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1
Bashour, Anne-Marie, J. J. Meng, Wallace Ip, Mia MacCollin, and Nancy Ratner. "The Neurofibromatosis Type 2 Gene Product, merlin, Reverses the F-Actin Cytoskeletal Defects in Primary Human Schwannoma Cells." Molecular and Cellular Biology 22, no. 4 (February 15, 2002): 1150–57. http://dx.doi.org/10.1128/mcb.22.4.1150-1157.2002.
Повний текст джерелаАнотація:
ABSTRACT Schwannoma tumors, which occur sporadically and in patients with neurofibromatosis, account for 8% of intracranial tumors and can only be treated by surgical removal. Most schwannomas have biallelic mutations in the NF2 tumor suppressor gene. We previously showed that schwannoma-derived Schwann cells exhibit membrane ruffling and aberrant cell spreading when plated onto laminin, indicative of fundamental F-actin cytoskeletal defects. Here we expand these observations to a large group of sporadic and NF2-related tumors and extend them to schwannomatosis-derived tumors. Mutation at NF2 correlated with F-actin abnormalities, but the extent of morphological change did not correlate with the type of NF2 mutation. We used a recently described molecular strategy, TAT-mediated protein transfer, to acutely introduce the NF2 protein, merlin, into primary human schwannoma cells in an attempt to reverse the cytoskeletal phenotype. Abnormal ruffling and cell spreading by cells with identified NF2 mutations were rapidly reversed by introduction of TAT-merlin. The effect is specific to TAT-merlin isoform 1, the growth-suppressive isoform of merlin. TAT-merlin isoform 2, a TAT-merlin mutant (L64P), and merlin lacking TAT were ineffective in reversing the cytoskeletal phenotype. Results show that merlin isoform 1 is sufficient to restore normal actin organization in NF2-deficient human tumor cells, demonstrating a key role for merlin in the NF2 phenotype. These results lay the foundation for epigenetic complementation studies in NF2 mouse models and possibly for experiments to evaluate the utility of merlin transduction into patients as protein therapy.
2
Eaton, Charlotte, Abrar Choudhury, Timothy Casey-Clyde, Danielle Swaney, Nevan Krogan, and David Raleigh. "CSIG-26. NF2/MERLIN DRIVES MENINGIOMA APOPTOSIS AND SUCEPTIBILITY TO CYTOTOXIC THERAPY." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi39. http://dx.doi.org/10.1093/neuonc/noab196.152.
Повний текст джерелаАнотація:
Abstract BACKGROUND Alterations in NF2 underlie meningioma tumorigenesis, but tumor suppressor functions of the NF2 gene product, Merlin, are incompletely understood in meningiomas. Here we integrate proteomic proximity-labelling mass spectrometry with CRISPR interference (CRISPRi), RNA sequencing, and biochemical approaches to discover Merlin drives meningioma apoptosis and susceptibility to cytotoxic therapy. METHODS RNA sequencing was performed on triplicate M10G meningioma cells stably expressing CRISPRi machinery and either non-targeting control sgRNAs, sgRNAs suppressing NF2, or sgRNAs suppressing NF2 with Merlin rescue. QPCR in IOMM-Lee and MSC1 meningioma cells expressing non-targeting control shRNAs or shRNAs suppressing NF2 was used for orthogonal validation in vitro. RNA sequencing of euploid meningiomas (n=52) or meningiomas with loss of NF2 as the only copy number variant (n=28) was used for orthogonal validation in vivo. Merlin interactors in meningioma cells were identified using APEX proteomic proximity-labelling mass spectrometry. Mechanistic and functional studies were performed using biochemical, molecular, and cell biology approaches in meningioma cells and CH-157MN meningioma xenografts treated with cytotoxic chemotherapy or ionizing radiation. RESULTS Merlin suppression in meningioma cells and xenografts inhibited pro-apoptotic interferon regulatory factor (IRF) target genes and attenuated meningioma apoptosis. Merlin suppression did not alter IRF stability or subcellular localization in meningioma cells, and proteomic proximity-labelling mass spectrometry revealed a novel interaction between wildtype Merlin and ARHGAP35, a DNA binding factor that inhibits glucocorticoid receptor expression (NR3C1). NR3C1 inhibits IRF activity to prevent apoptosis, and Merlin suppression in meningioma cells induced NR3C1expression, which was inhibited by Merlin rescue. Further, NR3C1 suppression rescued meningioma cell apoptosis in the absence of Merlin, and NR3C1 expression was increased in human meningiomas with loss of NF2 compared to euploid meningiomas. CONCLUSIONS These data shed light on a novel pro-apoptotic tumor suppressor function of Merlin regulating glucocorticoid signalling and susceptibility to cytotoxic therapy in meningiomas.
3
James, Marianne F., Sangyeul Han, Carolyn Polizzano, Scott R. Plotkin, Brendan D. Manning, Anat O. Stemmer-Rachamimov, James F. Gusella, and Vijaya Ramesh. "NF2/Merlin Is a Novel Negative Regulator of mTOR Complex 1, and Activation of mTORC1 Is Associated with Meningioma and Schwannoma Growth." Molecular and Cellular Biology 29, no. 15 (May 18, 2009): 4250–61. http://dx.doi.org/10.1128/mcb.01581-08.
Повний текст джерелаАнотація:
ABSTRACT Inactivating mutations of the neurofibromatosis 2 (NF2) gene, NF2, result predominantly in benign neurological tumors, schwannomas and meningiomas, in humans; however, mutations in murine Nf2 lead to a broad spectrum of cancerous tumors. The tumor-suppressive function of the NF2 protein, merlin, a membrane-cytoskeleton linker, remains unclear. Here, we identify the mammalian target of rapamycin complex 1 (mTORC1) as a novel mediator of merlin's tumor suppressor activity. Merlin-deficient human meningioma cells and merlin knockdown arachnoidal cells, the nonneoplastic cell counterparts of meningiomas, exhibit rapamycin-sensitive constitutive mTORC1 activation and increased growth. NF2 patient tumors and Nf2-deficient mouse embryonic fibroblasts demonstrate elevated mTORC1 signaling. Conversely, the exogenous expression of wild-type merlin isoforms, but not a patient-derived L64P mutant, suppresses mTORC1 signaling. Merlin does not regulate mTORC1 via the established mechanism of phosphoinositide 3-kinase-Akt or mitogen-activated protein kinase/extracellular signal-regulated kinase-mediated TSC2 inactivation and may instead regulate TSC/mTOR signaling in a novel fashion. In conclusion, the deregulation of mTORC1 activation underlies the aberrant growth and proliferation of NF2-associated tumors and may restrain the growth of these lesions through negative feedback mechanisms, suggesting that rapamycin in combination with phosphoinositide 3-kinase inhibitors may be therapeutic for NF2.
4
Lee, Hansoo, Donghwa Kim, Han C. Dan, Eric L. Wu, Tatiana M. Gritsko, Chuanhai Cao, Santo V. Nicosia, et al. "Identification and Characterization of Putative Tumor Suppressor NGB, a GTP-Binding Protein That Interacts with the Neurofibromatosis 2 Protein." Molecular and Cellular Biology 27, no. 6 (January 8, 2007): 2103–19. http://dx.doi.org/10.1128/mcb.00572-06.
Повний текст джерелаАнотація:
ABSTRACT Mutations of the neurofibromatosis 2 (NF2) tumor suppressor gene have frequently been detected not only in schwannomas and other central nervous system tumors of NF2 patients but also in their sporadic counterparts and malignant tumors unrelated to the NF2 syndrome such as malignant mesothelioma, indicating a broader role for the NF2 gene in human tumorigenesis. However, the mechanisms by which the NF2 product, merlin or schwannomin, is regulated and controls cell proliferation remain elusive. Here, we identify a novel GTP-binding protein, dubbed NGB (referring to NF2-associated GTP binding protein), which binds to merlin. NGB is highly conserved between Saccharomyces cerevisiae, Caenorhabditis elegans, and human cells, and its GTP-binding region is very similar to those found in R-ras and Rap2. However, ectopic expression of NGB inhibits cell growth, cell aggregation, and tumorigenicity in tumorigenic schwanomma cells. Down-regulation and infrequent mutation of NGB were detected in human glioma cell lines and primary tumors. The interaction of NGB with merlin impairs the turnover of merlin, yet merlin does not affect the GTPase nor GTP-binding activity of NGB. Finally, the tumor suppressor functions of NGB require merlin and are linked to its ability to suppress cyclin D1 expression. Collectively, these findings indicate that NGB is a tumor suppressor that regulates and requires merlin to suppress cell proliferation.
5
Kim, Bae-Hoon, Yeon-Ho Chung, Tae-Gyun Woo, So-mi Kang, Soyoung Park, Minju Kim, and Bum-Joon Park. "NF2-Related Schwannomatosis (NF2): Molecular Insights and Therapeutic Avenues." International Journal of Molecular Sciences 25, no. 12 (June 14, 2024): 6558. http://dx.doi.org/10.3390/ijms25126558.
Повний текст джерелаАнотація:
NF2-related schwannomatosis (NF2) is a genetic syndrome characterized by the growth of benign tumors in the nervous system, particularly bilateral vestibular schwannomas, meningiomas, and ependymomas. This review consolidates the current knowledge on NF2 syndrome, emphasizing the molecular pathology associated with the mutations in the gene of the same name, the NF2 gene, and the subsequent dysfunction of its product, the Merlin protein. Merlin, a tumor suppressor, integrates multiple signaling pathways that regulate cell contact, proliferation, and motility, thereby influencing tumor growth. The loss of Merlin disrupts these pathways, leading to tumorigenesis. We discuss the roles of another two proteins potentially associated with NF2 deficiency as well as Merlin: Yes-associated protein 1 (YAP), which may promote tumor growth, and Raf kinase inhibitory protein (RKIP), which appears to suppress tumor development. Additionally, this review discusses the efficacy of various treatments, such as molecular therapies that target specific pathways or inhibit neomorphic protein–protein interaction caused by NF2 deficiency. This overview not only expands on the fundamental understanding of NF2 pathophysiology but also explores the potential of novel therapeutic targets that affect the clinical approach to NF2 syndrome.
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Houshmandi, S. Sean, Ryan J. Emnett, Marco Giovannini, and David H. Gutmann. "The Neurofibromatosis 2 Protein, Merlin, Regulates Glial Cell Growth in an ErbB2- and Src-Dependent Manner." Molecular and Cellular Biology 29, no. 6 (December 22, 2008): 1472–86. http://dx.doi.org/10.1128/mcb.01392-08.
Повний текст джерелаАнотація:
ABSTRACT Individuals with the inherited cancer predisposition syndrome neurofibromatosis 2 (NF2) develop several central nervous system (CNS) malignancies, including glial cell neoplasms (ependymomas). Recent studies have suggested that the NF2 protein, merlin (or schwannomin), may regulate receptor tyrosine kinase signaling, intracellular mitogenic growth control pathways, or adherens junction organization in non-nervous-system cell types. For this report, we used glial fibrillary acidic protein conditional knockout mice and derivative glia to determine how merlin regulates CNS glial cell proliferation. We show that the loss of merlin in glial cells results in increased proliferation in vitro and in vivo. Merlin regulation of glial cell growth reflects deregulated Src activity, such that pharmacologic or genetic inhibition of Src activation reduces Nf2 −/− glial cell growth to wild-type levels. We further show that Src regulates Nf2 −/− glial cell growth by sequentially regulating FAK and paxillin phosphorylation/activity. Next, we demonstrate that Src activation results from merlin regulation of ErbB2 activation and that genetic or pharmacologic ErbB2 inhibition reduces Nf2 −/− glial cell Src/Src effector activation and proliferation to wild-type levels. Lastly, we show that merlin competes with Src for direct binding to ErbB2 and present a novel molecular mechanism for merlin regulation of ErbB2-dependent Src signaling and growth control.
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Xiao, Guang-Hui, Ryan Gallagher, Justin Shetler, Kristine Skele, Deborah A. Altomare, Richard G. Pestell, Suresh Jhanwar, and Joseph R. Testa. "The NF2 Tumor Suppressor Gene Product, Merlin, Inhibits Cell Proliferation and Cell Cycle Progression by Repressing Cyclin D1 Expression." Molecular and Cellular Biology 25, no. 6 (March 15, 2005): 2384–94. http://dx.doi.org/10.1128/mcb.25.6.2384-2394.2005.
Повний текст джерелаАнотація:
ABSTRACT Inactivation of the NF2 tumor suppressor gene has been observed in certain benign and malignant tumors. Recent studies have demonstrated that merlin, the product of the NF2 gene, is regulated by Rac/PAK signaling. However, the mechanism by which merlin acts as a tumor suppressor has remained obscure. In this report, we show that adenovirus-mediated expression of merlin in NF2-deficient tumor cells inhibits cell proliferation and arrests cells at G1 phase, concomitant with decreased expression of cyclin D1, inhibition of CDK4 activity, and dephosphorylation of pRB. The effect of merlin on cell cycle progression was partially overridden by ectopic expression of cyclin D1. RNA interference experiments showed that silencing of the endogenous NF2 gene results in upregulation of cyclin D1 and S-phase entry. Furthermore, PAK1-stimulated cyclin D1 promoter activity was repressed by cotransfection of NF2, and PAK activity was inhibited by expression of merlin. Interestingly, the S518A mutant form of merlin, which is refractory to phosphorylation by PAK, was more efficient than the wild-type protein in inhibiting cell cycle progression and in repressing cyclin D1 promoter activity. Collectively, our data indicate that merlin exerts its antiproliferative effect, at least in part, via repression of PAK-induced cyclin D1 expression, suggesting a unifying mechanism by which merlin inactivation might contribute to the overgrowth seen in both noninvasive and malignant tumors.
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Eaton, Charlotte, Paola Bisignano, and David Raleigh. "CSIG-22. CANCER-ASSOCIATED MISSENSE SINGLE NUCLEOTIDE VARIANTS REGULATE THE STABILITY AND SUBCELLULAR LOCALIZATION OF NF2/MERLIN." Neuro-Oncology 22, Supplement_2 (November 2020): ii32. http://dx.doi.org/10.1093/neuonc/noaa215.134.
Повний текст джерелаАнотація:
Abstract BACKGROUND Alterations in the NF2 tumor suppressor gene lead to meningiomas and schwannomas, but the tumor suppressor functions of the NF2 gene product, Merlin, are incompletely understood. To address this problem, we performed a structure-function analysis of Merlin by expressing cancer-associated missense single-nucleotide variants (mSNVs) in primary cancer cells for biochemical and cell biology experiments. METHODS All NF2 mSNVs were assembled from cBioPortal and COSMIC, and modelled on the FERM, a-helical, and C-terminal domains of Merlin (PDB 4ZRJ) using comparative structure prediction on the Robetta server and visually inspected using Pymol. mSNV hotspots were defined from sliding windows with at least 10 mutations within 5 residues in either direction. mSNVs from hotspots in meningiomas, schwannomas, or both, were selected for in vitro mechanistic analyses using immunofluorescence and immunoblotting of whole cell, plasma membrane, cytoskeletal, cytoplasmic, nuclear, and chromatin subcellular fractions from M10G meningioma cells and HEI-193 schwannoma cells. RESULTS We identified the following cancer-associated hotspot mSNVs in NF2, which were over-expressed for mechanistic studies: L46R, S156N, W191R, A211D, V219M, R418C and R462K. Endogenous Merlin was detected in all subcellular compartments, but was enriched in the nucleus. L46R and A211D mapped to hydrophobic pockets in the FERM domain, destabilized Merlin, and excluded Merlin from all subcellular compartments except the cytoskeleton. S156N, W191R and V219M also mapped to the FERM domain, but did not affect Merlin stability, and V219M attenuated chromatin localization, suggesting this motif may be involved in binding events that regulate subcellular localization. R418C and R463K mapped to the a-helical domain, but only R418C destabilized Merlin. CONCLUSION Our results suggest that cancer-associated mSNVs inactive the tumor suppressor functions of NF2 by altering the stability, subcellular localization, or binding partners of Merlin. Further work is required to identify and understand the impact of binding partners and subcellular localization on Merlin function.
9
Bachir, Suha, Sanjit Shah, Scott Shapiro, Abigail Koehler, Abdelkader Mahammedi, Ravi N. Samy, Mario Zuccarello, Elizabeth Schorry, and Soma Sengupta. "Neurofibromatosis Type 2 (NF2) and the Implications for Vestibular Schwannoma and Meningioma Pathogenesis." International Journal of Molecular Sciences 22, no. 2 (January 12, 2021): 690. http://dx.doi.org/10.3390/ijms22020690.
Повний текст джерелаАнотація:
Patients diagnosed with neurofibromatosis type 2 (NF2) are extremely likely to develop meningiomas, in addition to vestibular schwannomas. Meningiomas are a common primary brain tumor; many NF2 patients suffer from multiple meningiomas. In NF2, patients have mutations in the NF2 gene, specifically with loss of function in a tumor-suppressor protein that has a number of synonymous names, including: Merlin, Neurofibromin 2, and schwannomin. Merlin is a 70 kDa protein that has 10 different isoforms. The Hippo Tumor Suppressor pathway is regulated upstream by Merlin. This pathway is critical in regulating cell proliferation and apoptosis, characteristics that are important for tumor progression. Mutations of the NF2 gene are strongly associated with NF2 diagnosis, leading to benign proliferative conditions such as vestibular schwannomas and meningiomas. Unfortunately, even though these tumors are benign, they are associated with significant morbidity and the potential for early mortality. In this review, we aim to encompass meningiomas and vestibular schwannomas as they pertain to NF2 by assessing molecular genetics, common tumor types, and tumor pathogenesis.
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LaJeunesse, Dennis R., Brooke M. McCartney, and Richard G. Fehon. "Structural Analysis of Drosophila Merlin Reveals Functional Domains Important for Growth Control and Subcellular Localization." Journal of Cell Biology 141, no. 7 (June 29, 1998): 1589–99. http://dx.doi.org/10.1083/jcb.141.7.1589.
Повний текст джерелаАнотація:
Merlin, the product of the Neurofibromatosis type 2 (NF2) tumor-suppressor gene, is a member of the protein 4.1 superfamily that is most closely related to ezrin, radixin, and moesin (ERM). NF2 is a dominantly inherited disease characterized by the formation of bilateral acoustic schwannomas and other benign tumors associated with the central nervous system. To understand its cellular functions, we are studying a Merlin homologue in Drosophila. As is the case for NF2 tumors, Drosophila cells lacking Merlin function overproliferate relative to their neighbors. Using in vitro mutagenesis, we define functional domains within Merlin required for proper subcellular localization and for genetic rescue of lethal Merlin alleles. Remarkably, the results of these experiments demonstrate that all essential genetic functions reside in the plasma membrane– associated NH2-terminal 350 amino acids of Merlin. Removal of a seven–amino acid conserved sequence within this domain results in a dominant-negative form of Merlin that is stably associated with the plasma membrane and causes overproliferation when expressed ectopically in the wing. In addition, we provide evidence that the COOH-terminal region of Merlin has a negative regulatory role, as has been shown for ERM proteins. These results provide insights into the functions and functional organization of a novel tumor suppressor gene.
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Pachter, Jonathan A., Irina M. Shapiro, David T. Weaver, Christian M. Vidal, Jennifer E. Ring, Mitchell Keegan, Qunli Xu, Craig Menges, Joseph R. Testa, and Daniel Paterson. "Sensitivity of malignant mesothelioma lacking Merlin to the FAK inhibitor VS-6063: Evaluation of merlin/NF2 status in clinical samples." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e18541-e18541. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e18541.
Повний текст джерелаАнотація:
e18541 Background: Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung often resulting from prior exposure to asbestos. MPM patients are usually diagnosed at an advanced stage of disease and the prognosis is poor. Median survival after diagnosis is 9 to 12 months and standard-of-care agents such as cisplatin and pemetrexed have only a modest impact on median survival time for MPM patients. New therapeutic modalities are urgently needed to improve the prognosis of MPM patients. 40-50% of MPM patients exhibit homozygous disruption of the NF2 tumor suppressor gene by mutation and/or deletion resulting in lack of expression of functional merlin protein. Methods: Proliferation of drug-treated mesothelioma cell lines in 3-dimensional (3D) Matrigel culture was assessed by MTS, and MPM xenograft growth was measured in vehicle- vs. FAK inhibitor-treated SCID mice. Since absence of merlin expression can theoretically result from several mechanisms including NF2 mutation and chromosome 22 abnormalities, we assessed NF2 gene deletion by FISH and merlin protein levels by IHC in the same human mesothelioma tumor samples. Results: Among a panel of mesothelioma cell lines in 3D culture, MPM lines lacking expression of merlin protein were found to be especially sensitive to the selective FAK inhibitor VS-6063. In contrast, MPM cell lines with wildtype merlin were less sensitive with EC50 values greater than 1 μM. Accordingly, oral dosing with a FAK inhibitor induced significant tumor growth inhibition in a merlin-negative mesothelioma model in mice. To enable the planned stratification of MPM patients by merlin status, an immunohistochemistry (IHC) assay has been optimized to quantify merlin protein levels. A merlin IHC H-score below the defined cutoff was associated with loss of at least one copy of chromosome 22, indicating that chromosomal deletion is an important mechanism of merlin loss in mesothelioma patients. Conclusions: These data support the clinical development of VS-6063 for treatment of malignant pleural mesothelioma patients stratified by merlin/NF2 status. A potentially pivotal mesothelioma trial is set to initiate in 2013.
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Pećina-Šlaus, Nives. "Merlin, the NF2 Gene Product." Pathology & Oncology Research 19, no. 3 (May 12, 2013): 365–73. http://dx.doi.org/10.1007/s12253-013-9644-y.
Повний текст джерела
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Xiao, Guang-Hui, Jonathan Chernoff, and Joseph R. Testa. "NF2: The wizardry of merlin." Genes, Chromosomes and Cancer 38, no. 4 (October 14, 2003): 389–99. http://dx.doi.org/10.1002/gcc.10282.
Повний текст джерела
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Maxwell, Marius, Sarah D. Shih, Theofanis Galanopoulos, E. Tessa Hedley-Whyte, and G. Rees Cosgrove. "Familial meningioma: analysis of expression of neurofibromatosis 2 protein Merlin." Journal of Neurosurgery 88, no. 3 (March 1998): 562–69. http://dx.doi.org/10.3171/jns.1998.88.3.0562.
Повний текст джерелаАнотація:
✓ Meningiomas are primarily benign brain tumors thought to arise through multistep tumorigenesis, involving both the activation of oncogenes and the loss of tumor suppressor genes. The recently isolated neurofibromatosis 2 (NF2) tumor suppressor gene has been found to be mutated in a large proportion of meningiomas. Almost all cases of familial meningioma occur in association with NF2. Familial meningioma in isolation from NF2 (sporadic) is exceedingly rare, with only 14 reports since 1959. The authors report the existence of a family lacking any stigmata of NF2, in which two members had spinal meningiomas. Tumor specimens were subjected to immunocytochemical analysis for the NF2 protein product Merlin, which has been implicated in the tumorigenesis of meningioma. Merlin immunoreactivity was present in both tumor specimens, implying that the NF2 tumor suppressor gene was not deleted in these tumors. This supports the hypothesis that a second tumor suppressor gene locus, other than NF2, acts in the formation of familial sporadic meningioma. The results are discussed in the context of putative oncogenic mechanisms of familial meningiomas.
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LaJeunesse, Dennis R., Brooke M. McCartney, and Richard G. Fehon. "A Systematic Screen for Dominant Second-Site Modifiers of Merlin/NF2 Phenotypes Reveals an Interaction With blistered/DSRF and scribbler." Genetics 158, no. 2 (June 1, 2001): 667–79. http://dx.doi.org/10.1093/genetics/158.2.667.
Повний текст джерелаАнотація:
Abstract Merlin, the Drosophila homologue of the human tumor suppressor gene Neurofibromatosis 2 (NF2), is required for the regulation of cell proliferation and differentiation. To better understand the cellular functions of the NF2 gene product, Merlin, recent work has concentrated on identifying proteins with which it interacts either physically or functionally. In this article, we describe genetic screens designed to isolate second-site modifiers of Merlin phenotypes from which we have identified five multiallelic complementation groups that modify both loss-of-function and dominant-negative Merlin phenotypes. Three of these groups, Group IIa/scribbler (also known as brakeless), Group IIc/blistered, and Group IId/net, are known genes, while two appear to be novel. In addition, two genes, Group IIa/scribbler and Group IIc/blistered, alter Merlin subcellular localization in epithelial and neuronal tissues, suggesting that they regulate Merlin trafficking or function. Furthermore, we show that mutations in scribbler and blistered display second-site noncomplementation with one another. These results suggest that Merlin, blistered, and scribbler function together in a common pathway to regulate Drosophila wing epithelial development.
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Ikeda, Keiro, Yoshinaga Saeki, Charo Gonzalez-Agosti, Vijaya Ramesh, and E. Antonio Chiocca. "Inhibition of NF2-negative and NF2-positive primary human meningioma cell proliferation by overexpression of merlin due to vector-mediated gene transfer." Journal of Neurosurgery 91, no. 1 (July 1999): 85–92. http://dx.doi.org/10.3171/jns.1999.91.1.0085.
Повний текст джерелаАнотація:
Object. The absence of in vitro models of neurofibromatosis Type 2 (NF2)—defective meningiomas has limited investigative efforts to study the biological effects of this gene in the pathogenesis of these tumors. The goals of this report are to show that gene transfer vectors can efficiently express the wild-type NF2 transgene into primary meningioma cells and to determine effects on cellular proliferation.Methods. In this study, the authors have compared the transducing capacities of a retrovirus, an adenovirus, and a herpes simplex virus amplicon vector for use in primary human meningioma cells harvested from human tumors excised from patients with and without NF2. Transduction efficiencies with the latter vector approached 100% and it was selected to transfer the wild-type NF2 transgene into these cells. Western blot analysis confirmed that vector-mediated gene transfer mediated the expression of the NF2-encoded polypeptide merlin. Overexpression of merlin significantly inhibited the proliferation of both NF2-negative and NF2-positive human meningioma cells when compared to the proliferation of cells transduced with a control vector.Conclusions. This study demonstrates the feasibility of using vector-mediated gene transfer to study wild-type NF2 gene function in short-term cultures of primary human meningioma cells.
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Lee, Sungho, Patrick J. Karas, Caroline C. Hadley, James C. Bayley V, A. Basit Khan, Ali Jalali, Alex D. Sweeney, Tiemo J. Klisch, and Akash J. Patel. "The Role of Merlin/NF2 Loss in Meningioma Biology." Cancers 11, no. 11 (October 24, 2019): 1633. http://dx.doi.org/10.3390/cancers11111633.
Повний текст джерелаАнотація:
Mutations in the neurofibromin 2 (NF2) gene were among the first genetic alterations implicated in meningioma tumorigenesis, based on analysis of neurofibromatosis type 2 (NF2) patients who not only develop vestibular schwannomas but later have a high incidence of meningiomas. The NF2 gene product, merlin, is a tumor suppressor that is thought to link the actin cytoskeleton with plasma membrane proteins and mediate contact-dependent inhibition of proliferation. However, the early recognition of the crucial role of NF2 mutations in the pathogenesis of the majority of meningiomas has not yet translated into useful clinical insights, due to the complexity of merlin’s many interacting partners and signaling pathways. Next-generation sequencing studies and increasingly sophisticated NF2-deletion-based in vitro and in vivo models have helped elucidate the consequences of merlin loss in meningioma pathogenesis. In this review, we seek to summarize recent findings and provide future directions toward potential therapeutics for this tumor.
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Benton, Dorothy, Hoi Yee Chow, Sofiia Karchugina, and Jonathan Chernoff. "Synergistic effect of PAK and Hippo pathway inhibitor combination in NF2-deficient Schwannoma." PLOS ONE 19, no. 7 (July 31, 2024): e0305121. http://dx.doi.org/10.1371/journal.pone.0305121.
Повний текст джерелаАнотація:
Neurofibromatosis type 2 is a genetic disorder that results in the formation and progressive growth of schwannomas, ependymomas, and/or meningiomas. The NF2 gene encodes the Merlin protein, which links cell cortical elements to the actin cytoskeleton and regulates a number of key enzymes including Group I p21-activated kinases (PAKs), the Hippo-pathway kinase LATS, and mTORC. While PAK1 and PAK2 directly bind Merlin and transmit proliferation and survival signals when Merlin is mutated or absent, inhibition of Group 1 PAKs alone has not proven sufficient to completely stop the growth of NF2-deficient meningiomas or schwannomas in vivo, suggesting the need for a second pathway inhibitor. As the Hippo pathway is also activated in NF2-deficient cells, several inhibitors of the Hippo pathway have recently been developed in the form of YAP-TEAD binding inhibitors. These inhibitors prevent activation of pro-proliferation and anti-apoptotic Hippo pathway effectors. In this study, we show that PAK inhibition slows cell proliferation while TEAD inhibition promotes apoptotic cell death. Finally, we demonstrate the efficacy of PAK and TEAD inhibitor combinations in several NF2-deficient Schwannoma cell lines.
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Curto, Marcello, Banumathi K. Cole, Dominique Lallemand, Ching-Hui Liu, and Andrea I. McClatchey. "Contact-dependent inhibition of EGFR signaling by Nf2/Merlin." Journal of Cell Biology 177, no. 5 (June 4, 2007): 893–903. http://dx.doi.org/10.1083/jcb.200703010.
Повний текст джерелаАнотація:
The neurofibromatosis type 2 (NF2) tumor suppressor, Merlin, is a membrane/cytoskeleton-associated protein that mediates contact-dependent inhibition of proliferation. Here we show that upon cell–cell contact Merlin coordinates the processes of adherens junction stabilization and negative regulation of epidermal growth factor receptor (EGFR) signaling by restraining the EGFR into a membrane compartment from which it can neither signal nor be internalized. In confluent Nf2−/− cells, EGFR activation persists, driving continued proliferation that is halted by specific EGFR inhibitors. These studies define a new mechanism of tumor suppression, provide mechanistic insight into the poorly understood phenomenon of contact-dependent inhibition of proliferation, and suggest a therapeutic strategy for NF2-mutant tumors.
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Hennigan, Robert F., Jonathan S. Fletcher, Steven Guard, and Nancy Ratner. "Proximity biotinylation identifies a set of conformation-specific interactions between Merlin and cell junction proteins." Science Signaling 12, no. 578 (April 23, 2019): eaau8749. http://dx.doi.org/10.1126/scisignal.aau8749.
Повний текст джерелаАнотація:
Neurofibromatosis type 2 is an inherited, neoplastic disease associated with schwannomas, meningiomas, and ependymomas and that is caused by inactivation of the tumor suppressor gene NF2. The NF2 gene product, Merlin, has no intrinsic catalytic activity; its tumor suppressor function is mediated through the proteins with which it interacts. We used proximity biotinylation followed by mass spectrometry and direct binding assays to identify proteins that associated with wild-type and various mutant forms of Merlin in immortalized Schwann cells. We defined a set of 52 proteins in close proximity to wild-type Merlin. Most of the Merlin-proximal proteins were components of cell junctional signaling complexes, suggesting that additional potential interaction partners may exist in adherens junctions, tight junctions, and focal adhesions. With mutant forms of Merlin that cannot bind to phosphatidylinositol 4,5-bisphosphate (PIP2) or that constitutively adopt a closed conformation, we confirmed a critical role for PIP2 binding in Merlin function and identified a large cohort of proteins that specifically interacted with Merlin in the closed conformation. Among these proteins, we identified a previously unreported Merlin-binding protein, apoptosis-stimulated p53 protein 2 (ASPP2, also called Tp53bp2), that bound to closed-conformation Merlin predominately through the FERM domain. Our results demonstrate that Merlin is a component of cell junctional mechanosensing complexes and defines a specific set of proteins through which it acts.
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Hawley, Eric, Jeffrey Gehlhausen, Sofiia Karchugina, Hoi-Yee Chow, Daniela Araiza-Olivera, Maria Radu, Abbi Smith, et al. "PAK1 inhibition reduces tumor size and extends the lifespan of mice in a genetically engineered mouse model of Neurofibromatosis Type 2 (NF2)." Human Molecular Genetics 30, no. 17 (June 1, 2021): 1607–17. http://dx.doi.org/10.1093/hmg/ddab106.
Повний текст джерелаАнотація:
Abstract Neurofibromatosis Type II (NF2) is an autosomal dominant cancer predisposition syndrome in which germline haploinsufficiency at the NF2 gene confers a greatly increased propensity for tumor development arising from tissues of neural crest derived origin. NF2 encodes the tumor suppressor, Merlin, and its biochemical function is incompletely understood. One well-established function of Merlin is as a negative regulator of group A serine/threonine p21-activated kinases (PAKs). In these studies we explore the role of PAK1 and its closely related paralog, PAK2, both pharmacologically and genetically, in Merlin-deficient Schwann cells and in a genetically engineered mouse model (GEMM) that develops spontaneous vestibular and spinal schwannomas. We demonstrate that PAK1 and PAK2 are both hyper activated in Merlin-deficient murine schwannomas. In preclinical trials, a pan Group A PAK inhibitor, FRAX-1036, transiently reduced PAK1 and PAK2 phosphorylation in vitro, but had insignificant efficacy in vivo. NVS-PAK1-1, a PAK1 selective inhibitor, had a greater but still minimal effect on our GEMM phenotype. However, genetic ablation of Pak1 but not Pak2 reduced tumor formation in our NF2 GEMM. Moreover, germline genetic deletion of Pak1 was well tolerated, while conditional deletion of Pak2 in Schwann cells resulted in significant morbidity and mortality. These data support the further development of PAK1-specific small molecule inhibitors and the therapeutic targeting of PAK1 in vestibular schwannomas and argue against PAK1 and PAK2 existing as functionally redundant protein isoforms in Schwann cells.
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Sughrue, Michael E., Andrea H. Yeung, Martin J. Rutkowski, Steven W. Cheung, and Andrew T. Parsa. "Molecular biology of familial and sporadic vestibular schwannomas: implications for novel therapeutics." Journal of Neurosurgery 114, no. 2 (February 2011): 359–66. http://dx.doi.org/10.3171/2009.10.jns091135.
Повний текст джерелаАнотація:
Vestibular schwannomas (VSs) are benign tumors arising from the sheath of cranial nerve VIII. The pathogenesis underlying most familial and sporadic VSs has been linked to a mutation in a single gene, the neurofibromin 2 (NF2) gene located on chromosome 22, band q11–13.1. In this review, the authors summarized what is known about the epidemiology of NF2 mutations and patients with VSs. The authors also discuss the function of the NF2 gene product, merlin, and describe the known and hypothetical effects of genetic mutations that lead to merlin dysfunction on a broad variety of cellular and histological end points. A better understanding of the molecular pathobiology of VSs may lead to novel therapeutics to augment current modalities of treatment while minimizing morbidity.
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Gronholm, M., M. Sainio, F. Zhao, L. Heiska, A. Vaheri, and O. Carpen. "Homotypic and heterotypic interaction of the neurofibromatosis 2 tumor suppressor protein merlin and the ERM protein ezrin." Journal of Cell Science 112, no. 6 (March 15, 1999): 895–904. http://dx.doi.org/10.1242/jcs.112.6.895.
Повний текст джерелаАнотація:
Ezrin, radixin and moesin (ERM) are homologous proteins, which are linkers between plasma membrane components and the actin-containing cytoskeleton. The ERM protein family members associate with each other in a homotypic and heterotypic manner. The neurofibromatosis 2 (NF2) tumor suppressor protein merlin (schwannomin) is structurally related to ERM members. Merlin is involved in tumorigenesis of NF2-associated and sporadic schwannomas and meningiomas, but the tumor suppressor mechanism is poorly understood. We have studied the ability of merlin to self-associate and bind ezrin. Ezrin was coimmunoprecipitated with merlin from lysates of human U251 glioma cells and from COS-1 cells transfected with cDNA encoding for merlin isoform I. The interaction was further studied and the association domains were mapped with the yeast two-hybrid system and with blot overlay and affinity precipitation experiments. The heterotypic binding of merlin and ezrin and the homotypic association of merlin involves interaction between the amino- and carboxy-termini. The amino-terminal association domain of merlin involves residues 1–339 and has similar features with the amino-terminal association domain of ezrin. The carboxy-terminal association domain cannot be mapped as precisely as in ezrin, but it requires residues 585–595 and a more amino-terminal segment. Unlike ezrin, merlin does not require activation for self-association but native merlin molecules can interact with each other. Heterodimerization between merlin and ezrin, however, occurs only following conformational alterations in both proteins. These results biochemically connect merlin to the cortical cytoskeleton and indicate differential regulation of merlin from ERM proteins.
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Eaton, Charlotte, S. John Liu, Calixto-Hope Lucas, Tim Casey-Clyde, Abrar Choudhury, Vikas Daggubati, Harish Vasudevan, Danielle Swaney, and David Raleigh. "CSIG-37. MERLIN S13 DEPHOSPHORYLATION DRIVES MENINGIOMA WNT SIGNALLING AND CELL PROLIFERATION." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii47. http://dx.doi.org/10.1093/neuonc/noac209.186.
Повний текст джерелаАнотація:
Abstract How Merlin-intact meningiomas arise in the absence of NF2/Merlin inactivation is incompletely understood. Here, we integrate single-cell RNA sequencing of 86,000 cells from meningioma xenografts with APEX2 proteomic proximity-labelling mass spectrometry and functional biochemical approaches to discover Merlin Serine 13 (S13) dephosphorylation drives meningioma Wnt signalling and cell proliferation. Cell biology, molecular biology, and biochemical techniques were used to validate Merlin functions in meningioma cells or xenografts using wildtype Merlin constructs or Merlin constructs encoding S13A, phosphomimetic S13D, or cancer-associated missense substitutions (L46R, A211D). Single-cell RNA sequencing of meningioma xenografts showed Merlin rescue activated the Wnt pathway in Merlin-deficient meningiomas. Proteomic proximity-labelling mass spectrometry revealed b-catenin, PKC, and PP1A interactions with wildtype Merlin, but not with Merlin L46R or A211D. b-catenin does not interact with other FERM family members, and Merlin contains a unique N-terminal domain (NTD) with a PKC phosphorylation motif overlapping with a PP1A dephosphorylation motif at S13. Thus, we hypothesized the Merlin S13, PKC, and PP1A may be important for Wnt signalling in Merlin-intact meningiomas. In support of this hypothesis, over-expression of wildtype Merlin or Merlin S13A but not Merlin DNTD, S13D, L46R, A211D, or other FERM family members drove meningioma Wnt signalling and sustained meningioma cell proliferation in vivo. Moreover, b-catenin was detected in proximity to Merlin S13D but not Merlin S13A in meningioma cells. Meningioma cell fractionation and immunofluorescence showed Merlin S13D over-expression stabilized b-catenin at the plasma membrane and inhibited Wnt signalling. Phospho-proteomic mass spectrometry and custom phospho-specific antibodies integrated with shRNA or siRNA gene suppression demonstrated PKC phosphorylated Merlin S13, but meningioma Wnt pathway activation induced PP1A to dephosphorylate Merlin S13 and drive cell proliferation. In summary, Merlin S13 dephosphorylation drives meningioma Wnt signalling and cell proliferation. These data reveal a novel tumor-promoting function of NF2/Merlin in Merlin-intact meningiomas.
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Gonzalez, Maria Alejandra, Joseph Kissil, and Scott Troutman. "Abstract LB326: Combined inhibition of BRD4 and FAK1 as a novel therapeutic strategy for neurofibromatosis type 2 related schwannomas." Cancer Research 83, no. 8_Supplement (April 14, 2023): LB326. http://dx.doi.org/10.1158/1538-7445.am2023-lb326.
Повний текст джерелаАнотація:
Abstract Neurofibromatosis type 2 (NF2) is a rare disorder that is inherited in an autosomal-dominant manner and is attributed to the loss of heterozygosity (LOH) of the NF2 gene, which encodes for the tumor suppressor protein Merlin. Patients affected by the disease develop vestibular schwannomas (VS), meningiomas, and ependymomas resulting in high morbidity and premature mortality. To date, neurofibromatosis type 2 has no FDA-approved drug-based treatment. Merlin plays a central role in mediating cell contact inhibition (CI) of proliferation. Loss of Merlin leads to abnormal activation of multiple signaling pathways, including those regulated by small G-proteins Ras/Rac/cdc42 and the Hippo-YAP pathway. The Hippo-YAP pathway plays a major role in cell growth and organ size control and at its core is comprised of a kinase cascade that regulates the transcriptional regulator YAP. The function of YAP is crucial for VS development, and there are several mechanisms by which YAP regulates transcription. Some of these functions have been shown to involve the Bromodomain and Extra-Terminal domain (BET) proteins acting as co-factors. We have previously shown that the BET inhibitor JQ1 can selectively reduce the growth of the NF2-null schwannoma and Schwann cells in vitro and tumorigenesis in vivo. Additionally, evidence has shown that Merlin loss can lead to increased cell proliferation that it requires the activity of Focal Adhesion Kinase 1 (FAK1). We have previously demonstrated that FAK1 inhibition via Crizotinib has antiproliferative effects in NF2-null Schwann cells, and is currently in phase II clinical trials in NF2-related VS. In this study, wild-type and NF2-null Schwann cells and schwannoma cell lines were used to determine the impact on cell growth by employing the treatment with the BET inhibitor JQ1 and the FAK1 inhibitor Crizotinib. Our analysis in NF2-null Schwann cells and schwannoma cell lines shows that the combined inhibition exerts an antineoplastic effect at nanomolar concentrations. Moreover, this combination resulted in selective inhibition of NF2-null Schwann cell proliferation when compared to wild-type Schwann cells in vitro, when compared to either drug alone. Our preliminary data suggest that combined targeting of BET and FAK1 may offer a potential therapeutic option for the treatment of NF2-related schwannomas. Citation Format: Maria Alejandra Gonzalez, Joseph Kissil, Scott Troutman. Combined inhibition of BRD4 and FAK1 as a novel therapeutic strategy for neurofibromatosis type 2 related schwannomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB326.
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Gerardo-Ramírez, Monserrat, Vanessa Giam, Diana Becker, Marco Groth, Nils Hartmann, Helen Morrison, Helen L. May-Simera, et al. "Deletion of Cd44 Inhibits Metastasis Formation of Liver Cancer in Nf2-Mutant Mice." Cells 12, no. 9 (April 26, 2023): 1257. http://dx.doi.org/10.3390/cells12091257.
Повний текст джерелаАнотація:
Primary liver cancer is the third leading cause of cancer-related death worldwide. An increasing body of evidence suggests that the Hippo tumor suppressor pathway plays a critical role in restricting cell proliferation and determining cell fate during physiological and pathological processes in the liver. Merlin (Moesin-Ezrin-Radixin-like protein) encoded by the NF2 (neurofibromatosis type 2) gene is an upstream regulator of the Hippo signaling pathway. Targeting of Merlin to the plasma membrane seems to be crucial for its major tumor-suppressive functions; this is facilitated by interactions with membrane-associated proteins, including CD44 (cluster of differentiation 44). Mutations within the CD44-binding domain of Merlin have been reported in many human cancers. This study evaluated the relative contribution of CD44- and Merlin-dependent processes to the development and progression of liver tumors. To this end, mice with a liver-specific deletion of the Nf2 gene were crossed with Cd44-knockout mice and subjected to extensive histological, biochemical and molecular analyses. In addition, cells were isolated from mutant livers and analyzed by in vitro assays. Deletion of Nf2 in the liver led to substantial liver enlargement and generation of hepatocellular carcinomas (HCCs), intrahepatic cholangiocarcinomas (iCCAs), as well as mixed hepatocellular cholangiocarcinomas. Whilst deletion of Cd44 had no influence on liver size or primary liver tumor development, it significantly inhibited metastasis formation in Nf2-mutant mice. CD44 upregulates expression of integrin β2 and promotes transendothelial migration of liver cancer cells, which may facilitate metastatic spreading. Overall, our results suggest that CD44 may be a promising target for intervening with metastatic spreading of liver cancer.
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Карандашева, К. О., Е. С. Макашова, А. А. Мартьянова, К. И. Аношкин, С. В. Золотова, and В. В. Стрельников. "Clinical and molecular genetic features of neurofibromatosis type." Nauchno-prakticheskii zhurnal «Medicinskaia genetika, no. 10 (October 29, 2021): 3–12. http://dx.doi.org/10.25557/2073-7998.2021.10.3-12.
Повний текст джерелаАнотація:
Нейрофиброматоз 2 типа - редкое генетическое заболевание, этиологическим фактором развития которого являются мутации в гене-онкосупрессоре NF2, кодирующем белок мерлин. В обзоре подробно описаны структура, функции и посттрансляционные модификации мерлина, освещены клинические особенности нейрофиброматоза 2 типа, известные клинико-генетические корреляции, а также представлена информация о сайтах связывания мерлина и о функциональном вкладе расположенных в них мутаций, что закладывает базис персонализированной терапии нейрофиброматоза 2 типа. Neurofibromatosis type 2 is a rare genetic disorder caused by pathogenic mutations in the NF2 tumor suppressor gene which encodes a protein called merlin. This review describes the structure, functions, and post-translational modifications of merlin, highlights clinical features and known genotype-phenotype correlations of neurofibromatosis type 2, and provides information on the merlin binding sites and the functional contribution of mutations they harbor, which lays the basis for personalized therapy for neurofibromatosis type 2.
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Moesslacher, Christina S., Elisabeth Auernig, Jonathan Woodsmith, Andreas Feichtner, Evelyne Jany-Luig, Stefanie Jehle, Josephine M. Worseck, Christian L. Heine, Eduard Stefan, and Ulrich Stelzl. "Missense variant interaction scanning reveals a critical role of the FERM domain for tumor suppressor protein NF2 conformation and function." Life Science Alliance 6, no. 8 (June 6, 2023): e202302043. http://dx.doi.org/10.26508/lsa.202302043.
Повний текст джерелаАнотація:
NF2 (moesin–ezrin–radixin-like [MERLIN] tumor suppressor) is frequently inactivated in cancer, where its NF2 tumor suppressor functionality is tightly coupled to protein conformation. How NF2 conformation is regulated and how NF2 conformation influences tumor suppressor activity is a largely open question. Here, we systematically characterized three NF2 conformation-dependent protein interactions utilizing deep mutational scanning interaction perturbation analyses. We identified two regions in NF2 with clustered mutations which affected conformation-dependent protein interactions. NF2 variants in the F2–F3 subdomain and the α3H helix region substantially modulated NF2 conformation and homomerization. Mutations in the F2–F3 subdomain altered proliferation in three cell lines and matched patterns of disease mutations in NF2 related-schwannomatosis. This study highlights the power of systematic mutational interaction perturbation analysis to identify missense variants impacting NF2 conformation and provides insight into NF2 tumor suppressor function.
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Short, Ben. "Merlin casts its spell on the cortical cytoskeleton." Journal of Cell Biology 211, no. 2 (October 19, 2015): 207. http://dx.doi.org/10.1083/jcb.2112if.
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Srotyr, Marie, Liyam Laraba, Glenn M. Harper, Charlotte Lespade, Evyn Woodhouse, Alison C. Lloyd, and David B. Parkinson. "Use of a new mouse schwannoma tumour model to monitor changes in peripheral nerve morphology in Merlin null Schwann cells." Neuro-Oncology 23, Supplement_4 (October 1, 2021): iv7—iv8. http://dx.doi.org/10.1093/neuonc/noab195.014.
Повний текст джерелаАнотація:
Abstract Aims Our lab is interested in signals that trigger schwannoma tumour formation and we have previously shown that peripheral nerve injury triggers tumour formation in nerves with Schwann cell-specific loss of the Merlin (NF2) tumour suppressor. The Ras/Raf/MAPK/ERK pathway activity in myelinating Schwann cells is involved in nerve regeneration, causing demyelination and recruitment of inflammatory cells in areas of nerve damage, as well as dedifferentiation of myelinating Schwann cells into a repair-competent state. We have used a mouse model expressing a tamoxifen-inducible Raf-Kinase estrogen receptor fusion protein (Raf-TR) in myelinating Schwann cells of the PNS in either a control wild-type Merlin or Merlin-null background. This allows us to determine the effects of an injury-like signal in Schwann cells and its role in generating schwannoma tumour development. We present here a detailed analysis of the proliferation of Schwann cells within the nerve and morphological changes in PNS structure following Raf-TR activation. Method The P0-promotor driving the Raf-TR transgene is active in myelinating Schwann cells but inactive in the non-myelinating population, allowing specific targeting of the myelinating Schwann cell population. In addition to the Raf-TR gene, the mice exhibit a separate P0-promotor controlled Cre floxed NF2 gene which undergoes Cre-mediated recombinase at embryonic day 13.5 causing NF2 knockout in all developing Schwann cells. Mice aged between 4-6 weeks received intraperitoneal injections of either 2mg Tamoxifen or oil vehicle for 5 consecutive days and were then studied at either 10 or 21 days post-first injection. The peripheral nervous system of the mice was studied with fluorescent immuno-histochemistry staining, semithin sections and transmission electron microscopy (TEM) on sciatic nerves and dorsal root ganglia (DRG). Results Activation of the Ras/Raf/MAPK/ERK pathway in NF2 null Schwann cells led to higher rates of proliferation within sciatic nerves at 10d post-tamoxifen injections. At both 10d and 21d Raf-TR+ NF2-null mice sciatic nerve fascicles were visibly larger with significantly more cell bodies present than controls, however at 21d the rate of proliferation had reduced. In the DRG, proliferation was higher in Raf-TR+ NF2-null mice compared to controls, with proliferation remaining high at 21 days. Quantitative imaging of peripheral nerve semi-thins analysed to date showed no significant difference in the number of myelin rings present in the fascicles between different genotypes. Additionally, dual immuno-histochemistry staining with Myelin Basic Protein and EdU, markers for myelin and proliferation respectively, appeared to show proliferation in the non-myelinating Schwann cell population. Results from staining with other cell markers will also be presented, as well as a detailed analysis of nerve structure using TEM. Conclusion While developmental myelination of Merlin-null Schwann cells appears largely normal, the reaction of Merlin-null Schwann cells in the nerve to an injury signal (activation of the Raf-TR) is remarkably different from those of control nerves. The high levels of proliferation in Merlin-null Schwann cells may be indicative of a higher tumorigenesis potential. While the proliferation of Merlin-null cells does reduce over time in the sciatic nerve, further experiments are now testing whether there may be ongoing tumour growth at other locations in the nervous system that are associated with NF2 tumours in human patients.
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Woodhouse, Evyn, Liyam Laraba, Charlotte Lespade, Marie Srotyr, Alison C. Lloyd, and David B. Parkinson. "Activation of MAPK/ERK signalling in Merlin-null Schwann cells leads to increased and sustained immune cell infiltration in the peripheral nervous system." Neuro-Oncology 23, Supplement_4 (October 1, 2021): iv8. http://dx.doi.org/10.1093/neuonc/noab195.017.
Повний текст джерелаАнотація:
Abstract Aims Previous work has shown that increased numbers of macrophages are associated with more rapid schwannoma tumour growth and we are interested in signals that control entry of macrophages and other immune cells into these tumours. Activation of the Raf-kinase domain and the Raf/MEK/ERK pathway within Schwann cells has been observed to induce an inflammatory response in peripheral nerves in the absence of injury. Activation of an inducible Raf-kinase transgene in Schwann cells allows modelling of acute demyelination of peripheral nerves without nerve injury. This Raf-oestrogen receptor fusion protein (Raf-TR) is activated by the oestrogen analogue Tamoxifen and so allows targeted, controlled activation of the Raf/MEK/ERK pathway within the Schwann cells. Here, in order to understand drivers of tumour formation, we assess the effect of MAPK activation in Merlin-null Schwann cells upon immune cell infiltration within the PNS. Method RafTR-P0CRE-NF2fl/fl mice of 4-6 weeks age were injected daily (IP) with 2mg of 4-hydroxy-tamoxifen or vehicle (corn oil) control for 5 consecutive days. RafTR was activated on either a Merlin (NF2) wild-type (NF2 fl/fl, P0-CRE-) or NF2 null (NF2 fl/fl, P0-CRE+) background and effects on immune cell infiltration studied in each condition. Immunofluorescence was performed in the dorsal root ganglia (DRGs) and sciatic nerves of mice to identify various immune cell infiltrates at various timepoints. These will include neutrophils, mast cells, T-Cells and macrophages using the cell markers Csf3r, C-kit, CD3 and IBA1 respectively. Results At 21 days post treatment, a significantly increased infiltration of macrophages within the sciatic nerve and dorsal root ganglia was observed in mice treated with Tamoxifen when compared to vehicle controls. Loss of NF2 led to a massive increase in the number of macrophages recruited to peripheral nerves in tamoxifen-treated mice compared to Cre- mice and Cre+ treated with vehicle alone. Further assessment of other immune cell infiltration including neutrophils, mast cells and T cells are ongoing. Conclusion Raf/MEK/ERK signalling, in the absence of tumour suppressor Merlin, significantly increases the infiltration of inflammatory cells such as macrophages into peripheral nerves even in the absence of injury. As this effect is enhanced in NF2 null mice, this suggests that Merlin plays an important role in inhibiting the inflammatory response in peripheral nerves. It also suggests that Merlin could be involved in maintaining the blood nerve barrier (BNB), as in its absence the greater influx of immune cells into the nerves and DRGs suggests a more complete loss of BNB function than just activation of the Raf/MEK/ERK cascade alone.
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Roehrig, Anne E., Kristina Klupsch, Juan A. Oses-Prieto, Selim Chaib, Stephen Henderson, Warren Emmett, Lucy C. Young, et al. "Cell-cell adhesion regulates Merlin/NF2 interaction with the PAF complex." PLOS ONE 16, no. 8 (August 23, 2021): e0254697. http://dx.doi.org/10.1371/journal.pone.0254697.
Повний текст джерелаАнотація:
The PAF complex (PAFC) coordinates transcription elongation and mRNA processing and its CDC73/parafibromin subunit functions as a tumour suppressor. The NF2/Merlin tumour suppressor functions both at the cell cortex and nucleus and is a key mediator of contact inhibition but the molecular mechanisms remain unclear. In this study we have used affinity proteomics to identify novel Merlin interacting proteins and show that Merlin forms a complex with multiple proteins involved in RNA processing including the PAFC and the CHD1 chromatin remodeller. Tumour-derived inactivating mutations in both Merlin and the CDC73 PAFC subunit mutually disrupt their interaction and growth suppression by Merlin requires CDC73. Merlin interacts with the PAFC in a cell density-dependent manner and we identify a role for FAT cadherins in regulating the Merlin-PAFC interaction. Our results suggest that in addition to its function within the Hippo pathway, Merlin is part of a tumour suppressor network regulated by cell-cell adhesion which coordinates post-initiation steps of the transcription cycle of genes mediating contact inhibition.
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Hennigan, Robert F., Lauren A. Foster, Mary F. Chaiken, Timmy Mani, Michelle M. Gomes, Andrew B. Herr, and Wallace Ip. "Fluorescence Resonance Energy Transfer Analysis of Merlin Conformational Changes." Molecular and Cellular Biology 30, no. 1 (November 2, 2009): 54–67. http://dx.doi.org/10.1128/mcb.00248-09.
Повний текст джерелаАнотація:
ABSTRACT Neurofibromatosis type 2 is an inherited autosomal disorder caused by biallelic inactivation of the NF2 tumor suppressor gene. The NF2 gene encodes a 70-kDa protein, merlin, which is a member of the ezrin-radixin-moesin (ERM) family. ERM proteins are believed to be regulated by a transition between a closed conformation, formed by binding of their N-terminal FERM domain and C-terminal tail domain (CTD), and an open conformation, in which the two domains do not interact. Previous work suggests that the tumor suppressor function of merlin is similarly regulated and that only the closed form is active. Therefore, understanding the mechanisms that control its conformation is crucial. We have developed a series of probes that measures merlin conformation by fluorescence resonance energy transfer, both as purified protein and in live cells. Using these tools, we find that merlin exists predominately as a monomer in a stable, closed conformation that is mediated by the central α-helical domain. The contribution from the FERM-CTD interaction to the closed conformation appears to be less important. Upon phosphorylation or interaction with an effector protein, merlin undergoes a subtle conformational change, suggesting a novel mechanism that modulates the interaction between the FERM domain and the CTD.
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Guerrero, P. A., W. Yin, L. Camacho, and D. Marchetti. "Oncogenic role of Merlin/NF2 in glioblastoma." Oncogene 34, no. 20 (July 21, 2014): 2621–30. http://dx.doi.org/10.1038/onc.2014.185.
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Chiang, Ming-Fu, Shur-Tzu Chen, Chen-Peng Lo, Chun-I. Sze, Nan-Shan Chang, and Yu-Jen Chen. "Expression of WW Domain-Containing Oxidoreductase WOX1 in Human Nervous System Tumors." Analytical Cellular Pathology 36, no. 5-6 (2013): 133–47. http://dx.doi.org/10.1155/2013/945156.
Повний текст джерелаАнотація:
Background and ObjectiveS: We aimed to evaluate the expression levels of the tumor suppressor WOX1 in nervous system tumors and its co-expression with p53 and neurofibromatosis type 2/merlin (NF2) tumor suppressor gene products.Methods: Immunohistochemistry, western blotting andin situhybridization were used for WOX1 protein and WWOX mRNA expression. Immunofluorescence and electron microscopical immunohistochemistry were performed for colocalization of gene products.Results: WOX1 expression is low in normal cortical neurons, mainly on the axon fibers, whereas there is moderate to high immunoreactivity in the cytosol and nuclei of certain tumor cells. In the microcystic (WHO grade I) and malignant (WHO grade III) meningiomas, WOX1 expression is intense, but various in transitional (WHO grade I) and atypical (WHO grade II) subtypes. WOX1 levels are moderate to high in the menigiotheliomatous area, but relatively low in the fibroblastic area. WOX1 and NF2/merlin, but not p53, colocalized in certain tumor cells, primarily at the borders of nuclei. Schwannoma and astrocytoma specimens stained moderately to strongly positive for the WOX1 protein. Interestingly, the expression of WOX1, NF2/merlin and mutant p53 is intense in high grade glioblastoma, but WOX1 expression is low in metastatic carcinoma or adenocarcinoma.Conclusions: The expression of WOX1 on different types of nervous system tumors, including primary and metastatic tumors, is differential.
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McCartney, B. M., and R. G. Fehon. "Distinct cellular and subcellular patterns of expression imply distinct functions for the Drosophila homologues of moesin and the neurofibromatosis 2 tumor suppressor, merlin." Journal of Cell Biology 133, no. 4 (May 15, 1996): 843–52. http://dx.doi.org/10.1083/jcb.133.4.843.
Повний текст джерелаАнотація:
Interest in members of the protein 4.1 super-family, which includes the ezrin-radixin-moesin (ERM) group, has been stimulated recently by the discovery that the human neurofibromatosis 2 (NF2) tumor suppressor gene encodes an ERM-like protein, merlin. Although many proteins in this family are thought to act by linking the actin-based cytoskeleton to transmembrane proteins, the cellular functions of merlin have not been defined. To investigate the cellular and developmental functions of these proteins, we have identified and characterized Drosophila homologues of moesin (Dmoesin) and of the NF2 tumor suppressor merlin (Dmerlin). Using specific antibodies, we show that although these proteins are frequently coexpressed in developing tissues, they display distinct subcellular localizations. While Dmoesin is observed in continuous association with the plasma membrane, as is typical for an ERM family protein, Dmerlin is found in punctuate structures at the membrane and in the cytoplasm. Investigation of Dmerlin cultured cells demonstrates that it is associated with endocytic compartments. As a result of these studies, we propose that the merlin protein has unique functions in the cell which differ from those of other ERM family members.
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López-Lago, Miguel A., Tomoyo Okada, Miguel M. Murillo, Nick Socci, and Filippo G. Giancotti. "Loss of the Tumor Suppressor Gene NF2, Encoding Merlin, Constitutively Activates Integrin-Dependent mTORC1 Signaling." Molecular and Cellular Biology 29, no. 15 (May 18, 2009): 4235–49. http://dx.doi.org/10.1128/mcb.01578-08.
Повний текст джерелаАнотація:
ABSTRACT Integrin signaling promotes, through p21-activated kinase, phosphorylation and inactivation of the tumor suppressor merlin, thus removing a block to mitogenesis in normal cells. However, the biochemical function of merlin and the effector pathways critical for the pathogenesis of malignant mesothelioma and other NF2-related malignancies are not known. We report that integrin-specific signaling promotes activation of mTORC1 and cap-dependent mRNA translation. Depletion of merlin rescues mTORC1 signaling in cells deprived of anchorage to a permissive extracellular matrix, suggesting that integrin signaling controls mTORC1 through inactivation of merlin. This signaling pathway controls translation of the cyclin D1 mRNA and, thereby, cell cycle progression. In addition, it promotes cell survival. Analysis of a panel of malignant mesothelioma cell lines reveals a strong correlation between loss of merlin and activation of mTORC1. Merlin-negative lines are sensitive to the growth-inhibitory effect of rapamycin, and the expression of recombinant merlin renders them partially resistant to rapamycin. Conversely, depletion of merlin restores rapamycin sensitivity in merlin-positive lines. These results indicate that integrin-mediated adhesion promotes mTORC1 signaling through the inactivation of merlin. Furthermore, they reveal that merlin-negative mesotheliomas display unregulated mTORC1 signaling and are sensitive to rapamycin, thus providing a preclinical rationale for prospective, biomarker-driven clinical studies of mTORC1 inhibitors in these tumors.
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Petrilli, A. M., and C. Fernández-Valle. "Role of Merlin/NF2 inactivation in tumor biology." Oncogene 35, no. 5 (April 20, 2015): 537–48. http://dx.doi.org/10.1038/onc.2015.125.
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Smole, Zlatko, Claudio R. Thoma, Kathryn T. Applegate, Maria Duda, Katrin L. Gutbrodt, Gaudenz Danuser, and Wilhelm Krek. "Tumor Suppressor NF2/Merlin Is a Microtubule Stabilizer." Cancer Research 74, no. 1 (November 26, 2013): 353–62. http://dx.doi.org/10.1158/0008-5472.can-13-1334.
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Thurneysen, Claudio, Isabelle Opitz, Stefanie Kurtz, Walter Weder, Rolf A. Stahel, and Emanuela Felley-Bosco. "Functional inactivation of NF2/merlin in human mesothelioma." Lung Cancer 64, no. 2 (May 2009): 140–47. http://dx.doi.org/10.1016/j.lungcan.2008.08.014.
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Martin, Spencer D., Simon Cheung, and Andrew Churg. "Immunohistochemical Demonstration of Merlin/NF2 Loss in Mesothelioma." Modern Pathology 36, no. 1 (January 2023): 100036. http://dx.doi.org/10.1016/j.modpat.2022.100036.
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Chiasson-MacKenzie, Christine, Zachary S. Morris, Quentin Baca, Brett Morris, Joanna K. Coker, Rossen Mirchev, Anne E. Jensen, et al. "NF2/Merlin mediates contact-dependent inhibition of EGFR mobility and internalization via cortical actomyosin." Journal of Cell Biology 211, no. 2 (October 19, 2015): 391–405. http://dx.doi.org/10.1083/jcb.201503081.
Повний текст джерелаАнотація:
The proliferation of normal cells is inhibited at confluence, but the molecular basis of this phenomenon, known as contact-dependent inhibition of proliferation, is unclear. We previously identified the neurofibromatosis type 2 (NF2) tumor suppressor Merlin as a critical mediator of contact-dependent inhibition of proliferation and specifically found that Merlin inhibits the internalization of, and signaling from, the epidermal growth factor receptor (EGFR) in response to cell contact. Merlin is closely related to the membrane–cytoskeleton linking proteins Ezrin, Radixin, and Moesin, and localization of Merlin to the cortical cytoskeleton is required for contact-dependent regulation of EGFR. We show that Merlin and Ezrin are essential components of a mechanism whereby mechanical forces associated with the establishment of cell–cell junctions are transduced across the cell cortex via the cortical actomyosin cytoskeleton to control the lateral mobility and activity of EGFR, providing novel insight into how cells inhibit mitogenic signaling in response to cell contact.
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Cole, Banumathi K., Marcello Curto, Annie W. Chan, and Andrea I. McClatchey. "Localization to the Cortical Cytoskeleton Is Necessary for Nf2/Merlin-Dependent Epidermal Growth Factor Receptor Silencing." Molecular and Cellular Biology 28, no. 4 (December 17, 2007): 1274–84. http://dx.doi.org/10.1128/mcb.01139-07.
Повний текст джерелаАнотація:
ABSTRACT Merlin, the product of the NF2 tumor suppressor gene, is closely related to the ERM (ezrin, radixin, moesin) proteins, which provide anchorage between membrane proteins and the underlying cortical cytoskeleton; all four proteins are members of the band 4.1 superfamily. Despite their similarity, the subcellular distributions and functional properties of merlin and the ERM proteins are largely distinct. Upon cell-cell contact merlin prevents internalization of and signaling from the epidermal growth factor receptor (EGFR) by sequestering it into an insoluble membrane compartment. Here we show that the extreme amino (N) terminus directs merlin biochemically to an insoluble membrane compartment and physically to the cortical actin network, with a marked concentration along cell-cell boundaries. This insoluble-membrane distribution is required for the growth-suppressing function of merlin and for the functional association of merlin with EGFR and other membrane receptors. Our data support a model whereby locally activated merlin sequesters membrane receptors such as EGFR at the cortical network, contributing to the long-held observation that the cortical actin cytoskeleton can control the lateral mobility of and signaling from certain membrane receptors.
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Sainio, M., F. Zhao, L. Heiska, O. Turunen, M. den Bakker, E. Zwarthoff, M. Lutchman, et al. "Neurofibromatosis 2 tumor suppressor protein colocalizes with ezrin and CD44 and associates with actin-containing cytoskeleton." Journal of Cell Science 110, no. 18 (September 15, 1997): 2249–60. http://dx.doi.org/10.1242/jcs.110.18.2249.
Повний текст джерелаАнотація:
Neurofibromatosis 2 (NF2) protein (merlin; schwannomin) is a tumor suppressor involved in tumorigenesis of NF2-associated and sporadic schwannomas and meningiomas. The protein shares the domain structure of three homologous proteins: ezrin, radixin and moesin (ERM). ERM proteins function as membrane organizers and may act as linkers between plasma membrane molecules, such as CD44 and ICAM-2, and the cytoskeleton. We analyzed the distribution and effects of transfected NF2 protein in COS-1, CHO and 293 cells, and endogenous NF2 protein in U251 glioma cells. The distribution was compared to ezrin, CD44 and F-actin. Both transfected and endogenous NF2 protein localized underneath the plasma membrane in a pattern typical of an ERM protein. In COS-1 transfectants, NF2 protein typically codistributed with ezrin but, in cells with poorly developed actin cytoskeleton, it replaced ezrin in filopodia and ruffling edges. NF2 protein colocalized with CD44, which in transfected cells accumulated into restructured cell membrane protrusions. The association of CD44 and NF2 protein was further suggested by binding of CD44 from cellular lysates to recombinant NF2 protein. Interaction between NF2 protein and the actin-containing cytoskeleton was indicated by partial colocalization, by cytochalasin B-induced coclustering, and by retention of NF2 protein in the detergent-insoluble fraction. Transfected NF2 protein induced morphogenic changes. The cells contained restructured membrane extensions and blebs, and CHO cells expressing NF2 protein were more elongated than control transfectants. In conclusion, NF2 protein possesses functional properties of an ERM family member.
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Jindal, Hitesh K., Kazumi Yoshinaga, Pil-Soo Seo, Mohini Lutchman, Patrick A. Dion, Guy A. Rouleau, Toshihiko Hanada, and Athar H. Chishti. "Purification of the NF2 Tumor Suppressor Protein from Human Erythrocytes." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 33, no. 4 (November 2006): 394–402. http://dx.doi.org/10.1017/s0317167100005357.
Повний текст джерелаАнотація:
Background:Neurofibromatosis type 2 (NF2) is an autosomal dominant disease predisposing individuals to the risk of developing tumors of cranial and spinal nerves. The NF2 tumor suppressor protein, known as Merlin/Schwanomin, is a member of the protein 4.1 superfamily that function as links between the cytoskeleton and the plasma membrane.Methods:Upon selective extraction of membrane-associated proteins from erythrocyte plasma membrane (ghosts) using low ionic strength solution, the bulk of NF2 protein remains associated with the spectrin-actin depleted inside-out-vesicles. Western blot analysis showed a ~70 kDa polypeptide in the erythrocyte plasma membrane. Furthermore, quantitative removal of NF2 protein from the inside-out-vesicles was achieved using 1.0 M potassium iodide, a treatment known to remove tightly-bound peripheral membrane proteins.Results:These results suggest a novel mode of NF2 protein association with the erythrocyte membrane that is distinct from the known membrane interactions of protein 4.1. Based on these biochemical properties, several purification strategies were devised to isolate native NF2 protein from human erythrocyte ghosts. Using purified and recombinant NF2 protein as internal standards, we quantified approximately ~41-65,000 molecules of NF2 protein per erythrocyte.Conclusion:We provide evidence for the presence of NF2 protein in the human erythrocyte membrane. The identification of NF2 protein in the human erythrocyte membrane will make it feasible to discover novel interactions of NF2 protein utilizing powerful techniques of erythrocyte biochemistry and genetics in mammalian cells.
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Hennigan, Robert F., Craig S. Thomson, Kye Stachowski, Nicolas Nassar, and Nancy Ratner. "Merlin tumor suppressor function is regulated by PIP2-mediated dimerization." PLOS ONE 18, no. 2 (February 21, 2023): e0281876. http://dx.doi.org/10.1371/journal.pone.0281876.
Повний текст джерелаАнотація:
Neurofibromatosis Type 2 is an inherited disease characterized by Schwann cell tumors of cranial and peripheral nerves. The NF2 gene encodes Merlin, a member of the ERM family consisting of an N-terminal FERM domain, a central α-helical region, and a C-terminal domain. Changes in the intermolecular FERM-CTD interaction allow Merlin to transition between an open, FERM accessible conformation and a closed, FERM-inaccessible conformation, modulating Merlin activity. Merlin has been shown to dimerize, but the regulation and function Merlin dimerization is not clear. We used a nanobody based binding assay to show that Merlin dimerizes via a FERM-FERM interaction, orientated with each C-terminus close to each other. Patient derived and structural mutants show that dimerization controls interactions with specific binding partners, including HIPPO pathway components, and correlates with tumor suppressor activity. Gel filtration experiments showed that dimerization occurs after a PIP2 mediated transition from closed to open conformation monomers. This process requires the first 18 amino acids of the FERM domain and is inhibited by phosphorylation at serine 518. The discovery that active, open conformation Merlin is a dimer represents a new paradigm for Merlin function with implications for the development of therapies designed to compensate for Merlin loss.
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NEILL, Graham W., та Mark R. CROMPTON. "Binding of the merlin-I product of the neurofibromatosis type 2 tumour suppressor gene to a novel site in β-fodrin is regulated by association between merlin domains". Biochemical Journal 358, № 3 (10 вересня 2001): 727–35. http://dx.doi.org/10.1042/bj3580727.
Повний текст джерелаАнотація:
The mechanism underlying the tumour-suppressor activity of the neurofibromatosis type 2 (NF2) gene product, merlin, is largely undefined but there is evidence that the biological function of the protein might be mediated partly through interactions with the cytoskeleton. Merlin is expressed predominantly as two isoforms that differ at their C-termini owing to alternative splicing of exon 16. By expressing merlin isoform I as bait in a yeast two-hybrid screen, we isolated a clone encoding a region of the cytoskeletal protein β-fodrin. Confirmation of the merlin–fodrin interaction was provided by using the mammalian two-hybrid system and binding assays in vitro. In addition, these assays and co-immunoprecipitation from mammalian cells revealed that the binding site for fodrin is located in the C-terminal half of merlin at a site that is masked in the native protein. Co-expression of the N-terminus of merlin decreased the interaction of its C-terminus with fodrin, implicating homophilic interactions of merlin isoform I in masking the fodrin-binding site. The effect of three disease-associated mutations on the merlin–fodrin interaction and merlin dimerization was also investigated. The mutation L535P, but not L360P or K413E, significantly decreased the merlin–fodrin interaction but not dimerization, indicating that the tumour suppressor ability of merlin might reside partly in its ability to interact with the cytoskeleton via fodrin.
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Belliveau, Michael J., Mohini Lutchman, Jaime O. Claudio, Claude Marineau, and Guy A. Rouleau. "Schwannomin: new insights into this member of the band 4.1 superfamily." Biochemistry and Cell Biology 73, no. 9-10 (September 1, 1995): 733–37. http://dx.doi.org/10.1139/o95-081.
Повний текст джерелаАнотація:
Neurofibromatosis type 2 (NF2) is an autosomal dominant disease characterized by the development of central nervous system tumours. The NF2 gene was recently cloned and found to encode a protein, schwannomin (or merlin), with homology to the band 4.1 superfamily. This superfamily of proteins includes ezrin, moesin, radixin, and talin, as well as several protein tyrosine phosphatases. How does a cytoskeleton-associated protein act as a tumour suppressor? While this fundamental question remains unanswered, recent studies have begun to address key questions regarding the function of schwannomin. In this review, we examine what is known about the band 4.1 superfamily and how this information pertains to schwannomin. In addition, we summarize recent studies of schwannomin itself.Key words: NF2, band 4.1, tumour suppressor, cytoskeleton.
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Benton, Dorothy, and Jonathan Chernoff. "Abstract 2629: Single and combined inhibition of PAK and Hippo pathway in NF2-deficient schwannoma." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2629. http://dx.doi.org/10.1158/1538-7445.am2023-2629.
Повний текст джерелаАнотація:
Abstract Neurofibromatosis 2 (NF2) Syndrome is a rare, but devastating genetic condition that leads to non-cancerous tumors of the nervous system. NF2 patients are likely to develop Schwannomas on the eighth cranial nerve that lead to progressive deafness and spinal cord compression as well as meningiomas and peripheral nerve tumors. Effective treatment for these patients is lacking, with risky surgery being the most reliable approach and pharmacotherapies having inadequate results. The hallmark mutation of this condition is inactivation of NF2, which codes for the protein Merlin. Merlin plays several roles in the cell, two of the most consequential being inhibition of PAK1 and activation of the Hippo tumor suppressor pathway. However, drugs targeting these pathways have not yet been investigated in NF2-deficient Schwannoma. In this study, we explored the use of YAP-TEAD inhibitors as well as the combination of Hippo family and Group I PAK inhibition in NF2-deficient Schwannoma cells. We used several Schwannoma cells lines of human, mouse, and rat origin as well as a human Schwann cell line with NF2 knocked out via CRISPR compared to its wild-type control line. We investigated the role of YAP, the main effector of the Hippo pathway, and PAK1/2 in NF2 Schwannoma cells via genetic and pharmacologic inhibition. We also combined YAP-TEAD inhibitors with several PAK family inhibitors to induce a synergistic reduction in cell viability and proliferation as well as an increase in apoptosis. We found that genetic inhibition of both YAP and Group I PAK proteins led to partial reduction in Schwannoma growth. Using several YAP-TEAD binding inhibitors (TED-347, NSC682769, IK-930), Group I PAK inhibitors (FRAX-1036, G555) and PAK1-specific inhibitor (NVS-1-PAK1) we found that YAP-TEAD binding inhibition combined with Group I PAK inhibition has the greatest reduction on Schwannoma cell viability, proliferation, and increase in cell death. Taken together, our findings indicate that both the Hippo pathway and PAK proteins may be viable targets for Schwannoma therapies. Furthermore, combining the two may lead to a synergistic effect and further prevent growth of NF2-deficient Schwannomas. Citation Format: Dorothy Benton, Jonathan Chernoff. Single and combined inhibition of PAK and Hippo pathway in NF2-deficient schwannoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2629.
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Primi, Marina C., Erumbi S. Rangarajan, Dipak N. Patil, and Tina Izard. "Conformational flexibility determines the Nf2/merlin tumor suppressor functions." Matrix Biology Plus 12 (December 2021): 100074. http://dx.doi.org/10.1016/j.mbplus.2021.100074.
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