

et al. 2016

Oncology Letters

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Abstract. The identification of a specific molecular marker for aggressiveness of nonfunctioning pituitary adenomas (NFPAs) is urgently required in order to guide the clinical diagnosis and treatment of NFPAs. In the present study, low expression of secreted frizzled-related protein 2 (sFRP2) in NFPAs was demonstrated by reverse transcription-quantitative polymerase chain reaction, western blot and immunohistochemical analyses. The results confirmed an abnormal accumulation of free β-catenin in the nuclei of NFPAs, which is the core step for the activation of the Wnt canonical signaling pathway. Furthermore, cyclin D1 and c-Myc, the downstream proteins of the Wnt canonical signaling pathway, were overexpressed in aggressive NFPAs. These findings demonstrated the activation of the Wnt canonical signaling pathway in aggressive NFPAs. In addition, sFRP2 expression was observed to be inversely correlated to the aggressiveness of NFPAs. Therefore, sFRP2 may act as a tumor suppressor through modulation of the cellular cytosolic pool of β-catenin in NFPAs. Furthermore, the expression of sFRP2 may serve as a biomarker for NFPAs aggressiveness and prognosis.

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WNT secretion and signalling in human disease

Cited by 141 publications

References 109 publications

Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974

Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974

WNT Signaling in Cutaneous Squamous Cell Carcinoma: A Future Treatment Strategy?

Low expression of secreted frizzled-related protein 2 and nuclear accumulation of β-catenin in aggressive nonfunctioning pituitary adenoma

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