Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
???displayArticle.abstract??? Merlin, encoded by the NF2 gene, is a tumor suppressor that acts by inhibiting mitogenic signaling and is mutated in Neurofibromatosis type II (NF2) disease, although its molecular mechanism is not fully understood. Here, we observed that Merlin inhibited Wnt/β-catenin signaling by blocking phosphorylation of LRP6, which is necessary for Wnt signal transduction, whereas mutated Merlin in NF2 patients did not. Treatment with Wnt3a enhanced phosphorylation of Ser518 in Merlin via activation of PAK1 in a PIP2-dependent manner. Phosphorylated Merlin dissociated from LRP6, allowing for phosphorylation of LRP6. Tissues from NF2 patients exhibited higher levels of β-catenin, and proliferation of RT4-D6P2T rat schwannoma cells was significantly reduced by treatment with chemical inhibitors of Wnt/β-catenin signaling. Taken together, our findings suggest that sustained activation of Wnt/β-catenin signaling due to abrogation of Merlin-mediated inhibition of LRP6 phosphorylation may be a cause of NF2 disease.
Abramowicz,
Neurofibromin in neurofibromatosis type 1 - mutations in NF1gene as a cause of disease.
2014, Pubmed
Abramowicz,
Neurofibromin in neurofibromatosis type 1 - mutations in NF1gene as a cause of disease.
2014,
Pubmed Ahronowitz,
Mutational spectrum of the NF2 gene: a meta-analysis of 12 years of research and diagnostic laboratory findings.
2007,
Pubmed Anastas,
WNT signalling pathways as therapeutic targets in cancer.
2013,
Pubmed Baron,
WNT signaling in bone homeostasis and disease: from human mutations to treatments.
2013,
Pubmed Beauchamp,
A high-throughput kinome screen reveals serum/glucocorticoid-regulated kinase 1 as a therapeutic target for NF2-deficient meningiomas.
2015,
Pubmed Bosco,
NF2-deficient cells depend on the Rac1-canonical Wnt signaling pathway to promote the loss of contact inhibition of proliferation.
2010,
Pubmed Bretscher,
ERM-Merlin and EBP50 protein families in plasma membrane organization and function.
2000,
Pubmed Chen,
Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer.
2009,
Pubmed Chen,
High-efficiency transformation of mammalian cells by plasmid DNA.
1987,
Pubmed Clevers,
Wnt/β-catenin signaling and disease.
2012,
Pubmed Collu,
Wnt-Notch signalling crosstalk in development and disease.
2014,
Pubmed Emami,
A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected].
2004,
Pubmed Gabev,
Binding of neomycin to phosphatidylinositol 4,5-bisphosphate (PIP2).
1989,
Pubmed Guo,
Signaling cross-talk between TGF-beta/BMP and other pathways.
2009,
Pubmed Gutmann,
Functional analysis of neurofibromatosis 2 (NF2) missense mutations.
2001,
Pubmed Hadfield,
Rates of loss of heterozygosity and mitotic recombination in NF2 schwannomas, sporadic vestibular schwannomas and schwannomatosis schwannomas.
2010,
Pubmed Harvey,
The Hippo pathway and human cancer.
2013,
Pubmed Heasman,
Patterning the early Xenopus embryo.
2006,
Pubmed
,
Xenbase Hu,
Convergence between Wnt-β-catenin and EGFR signaling in cancer.
2010,
Pubmed Huang,
Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling.
2009,
Pubmed Kim,
ADP-ribosylation factors 1 and 6 regulate Wnt/β-catenin signaling via control of LRP6 phosphorylation.
2013,
Pubmed Kim,
Wnt/β-catenin signalling: from plasma membrane to nucleus.
2013,
Pubmed Lallemand,
Merlin regulates transmembrane receptor accumulation and signaling at the plasma membrane in primary mouse Schwann cells and in human schwannomas.
2009,
Pubmed Lallemand,
NF2 deficiency promotes tumorigenesis and metastasis by destabilizing adherens junctions.
2003,
Pubmed Lee,
Neurofibromatosis 2 (NF2) controls the invasiveness of glioblastoma through YAP-dependent expression of CYR61/CCN1 and miR-296-3p.
2016,
Pubmed Li,
Merlin/NF2 loss-driven tumorigenesis linked to CRL4(DCAF1)-mediated inhibition of the hippo pathway kinases Lats1 and 2 in the nucleus.
2014,
Pubmed Li,
Merlin/NF2 suppresses tumorigenesis by inhibiting the E3 ubiquitin ligase CRL4(DCAF1) in the nucleus.
2010,
Pubmed Li,
Wnt signaling through inhibition of β-catenin degradation in an intact Axin1 complex.
2012,
Pubmed MacDonald,
Wnt/beta-catenin signaling: components, mechanisms, and diseases.
2009,
Pubmed
,
Xenbase Maitra,
The tumor suppressors Merlin and Expanded function cooperatively to modulate receptor endocytosis and signaling.
2006,
Pubmed McClatchey,
Merlin and the ERM proteins--regulators of receptor distribution and signaling at the cell cortex.
2009,
Pubmed Okada,
Shedding light on Merlin's wizardry.
2007,
Pubmed Pan,
Wnt3a-mediated formation of phosphatidylinositol 4,5-bisphosphate regulates LRP6 phosphorylation.
2008,
Pubmed
,
Xenbase Pan,
The hippo signaling pathway in development and cancer.
2010,
Pubmed Pilot,
Spatial control of actin organization at adherens junctions by a synaptotagmin-like protein Btsz.
2006,
Pubmed Regimbald-Dumas,
Wnt signalling: What The X@# is WTX?
2011,
Pubmed Rong,
Serine 518 phosphorylation modulates merlin intramolecular association and binding to critical effectors important for NF2 growth suppression.
2004,
Pubmed Shaw,
The Nf2 tumor suppressor, merlin, functions in Rac-dependent signaling.
2001,
Pubmed Sher,
The tumor suppressor merlin controls growth in its open state, and phosphorylation converts it to a less-active more-closed state.
2012,
Pubmed Smith,
Dorsalization and neural induction: properties of the organizer in Xenopus laevis.
1983,
Pubmed
,
Xenbase Strochlic,
Phosphoinositides are essential coactivators for p21-activated kinase 1.
2010,
Pubmed
,
Xenbase Surace,
Effect of merlin phosphorylation on neurofibromatosis 2 (NF2) gene function.
2004,
Pubmed Tamai,
A mechanism for Wnt coreceptor activation.
2004,
Pubmed
,
Xenbase Tanneberger,
Amer1/WTX couples Wnt-induced formation of PtdIns(4,5)P2 to LRP6 phosphorylation.
2011,
Pubmed Wu,
Rac1 activation controls nuclear localization of beta-catenin during canonical Wnt signaling.
2008,
Pubmed Yeo,
FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine.
2016,
Pubmed Yu,
The Hippo pathway: regulators and regulations.
2013,
Pubmed Zeng,
A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation.
2005,
Pubmed
,
Xenbase Zhou,
Merlin-deficient human tumors show loss of contact inhibition and activation of Wnt/β-catenin signaling linked to the PDGFR/Src and Rac/PAK pathways.
2011,
Pubmed Zhu,
A Rac1/PAK1 cascade controls β-catenin activation in colon cancer cells.
2012,
Pubmed
