Merlin inhibits Wnt/β-catenin signaling by blocking LRP6 phosphorylation

Kim, Mi‐Hyun; S, Kim; Sh, Lee; Kim, Won‐Seok; Sohn, Moon‐Jun; Hs, Kim; J, Kim; Jho, Eek‐hoon

doi:10.1038/cdd.2016.54

Cited by 35 publications

(42 citation statements)

References 48 publications

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“…Thus, β-catenin avoids degradation by Axin-GSK3β-CK1-APC complexes. In the cytoplasm, β-catenin accumulates and enters the nucleus to activate different genes that regulate cellular proliferation and differentiation (25).…”

Section: Introductionmentioning

confidence: 99%

The Wnt inhibitor LGK-974 enhances radiosensitivity of HepG2 cells by modulating Nrf2 signaling

Tian

Shi

Chen

et al. 2017

International Journal of Oncology

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Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of antioxidant and detoxification activities that can eliminate reactive oxygen species (ROS) produced via irradiation. However, Nrf2 overexpression in liver cancer cells may cause both radioresistance and chemoresistance. Reducing Nrf2 levels can enhance the radiosensitivity of HepG2 cells. Wingless/int-3A (Wnt3A) is a Wnt family protein that mainly activates the canonical Wnt signaling pathway. Recent studies showed that the Axin1-GSK-3β protein complex, a component of the canonical Wnt signaling pathway, can capture Nrf2 and facilitate its ubiquitination and proteasomal degradation in the cytoplasm. This protein complex is degraded upon activation of the Wnt signaling pathway. In the present study, we treated HepG2 cells with the Wnt3A inhibitor LGK-974, an effective and specific PORCN inhibitor that can prevent the formation of a proper folding of the Wnt protein in the endoplasmic reticulum. We found that HepG2 cells became more sensitive to radiation with increasing LGK-974 concentrations. Upon 2 Gy or 4 Gy irradiation, the cells treated with LGK-974 more frequently underwent apoptosis and grew less rapidly. PCR and western blot results showed that inhibiting the secretion of Wnt3A blocked the Wnt signaling pathway and prevented Nrf2 signaling. Notably, the Wnt inhibitor may serve as a radiosensitizing drug.

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Section: Introductionmentioning

confidence: 99%

The Wnt inhibitor LGK-974 enhances radiosensitivity of HepG2 cells by modulating Nrf2 signaling

Tian

Shi

Chen

et al. 2017

International Journal of Oncology

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“…This inhibitory status is reversed when secreted WNT ligands bind to and activate Frizzled (FZD) transmembrane receptor and LRP coreceptor. The ensuing signaling events result in nuclear translocation of β-catenin and together with TCF/LEF transcription factors, culminate in activation of target gene expression [21].…”

Section: Wnt/β-catenin Signaling Pathwaymentioning

confidence: 99%

“…The fact that these type of tumors also show some levels of Merlin loss or inactivation [2,24] suggests a connection between Merlin and the WNT/β-catenin pathway. Moreover, Neurofibromatosis type 2 patients with schwannoma, a clinical manifestation of the disorder, accumulate high levels of βcatenin, further indicating that elevated WNT/ β-catenin signaling activity is associated with deficient Merlin expression [21].…”

Section: Wnt/β-catenin Signaling Pathwaymentioning

confidence: 99%

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Merlin regulates signaling events at the nexus of development and cancer

Mota

Shevde

2020

Cell Commun Signal

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Background: In this review, we describe how the cytoskeletal protein Merlin, encoded by the Neurofibromin 2 (NF2) gene, orchestrates developmental signaling to ensure normal ontogeny, and we discuss how Merlin deficiency leads to aberrant activation of developmental pathways that enable tumor development and malignant progression. Main body: Parallels between embryonic development and cancer have underscored the activation of developmental signaling pathways. Hippo, WNT/β-catenin, TGF-β, receptor tyrosine kinase (RTK), Notch, and Hedgehog pathways are key players in normal developmental biology. Unrestrained activity or loss of activity of these pathways causes adverse effects in developing tissues manifesting as developmental syndromes. Interestingly, these detrimental events also impact differentiated and functional tissues. By promoting cell proliferation, migration, and stem-cell like phenotypes, deregulated activity of these pathways promotes carcinogenesis and cancer progression. The NF2 gene product, Merlin, is a tumor suppressor classically known for its ability to induce contactdependent growth inhibition. Merlin plays a role in different stages of an organism development, ranging from embryonic to mature states. While homozygous deletion of Nf2 in murine embryos causes embryonic lethality, Merlin loss in adult tissue is implicated in Neurofibromatosis type 2 disorder and cancer. These manifestations, cumulatively, are reminiscent of dysregulated developmental signaling. Conclusion: Understanding the molecular and cellular repercussions of Merlin loss provides fundamental insights into the etiology of developmental disorders and cancer and has the potential, in the long term, to identify new therapeutic strategies.

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“…However, gain of function of the pathway by disruption of the Wnt/β-catenin inhibitor Axin2 can also result in coloboma, with persistent expression of MITF and OTX2 (19) similarly to Nf2 CKO . Importantly, several studies have shown that NF2 can associate with LRP6 and block its phosphorylation resulting in inhibition of Wnt/β-catenin pathway activation (97).…”

Section: Loss Of Nf2 Function Leads To a Narrow Coloboma In The Ventrmentioning

confidence: 99%

Nf2 fine-tunes proliferation and tissue alignment during closure of the optic fissure in the embryonic mouse eye

Sun

Ramirez

Spiller

et al. 2020

Preprint

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Uveal coloboma represents one of the most common congenital ocular malformations accounting for up to 10% of childhood blindness (1~ in 5,000 live birth). Coloboma originates from defective fusion of the optic fissure (OF), a transient gap that forms during eye morphogenesis by asymmetric, ventral invagination. Genetic heterogeneity combined with the activity of developmentally regulated genes suggest multiple mechanisms regulating OF closure. The tumor suppressor and FERM domain protein neurofibromin 2 (NF2) controls diverse processes in cancer, development and regeneration, via Hippo pathway and cytoskeleton regulation. In humans, NF2 mutations can cause ocular abnormalities, including coloboma, however, its actual role in OF closure is unknown. Using conditional inactivation in the embryonic mouse eye, our data indicates that loss of Nf2 function results in a novel underlying cause for coloboma. In particular, mutant eyes show substantially increased RPE proliferation in the fissure region with concomitant acquisition of RPE cell fate. Cells lining the OF margin can maintain RPE fate ectopically and fail to transition from neuroepithelial to cuboidal shape. In the dorsal RPE of the optic cup, Nf2 inactivation leads to a robust increase in cell number, with local disorganization of the cytoskeleton components F--actin and pMLC2. We propose that RPE hyperproliferation is the primary cause for the observed defects causing insufficient alignment of the OF margins in Nf2 mutants and failure to fuse properly, resulting in persistent coloboma. Our findings indicate that limiting proliferation particularly in the RPE layer is a critical mechanism during optic fissure closure.

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Merlin inhibits Wnt/β-catenin signaling by blocking LRP6 phosphorylation

Cited by 35 publications

References 48 publications

The Wnt inhibitor LGK-974 enhances radiosensitivity of HepG2 cells by modulating Nrf2 signaling

The Wnt inhibitor LGK-974 enhances radiosensitivity of HepG2 cells by modulating Nrf2 signaling

Merlin regulates signaling events at the nexus of development and cancer

Nf2 fine-tunes proliferation and tissue alignment during closure of the optic fissure in the embryonic mouse eye

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