Merlin regulates signaling events at the nexus of development and cancer

Mota, Mateus; Shevde, Lalita A.

doi:10.1186/s12964-020-00544-7

Cited by 40 publications

(29 citation statements)

References 54 publications

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“…NF2 encodes Merlin (Moesin-ezrin-radixin-like protein), also known as Neurofibromin 2 and Schwannomin. Merlin is a tumor suppressor classically known for its ability to induce contact-dependent growth inhibition (46). Loss-of-function mutations or deletions in NF2 cause neurofibromatosis type 2, a multiple tumor forming disease of the nervous system, characterized by the development of bilateral schwannomas, as well as meningiomas and ependymomas (47).…”

Section: Discussionmentioning

confidence: 99%

Novel Driver Strength Index highlights important cancer genes in TCGA PanCanAtlas patients

Belikov

Otnyukov

Vyatkin

et al. 2021

Preprint

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Elucidating crucial driver genes is paramount for understanding the cancer origins and mechanisms of progression, as well as selecting targets for molecular therapy. Cancer genes are usually ranked by the frequency of mutation, which, however, does not necessarily reflect their driver strength. Here we hypothesize that driver strength is higher for genes that are preferentially mutated in patients with few driver mutations overall, because these few mutations should be strong enough to initiate cancer. We propose a formula to calculate the corresponding Driver Strength Index (DSI), as well as the Normalized Driver Strength Index (NDSI), the latter completely independent of the overall gene mutation frequency. We validate these indices using the largest database of human cancer mutations - TCGA PanCanAtlas, multiple established algorithms for cancer driver prediction (2020plus, CHASMplus, CompositeDriver, dNdScv, DriverNet, HotMAPS, IntOGen Plus, OncodriveCLUSTL, OncodriveFML) and four custom computational pipelines that integrate driver contributions from SNA, CNA and aneuploidy at the patient-level resolution. We demonstrate that NDSI provides substantially different rankings of genes as compared to DSI and frequency approach. For example, NDSI highlighted the importance of guanine nucleotide-binding protein subunits GNAQ, GNA11, GNAI1, GNAZ and GNB3, General Transcription Factor II family members GTF2I and GTF2F2, as well as fibroblast growth factor receptors FGFR2 and FGFR3. Intriguingly, NDSI prioritized CIC, FUBP1, IDH1 and IDH2 mutations, as well as 19q and 1p chromosome arm losses, that comprise characteristic molecular alterations of gliomas. KEGG analysis shows that top NDSI-ranked genes comprise PDGFRA-GRB2-SOS2-HRAS/NRAS-BRAF pathway, GNAQ/GNA11-HRAS/NRAS-BRAF pathway, GNB3-AKT1-IKBKG/GSK3B/CDKN1B pathway and TCEB1-VHL pathway. NDSI does not seem to correlate with the number of protein-protein interactions. We share our software to enable calculation of DSI and NDSI for outputs of any third-party driver prediction algorithms or their combinations.

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Section: Discussionmentioning

confidence: 99%

Novel Driver Strength Index highlights important cancer genes in TCGA PanCanAtlas patients

Belikov

Otnyukov

Vyatkin

et al. 2021

Preprint

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“…With regard to the alterations of Hippo signalling (Yap level) and cell proliferation in tongue regions at late embryonic stages (E15.5–E18.5), which are not consistent with conventional Nf2/Hippo/Yap‐cell proliferation pathway, it is possible that Nf2 deletion causes changes in other signalling pathways that overwrite the effects of diminished Hippo signalling in the tongue, for example Wnt/β‐catenin, TGF‐β, Hedgehog 52 4 and is likely to be involved in the regulatory role of Nf2/Hippo signalling in tongue mesenchyme in promoting tongue formation.…”

Section: Discussionmentioning

confidence: 95%

Deletion of Nf2 in neural crest‐derived tongue mesenchyme alters tongue shape and size, Hippo signalling and cell proliferation in a region‐ and stage‐specific manner

Ishan

Chen

et al. 2021

Cell Proliferation

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Objectives The mammalian tongue develops from the branchial arches (1–4) and comprises highly organized tissues compartmentalized by mesenchyme/connective tissue that is largely derived from neural crest (NC). This study aimed to understand the roles of tumour suppressor Neurofibromin 2 (Nf2) in NC‐derived tongue mesenchyme in regulating Hippo signalling and cell proliferation for the proper development of tongue shape and size. Materials and methods Conditional knockout (cKO) of Nf2 in NC cell lineage was generated using Wnt1‐Cre (Wnt1‐Cre/Nf2cKO). Nf2 expression, Hippo signalling activities, cell proliferation and tongue shape and size were thoroughly analysed in different tongue regions and tissue types of Wnt1‐Cre/Nf2cKO and Cre‐/Nf2fx/fx littermates at various stages (E10.5–E18.5). Results In contrast to many other organs in which the Nf2/Hippo pathway activity restrains growth and cell proliferation and as a result, loss of Nf2 decreases Hippo pathway activity and promotes an enlarged organ development, here we report our observations of distinct, tongue region‐ and stage‐specific alterations of Hippo signalling activity and cell proliferation in Nf2cKO in NC‐derived tongue mesenchyme. Compared to Cre−/Nf2fx/fx littermates, Wnt1‐Cre/Nf2cKO depicted a non‐proportionally enlarged tongue (macroglossia) at E12.5–E13.5 and microglossia at later stages (E15.5–E18.5). Specifically, at E12.5 Nf2cKO mutants had a decreased level of Hippo signalling transcription factor Yes‐associated protein (Yap), Yap target genes and cell proliferation anteriorly, while having an increased Yap, Yap target genes and cell proliferation posteriorly, which lead to a tip‐pointed and posteriorly widened tongue. At E15.5, loss of Nf2 in the NC lineage resulted in distinct changes in cell proliferation in different regions, that is, high in epithelium and mesenchyme subjacent to the epithelium, and lower in deeper layers of the mesenchyme. At E18.5, cell proliferation was reduced throughout the Nf2cKO tongue.

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“…The Nf2 gene encodes the FERM domain protein MERLIN, affiliated with Ezrin, Radixin, and Moesin (ERM) proteins. It exerts multiple functions in tumor suppression, development, and regeneration in diverse organs and tissues, for example by restricting proliferation, controlling apoptosis, and promoting differentiation, apicobasal polarity and junctional complex formation (60)(61)(62). NF2 localizes primarily to the cell cortex and links the cortical actomyosin cytoskeleton to the plasma membrane.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, NF2 can localize to the nucleus and act as a contact-dependent tumor suppressor by inhibiting CRL4DCAF1 ubiquitin ligase (61). Importantly, among other regulatory inputs, NF2 also controls the Hippo pathway to balance organ size, proliferation and behavior of stem cells; it binds to and activates several Hippo pathway components, including the Hippo kinases MST1/2 and LATS1/2 (61,62). Loss of Hippo signaling leads to nuclear translocation of the transcriptional co-activators YAP/TAZ, often associated with abnormal proliferation in cancer (which was not certified by peer review) is the author/funder.…”

Section: Introductionmentioning

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

Human Molecular Genetics

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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 regulates signaling events at the nexus of development and cancer

Cited by 40 publications

References 54 publications

Novel Driver Strength Index highlights important cancer genes in TCGA PanCanAtlas patients

Novel Driver Strength Index highlights important cancer genes in TCGA PanCanAtlas patients

Deletion of Nf2 in neural crest‐derived tongue mesenchyme alters tongue shape and size, Hippo signalling and cell proliferation in a region‐ and stage‐specific manner

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

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