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Journal articles on the topic 'Merlin'

Author: Grafiati

Published: 4 June 2021

Last updated: 12 October 2024

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1

Liu, Tzu-Yu. "White Merlin: A Modern Misconception about the Legendary Merlin." Arthuriana 33, no. 3 (September 2023): 10–35. http://dx.doi.org/10.1353/art.2023.a910869.

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Abstract: Different from the predominantly white Merlins on both big and small screens today, Merlins in medieval legends are never described as having white skin. In fact, in various texts Merlin is specifically depicted as a dark-skinned character capable of making legendary accomplishments. The few Merlins of color onscreen have informed our understanding of Merlin as a legendary character in various ways, and more diverse representations of Merlin onscreen could help to dispel the misconception that the legendary Merlin is by default white. (TL)

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2

Price, Katie. "The Merlin Trust." Sibbaldia: the International Journal of Botanic Garden Horticulture, no. 14 (January 17, 2017): 157–67. http://dx.doi.org/10.24823/sibbaldia.2016.206.

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In 1990, the renowned plantswoman Valerie Finnis VMH founded the Merlin Trust, a charity that awards travel grants to young horticulturists. Ten years after her death in 2006, the Merlin Trust remains true to her vision, and the ever-growing band of ‘Merlins’ enrich the horticultural world with the knowledge and skills they have gained on their travels. Many of these horticulturists havegone on to work in botanic and physic gardens and this paper gives some examples of these.

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3

Baudry, Robert. "La Vita Merlini : ou les Métamorphoses Merlin." Bien Dire et Bien Aprandre, no. 20 (April 1, 2022): 7–24. http://dx.doi.org/10.54563/bdba.1555.

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4

Gracia, Paloma. "Los Baladros de Burgos (1498) y Sevilla (1535) frente a frente: su idiosincrasia y la de su modelo." Revista de Filología Española 102, no. 1 (July 7, 2022): 111–32. http://dx.doi.org/10.3989/rfe.2022.005.

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El artículo confronta las dos versiones impresas de Merlin —el Baladro del sabio Merlín con sus profecías impreso por Juan de Burgos (Burgos, 1498) y el “Baladro” publicado como primer libro de la Demanda del Sancto Grial con los maravillosos fechos de Lanzarote y de Galaz su hijo (Sevilla, 1535)— con su modelo francés: La Suite du Roman de Merlin, al objeto de discurrir sobre la naturaleza de los impresos.

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5

Wiklund, Christer G., and Bengt L. Larsson. "The distribution of breeding Merlins Falco columbarius in relation to food and nest sites." Ornis Svecica 4, no. 2–3 (July 1, 1994): 113–22. http://dx.doi.org/10.34080/os.v4.23025.

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This study deals with nest site selection and with the importance of food and nest sites as determinants of breeding density of Merlins Falco columbarius. Merlins preferred Hooded Crow Corvus corone comix nests less than 2 years old, which had not been used previously by Merlins. Artificial nests meeting these requirements were provided in a study area where the number of suitable nests for Merlins was low. Food abundance (number of passerines) was estimated in this area and in a control area where up to 15 Merlin pairs could breed. The number of breeding Merlin pairs did not increase in the nest provision area in relation to the number of nests provided. One possible reason was that the accessibility of prey was limited by snow, which was much more abundant in the nest provision area than in the control area. Therefore, we suggest that the density of breeding Merlins in this area was mainly determined by food particularly during the mating period.

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6

Berthelot, Anne. ""Translatio Merlini": a French Merlin returns to England." Bulletin des anglicistes médiévistes 76, no. 1 (2009): 1–19. http://dx.doi.org/10.3406/bamed.2009.2468.

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7

Lamarche, Caroline, and Paul Curtis Daw. "Merlin." Massachusetts Review 62, no. 1 (2021): 88–94. http://dx.doi.org/10.1353/mar.2021.0014.

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8

Carlile, Henry. "Merlin." Iowa Review 15, no. 1 (January 1985): 98. http://dx.doi.org/10.17077/0021-065x.3193.

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9

Snook, Joann. "Merlin." English Journal 83, no. 3 (March 1994): 103. http://dx.doi.org/10.2307/820943.

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10

Kaliorakis, Manolis, Dimitris Gizopoulos, Ramon Canal, and Antonio Gonzalez. "MeRLiN." ACM SIGARCH Computer Architecture News 45, no. 2 (September 14, 2017): 241–54. http://dx.doi.org/10.1145/3140659.3080225.

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11

Ron Pretty. "Merlin." Antipodes 31, no. 1 (2017): 145. http://dx.doi.org/10.13110/antipodes.31.1.0145.

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12

Livshits, Benjamin, Aditya V. Nori, Sriram K. Rajamani, and Anindya Banerjee. "Merlin." ACM SIGPLAN Notices 44, no. 6 (May 28, 2009): 75–86. http://dx.doi.org/10.1145/1543135.1542485.

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13

Santha, Miklos. "Relativized Arthur-Merlin versus Merlin-Arthur games." Information and Computation 80, no. 1 (January 1989): 44–49. http://dx.doi.org/10.1016/0890-5401(89)90022-9.

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14

Sodhi, Navjot S., Andrew Didiuk, and Lynn W. Oliphant. "Differences in bird abundance in relation to proximity of Merlin nests." Canadian Journal of Zoology 68, no. 5 (May 1, 1990): 852–54. http://dx.doi.org/10.1139/z90-123.

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Point counts made at different distances from Merlin (Falco columbarius) nests revealed that there were fewer birds near the nests than further away. All species showed this trend, regardless of the likelihood of predation by the Merlins. We propose that this is primarily an avoidance reaction of birds towards nesting Merlins to avoid predation and (or) potential injuries. Point counts made after the Merlins left their nests showed that the number of birds was independent of the distance from the nests.

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15

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.

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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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16

Fleissner, R. F. "Merlin Reclad." Ben Jonson Journal 7, no. 1 (January 2000): 555–66. http://dx.doi.org/10.3366/bjj.2000.7.1.26.

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17

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.

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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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18

Carrión Molina, Claudia. "La representación de Merlín en 'Merlín e Familia' de Álvaro Cunqueiro." Cartaphilus 21 (April 7, 2024): 124–40. http://dx.doi.org/10.6018/cartaphilus.571171.

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Merlin’s symbolic enrichment achieves such a significance throughout the Arthurian cycle and its medieval stage as to encourage several intertextual transpositions in subsequent narrative structures, reaching our present days, full of literary richness and consequence. A meaningful example arises in Álvaro Cunqueiro’s novel Merlín e familia (1955), the subject of study of this article. Cunqueiro develops the story from the desire to scape reality and seek refuge in the myths and legends of yesteryear. Cunqueiro interconnects these legendary elements through rewriting them into the creation of a new reality. This rework of Merlin has several characteristic traits and roles selected from the medieval figure; nonetheless, he loses altogether other of his original facets, generating a complex Merlin in which the traditional and the modern unite. El enriquecimiento simbólico del mago Merlín adquiere tal dimensión a lo largo del ciclo artúrico y su etapa medieval que propicia toda una serie de transposiciones intertextuales de gran riqueza literaria en estructuras narrativas posteriores y hasta nuestros días. Un ejemplo significativo se encuentra en la novela Merlín e familia (1955), de Álvaro Cunqueiro: con ella, Cunqueiro trata de escapar de la realidad, buscando refugio en unos mitos y leyendas de antaño que interconecta, a través de la reescritura, con la creación de una nueva realidad. El Merlín reescrito en su novela retiene una serie de rasgos y roles característicos de la figura medieval y, por el contrario, pierde muchas de sus características o atributos originales, lo que da lugar a un Merlín poliédrico que reúne en sí lo tradicional y lo moderno.

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19

JAMES, Marianne F., Nitasha MANCHANDA, Charo GONZALEZ-AGOSTI, John H. HARTWIG, and Vijaya RAMESH. "The neurofibromatosis 2 protein product merlin selectively binds F-actin but not G-actin, and stabilizes the filaments through a lateral association." Biochemical Journal 356, no. 2 (May 24, 2001): 377–86. http://dx.doi.org/10.1042/bj3560377.

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The neurofibromatosis 2 protein product merlin, named for its relatedness to the ezrin, radixin and moesin (ERM) family of proteins, is a tumour suppressor whose absence results in the occurrence of multiple tumours of the nervous system, particularly schwannomas and meningiomas. Merlin's similarity to ERMs suggests that it might share functions, acting as a link between cytoskeletal components and the cell membrane. The N-terminus of merlin has strong sequence identity to the N-terminal actin-binding region of ezrin; here we describe in detail the merlin–actin interaction. Employing standard actin co-sedimentation assays, we have determined that merlin isoform 2 binds F-actin with an apparent binding constant of 3.6μM and a stoichiometry of 1mol of merlin per 11.5mol of actin in filaments at saturation. Further, solid-phase binding assays reveal that merlin isoforms 1 and 2 bind actin filaments differentially, suggesting that the intramolecular interactions in isoform 1 might hinder its ability to bind actin. However, merlin does not bind G-actin. Studies of actin filament dynamics show that merlin slows filament disassembly with no influence on the assembly rate, indicating that merlin binds along actin filament lengths. This conclusion is supported by electron microscopy, which demonstrates that merlin binds periodically along cytoskeletal actin filaments. Comparison of these findings with those reported for ERM proteins reveal a distinct role for merlin in actin filament dynamics.

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20

NEILL, Graham W., and 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, no. 3 (September 10, 2001): 727–35. http://dx.doi.org/10.1042/bj3580727.

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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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21

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.

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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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22

Frontzek, Fabian, Svenja Nitzlaff, Malte Horstmann, Albrecht Schwab, and Christian Stock. "Functional interdependence of NHE1 and merlin in human melanoma cells." Biochemistry and Cell Biology 92, no. 6 (December 2014): 530–40. http://dx.doi.org/10.1139/bcb-2014-0041.

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Upregulation of the Na+/H+ exchanger isoform 1 (NHE1) has been correlated with tumor malignancy. In contrast, moesin-radixin-ezrin–like protein (merlin) is a tumor suppressor that protects from cancerogenesis. Merlin is highly related to the members of the ezrin, radixin, and moesin (ERM) protein family that are directly attached to and functionally linked with NHE1. In addition, merlin inhibits the MAPK cascade and the Rho-GTPases known to activate NHE1 activity. The present study investigates whether NHE1 expression and activity affect merlin or, conversely, whether merlin has an impact on NHE1 in human melanoma (MV3) cells. Indeed, features of merlin-deficient MV3 cells point to a functional link: merlin-deficient cells showed a decreased NHE1 expression and, paradoxically, an increase in NHE1 activity as measured upon cytosolic acidification (NH4Cl prepulse method). Loss of merlin also led to an elevated cell motility that could be further increased by NHE1 overexpression, whereas NHE1 overexpression alone had no effect on migration. In contrast, neither NHE1 expression nor its activity had an impact on merlin expression. These results suggest a novel tumor suppressor function of merlin in melanoma cells: the inhibition of the proto-oncogenic NHE1 activity, possibly including its downstream signaling pathways.

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23

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.

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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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McCartney, B. M., R. M. Kulikauskas, D. R. LaJeunesse, and R. G. Fehon. "The neurofibromatosis-2 homologue, Merlin, and the tumor suppressor expanded function together in Drosophila to regulate cell proliferation and differentiation." Development 127, no. 6 (March 15, 2000): 1315–24. http://dx.doi.org/10.1242/dev.127.6.1315.

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Neurofibromatosis-2 is an inherited disorder characterized by the development of benign schwannomas and other Schwann-cell-derived tumors associated with the central nervous system. The Neurofibromatosis-2 tumor suppressor gene encodes Merlin, a member of the Protein 4.1 superfamily most closely related to Ezrin, Radixin and Moesin. This discovery suggested a novel function for Protein 4.1 family members in the regulation of cell proliferation; proteins in this family were previously thought to function primarily to link transmembrane proteins to underlying cortical actin. To understand the basic cellular functions of Merlin, we are investigating a Drosophila Neurofibromatosis-2 homologue, Merlin. Loss of Merlin function in Drosophila results in hyperplasia of the affected tissue without significant disruptions in differentiation. Similar phenotypes have been observed for mutations in another Protein 4.1 superfamily member in Drosophila, expanded. Because of the phenotypic and structural similarities between Merlin and expanded, we asked whether Merlin and Expanded function together to regulate cell proliferation. In this study, we demonstrate that recessive loss of function of either Merlin or expanded can dominantly enhance the phenotypes associated with mutations in the other. Consistent with this genetic interaction, we determined that Merlin and Expanded colocalize in Drosophila tissues and cells, and physically interact through a conserved N-terminal region of Expanded, characteristic of the Protein 4.1 family, and the C-terminal domain of Merlin. Loss of function of both Merlin and expanded in clones revealed that these proteins function to regulate differentiation in addition to proliferation in Drosophila. Further genetic analyses suggest a role for Merlin and Expanded specifically in Decapentaplegic-mediated differentiation events. These results indicate that Merlin and Expanded function together to regulate proliferation and differentiation, and have implications for understanding the functions of other Protein 4.1 superfamily members.

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25

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.

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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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26

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.

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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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27

Salus, Peter H. "Merlin and Myth." American Journal of Semiotics 7, no. 4 (1990): 131–47. http://dx.doi.org/10.5840/ajs1990747.

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28

Cashman, Seamus, and Shirley Kelly. "Merlin Swallows Wolfhound." Books Ireland, no. 245 (2001): 323. http://dx.doi.org/10.2307/20623951.

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29

Fike, Matthew A. "Spenser’s Merlin Reconsidered." Spenser Studies 13 (January 1, 1999): 89–99. http://dx.doi.org/10.1086/spsv13p89.

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30

VADÉ, Yves. "L'ombre de Merlin." Pleine Marge 42 (December 1, 2005): 153–80. http://dx.doi.org/10.2143/pm.42.0.2013894.

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31

Wai, Isabella. "Wilbur's Merlin Enthralled." Explicator 62, no. 4 (January 2004): 231–33. http://dx.doi.org/10.1080/00144940409597231.

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32

Barker, J. C. "Merlin to 2000." Proceedings of the Institution of Mechanical Engineers, Part G: Journal of Aerospace Engineering 212, no. 4 (April 1, 1998): 217–24. http://dx.doi.org/10.1243/0954410981532397.

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This paper traces the history and development of the EH101 helicopter from its inception to its imminent delivery. It is the product of a joint venture between the industries and governments of Britain and Italy and is due to be in service in 1998 in Britain and 2000 in Italy. With five operators beginning operations in the next four years there are exciting prospects for the use and development of the helicopter.

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33

SIMPSON, ROGER. "NEWTON'S MERLIN LOCATED." Notes and Queries 35, no. 3 (September 1, 1988): 313—a—313. http://dx.doi.org/10.1093/nq/35-3-313a.

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34

Bewley, Robert. "Merlin project begins." Neutron News 13, no. 4 (January 2002): 6. http://dx.doi.org/10.1080/10448630208218484.

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35

Goodrich, Peter H. "The Erotic Merlin." Arthuriana 10, no. 1 (2000): 94–115. http://dx.doi.org/10.1353/art.2000.0003.

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36

Baudry, Robert. "Et toujours Merlin !…" Traduction, transcription, adaptation au Moyen Âge, no. 13 (April 1, 2022): 159–78. http://dx.doi.org/10.54563/bdba.1405.

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Laburthe-Tolra, Philippe. "MERLIN, Pierre et Odile MERLIN, Ingénieur en Afrique, 1938-1961." Journal des Africanistes, no. 77-1 (September 30, 2007): 171–73. http://dx.doi.org/10.4000/africanistes.1912.

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Herbin, Jean-Charles. "Mots et merveilles dans le Merlin 747 ou Merlin l'enchanteur ?" L Information Grammaticale 87, no. 1 (2000): 37–43. http://dx.doi.org/10.3406/igram.2000.2744.

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Papageorgiou, D. G., I. N. Demetropoulos, and I. E. Lagaris. "MERLIN-3.1.1. A new version of the Merlin optimization environment." Computer Physics Communications 159, no. 1 (May 2004): 70–71. http://dx.doi.org/10.1016/j.cpc.2003.12.005.

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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.

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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.

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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.

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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.

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Pipchuk, Alexander J., and Xiaolong Yang. "Abstract 858: Development of ultrasensitive split luciferase biosensors monitoring activity of the merlin tumor suppressor." Cancer Research 82, no. 12_Supplement (June 15, 2022): 858. http://dx.doi.org/10.1158/1538-7445.am2022-858.

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Abstract Understanding features common to all forms of cancer is a vital component of treatment and research into malignant disease. All solid tumours share the ability to overcome contact inhibition of proliferation (CIP), the process by which intercellular contacts engage signalling to stop proliferation. Merlin, a tumour suppressor protein that is inactivated in a wide variety of cancers, plays a crucial role in CIP; merlin-deficient cells lose the ability to be contact-inhibited and subsequently form tumours. Although the role of merlin in cancer has been investigated extensively over the past 28 years, this protein has been notoriously difficult to study. To address this issue, we develop and utilize 2 split-luciferase biosensor systems that enable accurate quantification of merlin activity in real time. Merlin undergoes a conformational change that is functionally important in tumour suppression. Phosphorylation at a key C-terminal residue promotes transition of the protein from an open, active conformation to a closed, N-to-C terminal autoinhibited conformation. Therefore, monitoring this conformation change in real time could provide unique insights into merlin function. To do this, we apply NanoBiT split-luciferase technology to develop an intramolecular merlin biosensor (intra-Mer-BS). In brief, 2 split-luciferase components, LgBiT and SmBiT, are fused to the N- and C-terminus of merlin, respectively. Upon open-to-closed conformation change of merlin, LgBiT and SmBiT complement to reconstitute a functional luciferase and emit light. This enables accurate quantification of merlin’s functionally relevant conformation changes in real time. Importantly, cotransfection of the intra-Mer-BS alongside PAK1, an upstream merlin regulator that promotes transition to the closed conformation, significantly increases luminescent activity of the intra-Mer-BS, indicating that the biosensor faithfully reports on merlin’s conformation. Moreover, merlin has been shown to exert its tumour suppressive function through activation of LATS, the central mediator of the Hippo signalling pathway. In addition to the intra-Mer-BS, we develop and validate a NanoBiT biosensor to monitor the interaction between merlin and LATS (Mer-LATS-BS). This Mer-LATS-BS is used to quantify the effect of merlin activators and inhibitors on merlin/LATS tumour suppressive activity in cancer cells. In summary, we develop and validate 2 novel bioluminescent biosensors to monitor merlin’s conformation changes and activity in cancer cells. The intra-Mer-BS and Mer-LATS-BS provide real time information with high sensitivity and excellent reproducibility. Ultimately, these biosensors enable high throughput screening to discover novel upstream regulators of merlin in cancer and provide mechanistic insight into how contact inhibitive signalling is propagated through merlin and the Hippo pathway. Citation Format: Alexander J. Pipchuk, Xiaolong Yang. Development of ultrasensitive split luciferase biosensors monitoring activity of the merlin tumor suppressor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 858.

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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.

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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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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.

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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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Wei, Bangdong L., Vivek K. Arora, Alexa Raney, Lillian S. Kuo, Guang-Hui Xiao, Eduardo O'Neill, Joseph R. Testa, John L. Foster, and J. Victor Garcia. "Activation of p21-Activated Kinase 2 by Human Immunodeficiency Virus Type 1 Nef Induces Merlin Phosphorylation." Journal of Virology 79, no. 23 (December 15, 2005): 14976–80. http://dx.doi.org/10.1128/jvi.79.23.14976-14980.2005.

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ABSTRACT The accessory human immunodeficiency virus type 1 (HIV-1) protein Nef activates the autophosphorylation activity of p21-activated kinase 2 (PAK2). Merlin, a cellular substrate of PAK2, is homologous to the ezrin-radixin-moesin family and plays a critical role in Rac signaling. To assess the possible impact on host cell metabolism of Nef-induced PAK2 activation, we investigated the phosphorylation of merlin in Nef expressing cells. Here we report that Nef induces merlin phosphorylation in multiple cell lines independently of protein kinase A. This intracellular phosphorylation of merlin directly correlates with in vitro assay of the autophosphorylation activity of Nef-activated PAK2. Importantly, merlin phosphorylation induced by Nef was also observed in human primary T cells. The finding that Nef induces phosphorylation of the key signaling molecule merlin suggests several possible roles for PAK2 activation in HIV pathogenesis.

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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.

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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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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.

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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.

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Lopes, Ana Luisa Kalb, Eva Kriegová, Julius Lukeš, Marco Aurélio Krieger, and Adriana Ludwig. "Distribution of Merlin in eukaryotes and first report of DNA transposons in kinetoplastid protists." PLOS ONE 16, no. 5 (May 6, 2021): e0251133. http://dx.doi.org/10.1371/journal.pone.0251133.

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DNA transposons are defined as repeated DNA sequences that can move within the host genome through the action of transposases. The transposon superfamily Merlin was originally found mainly in animal genomes. Here, we describe a global distribution of the Merlin in animals, fungi, plants and protists, reporting for the first time their presence in Rhodophyceae, Metamonada, Discoba and Alveolata. We identified a great variety of potentially active Merlin families, some containing highly imperfect terminal inverted repeats and internal tandem repeats. Merlin-related sequences with no evidence of mobilization capacity were also observed and may be products of domestication. The evolutionary trees support that Merlin is likely an ancient superfamily, with early events of diversification and secondary losses, although repeated re-invasions probably occurred in some groups, which would explain its diversity and discontinuous distribution. We cannot rule out the possibility that the Merlin superfamily is the product of multiple horizontal transfers of related prokaryotic insertion sequences. Moreover, this is the first account of a DNA transposon in kinetoplastid flagellates, with conserved Merlin transposase identified in Bodo saltans and Perkinsela sp., whereas it is absent in trypanosomatids. Based on the level of conservation of the transposase and overlaps of putative open reading frames with Merlin, we propose that in protists it may serve as a raw material for gene emergence.

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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.

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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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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.

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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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