Genomes and Genes
Summary: A membrane protein homologous to the ERM (Ezrin-Radixin-Moesin) family of cytoskeleton-associated proteins which regulate physical properties of membranes. Alterations in neurofibromin 2 are the cause of NEUROFIBROMATOSIS 2.
- Gautreau A, Manent J, Fievet B, Louvard D, Giovannini M, Arpin M. Mutant products of the NF2 tumor suppressor gene are degraded by the ubiquitin-proteasome pathway. J Biol Chem. 2002;277:31279-82 pubmed..Altogether these results suggest that degradation of mutant Sch mediated by the ubiquitin-proteasome pathway is a physiopathological pathway contributing to the loss of Sch function in NF2 patients. ..
- Huang L, Ichimaru E, Pestonjamasp K, Cui X, Nakamura H, Lo G, et al. Merlin differs from moesin in binding to F-actin and in its intra- and intermolecular interactions. Biochem Biophys Res Commun. 1998;248:548-53 pubmed..Merlin 1 function in cells may thus depend on intra- and intermolecular interactions and their modulation, which include interactions with other members of this protein family. ..
- Gutmann D, Haipek C, Burke S, Sun C, Scoles D, Pulst S. The NF2 interactor, hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), associates with merlin in the "open" conformation and suppresses cell growth and motility. Hum Mol Genet. 2001;10:825-34 pubmed..These results suggest the possibility that merlin and HRS may regulate cell growth in schwannoma cells through interacting pathways. ..
- Reed N, Gutmann D. Tumorigenesis in neurofibromatosis: new insights and potential therapies. Trends Mol Med. 2001;7:157-62 pubmed..By understanding the function of these tumor suppressors, we have a unique opportunity to develop targeted pharmacotherapeutic interventions for these disorders. ..
- Gutmann D, Wright D, Geist R, Snider W. Expression of the neurofibromatosis 2 (NF2) gene isoforms during rat embryonic development. Hum Mol Genet. 1995;4:471-8 pubmed
- Thurneysen C, Opitz I, Kurtz S, Weder W, Stahel R, Felley Bosco E. Functional inactivation of NF2/merlin in human mesothelioma. Lung Cancer. 2009;64:140-7 pubmed publisher..In tumors where no NF2 truncation can be detected, NF2 is rendered inactive by phosphorylation of Ser 518 and this can be explained at least in part by an increased expression of CPI-17. ..
- Wilkes M, Repellin C, Hong M, Bracamonte M, Penheiter S, Borg J, et al. Erbin and the NF2 tumor suppressor Merlin cooperatively regulate cell-type-specific activation of PAK2 by TGF-beta. Dev Cell. 2009;16:433-44 pubmed publisher..These results not only identify Erbin as a key determinant of epithelial resistance to TGF-beta signaling, they also show that Erbin controls Merlin tumor suppressor function by switching the functional valence of PAK2 binding. ..
- Jukam D, Desplan C. Binary regulation of Hippo pathway by Merlin/NF2, Kibra, Lgl, and Melted specifies and maintains postmitotic neuronal fate. Dev Cell. 2011;21:874-87 pubmed publisher..These results reveal roles for Merlin, Kibra, and Lgl in neuronal specification and maintenance and show that the Hippo pathway is reimplemented for sensory neuron fate by combining canonical and noncanonical regulatory steps. ..
- Golovnina K, Blinov A, Akhmametyeva E, Omelyanchuk L, Chang L. Evolution and origin of merlin, the product of the Neurofibromatosis type 2 (NF2) tumor-suppressor gene. BMC Evol Biol. 2005;5:69 pubmed..The overall similarity among the primary and secondary structures of all merlin proteins and the conservation of several functionally important residues suggest a universal role for merlin in a wide range of metazoa. ..
- Gutmann D, Hirbe A, Haipek C. Functional analysis of neurofibromatosis 2 (NF2) missense mutations. Hum Mol Genet. 2001;10:1519-29 pubmed..These results suggest that the key functional domains of merlin lie within the highly conserved FERM domain and the unique C-terminus of the protein. ..
- McLaughlin M, Kruger G, Slocum K, Crowley D, Michaud N, Huang J, et al. The Nf2 tumor suppressor regulates cell-cell adhesion during tissue fusion. Proc Natl Acad Sci U S A. 2007;104:3261-6 pubmed..Our work reveals that regulation of Nf2 expression is a previously unrecognized means of controlling adhesion at the leading front, thereby ensuring successful tissue fusion. ..
- Bashour A, Meng J, Ip W, MacCollin M, Ratner N. The neurofibromatosis type 2 gene product, merlin, reverses the F-actin cytoskeletal defects in primary human Schwannoma cells. Mol Cell Biol. 2002;22:1150-7 pubmed..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. ..
- Manchanda N, Lyubimova A, Ho H, James M, Gusella J, Ramesh N, et al. The NF2 tumor suppressor Merlin and the ERM proteins interact with N-WASP and regulate its actin polymerization function. J Biol Chem. 2005;280:12517-22 pubmed..This novel function of merlin and the ERMs illustrates a mechanism by which these proteins directly exert their effects on actin reorganization and also provides new insight into N-WASP regulation. ..
- Denisenko Nehrbass N, Goutebroze L, Galvez T, Bonnon C, Stankoff B, Ezan P, et al. Association of Caspr/paranodin with tumour suppressor schwannomin/merlin and beta1 integrin in the central nervous system. J Neurochem. 2003;84:209-21 pubmed..Since integrin beta1 and schwannomin do not appear to be enriched in paranodes they may be quantitatively minor partners of paranodin in these regions and/or be associated with paranodin at other locations. ..
- Gonzalez Agosti C, Xu L, Pinney D, Beauchamp R, Hobbs W, Gusella J, et al. The merlin tumor suppressor localizes preferentially in membrane ruffles. Oncogene. 1996;13:1239-47 pubmed..Thus, merlin is associated with motile regions of the cell and its participation in these structures may be intimately involved in control of proliferation in Schwann cells and meningeal cells. ..
- Gautreau A, Louvard D, Arpin M. ERM proteins and NF2 tumor suppressor: the Yin and Yang of cortical actin organization and cell growth signaling. Curr Opin Cell Biol. 2002;14:104-9 pubmed..Recent studies have revealed that ERM proteins transduce growth signals, and have shed new light on how merlin links cell growth to the cytoskeleton. ..
- LaJeunesse D, McCartney B, Fehon R. A systematic screen for dominant second-site modifiers of Merlin/NF2 phenotypes reveals an interaction with blistered/DSRF and scribbler. Genetics. 2001;158:667-79 pubmed..These results suggest that Merlin, blistered, and scribbler function together in a common pathway to regulate Drosophila wing epithelial development. ..
- Turunen O, Sainio M, Jaaskelainen J, Carpen O, Vaheri A. Structure-function relationships in the ezrin family and the effect of tumor-associated point mutations in neurofibromatosis 2 protein. Biochim Biophys Acta. 1998;1387:1-16 pubmed..Some known mutations are observed at a site potentially interacting with cell adhesion molecules. We will also discuss the implications of the evolutionary information and the actin-binding models in the ezrin family. ..
- Baser M, Kuramoto L, Woods R, Joe H, Friedman J, Wallace A, et al. The location of constitutional neurofibromatosis 2 (NF2) splice site mutations is associated with the severity of NF2. J Med Genet. 2005;42:540-6 pubmed
- Scoles D, Huynh D, Chen M, Burke S, Gutmann D, Pulst S. The neurofibromatosis 2 tumor suppressor protein interacts with hepatocyte growth factor-regulated tyrosine kinase substrate. Hum Mol Genet. 2000;9:1567-74 pubmed..The identification of schwannomin as a HRS interactor implicates schwannomin in HRS-mediated cell signaling. ..
- Hughes S, Fehon R. Phosphorylation and activity of the tumor suppressor Merlin and the ERM protein Moesin are coordinately regulated by the Slik kinase. J Cell Biol. 2006;175:305-13 pubmed..These results suggest the existence of a novel mechanism for coordinate regulation of cell proliferation and epithelial integrity in developing tissues. ..
- Durand A, Champier J, Jouvet A, Labrousse F, Honnorat J, Guyotat J, et al. Expression of c-Myc, neurofibromatosis Type 2, somatostatin receptor 2 and erb-B2 in human meningiomas: relation to grades or histotypes. Clin Neuropathol. 2008;27:334-45 pubmed
- Yokoyama T, Osada H, Murakami H, Tatematsu Y, Taniguchi T, Kondo Y, et al. YAP1 is involved in mesothelioma development and negatively regulated by Merlin through phosphorylation. Carcinogenesis. 2008;29:2139-46 pubmed publisher..Future studies of transcriptional targets of YAP1 in MPMs may shed light on the molecular mechanisms of MPM development and lead to new therapeutic strategies. ..
- Okada T, You L, Giancotti F. Shedding light on Merlin's wizardry. Trends Cell Biol. 2007;17:222-9 pubmed..Here, we review these recent findings and their relevance to the tumor suppressor function of Merlin. ..
- Ammoun S, Schmid M, Ristic N, Zhou L, Hilton D, Ercolano E, et al. The role of insulin-like growth factors signaling in merlin-deficient human schwannomas. Glia. 2012;60:1721-33 pubmed publisher..PI3K is relevant for both IGF-IR and previously described PDGFR-? signaling in schwannoma...
- Shaw R, McClatchey A, Jacks T. Localization and functional domains of the neurofibromatosis type II tumor suppressor, merlin. Cell Growth Differ. 1998;9:287-96 pubmed..Thus, as has been described for the erzin, radixin, and moesin proteins, the activities of the carboxyl-terminal domain of merlin may be suppressed by the amino-terminal domain. ..
- Haase V, Trofatter J, MacCollin M, Tarttelin E, Gusella J, Ramesh V. The murine NF2 homologue encodes a highly conserved merlin protein with alternative forms. Hum Mol Genet. 1994;3:407-11 pubmed..The mouse NF2 homologue maps to Chr 11, in a region homologous to human Chr 22, but devoid of any mouse mutations which could be models of the human disorder. ..
- Pylkkanen L, Sarlomo Rikala M, Wessman M, Hämäläinen E, Sainio M, Husgafvel Pursiainen K, et al. Chromosome 22q alterations and expression of the NF2 gene product, merlin, in gastrointestinal stromal tumors. Hum Pathol. 2003;34:872-9 pubmed..The findings suggest that allelic losses at 22q are associated with high mitotic activity and recurring disease, and that alterations in the NF2 gene are unlikely to participate in the pathogenesis of GIST. ..
- Szijan I, Rochefort D, Bruder C, Surace E, Machiavelli G, Dalamon V, et al. NF2 tumor suppressor gene: a comprehensive and efficient detection of somatic mutations by denaturing HPLC and microarray-CGH. Neuromolecular Med. 2003;3:41-52 pubmed..Denaturing HPLC analysis of small mutations and microarray-CGH of large deletions are complementary, fast, and efficient methods for the detection of mutations in tumor tissues. ..
- Lallemand D, Saint Amaux A, Giovannini M. Tumor-suppression functions of merlin are independent of its role as an organizer of the actin cytoskeleton in Schwann cells. J Cell Sci. 2009;122:4141-9 pubmed publisher..Thus, tumor suppression by merlin is independent of its role as an organizer of the actin cytoskeleton in Schwann cells. ..
- Yogesha S, Sharff A, Giovannini M, Bricogne G, Izard T. Unfurling of the band 4.1, ezrin, radixin, moesin (FERM) domain of the merlin tumor suppressor. Protein Sci. 2011;20:2113-20 pubmed publisher..We conclude the "closed" tumor suppressor conformer of merlin-1 is in fact an "open" dimer whose functions are disabled by Nf2 mutations that disrupt this architecture. ..
- Claudio J, Lutchman M, Rouleau G. Widespread but cell type-specific expression of the mouse neurofibromatosis type 2 gene. Neuroreport. 1995;6:1942-6 pubmed..In non-neuronal tissues immunostaining showed expression in cells of the tunica intima of blood vessels. We conclude that there is a widespread but cell type-specific expression of schwannomin. ..
- Yu J, Zheng Y, Dong J, Klusza S, Deng W, Pan D. Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. Dev Cell. 2010;18:288-99 pubmed publisher..These results shed light on the mechanism of Ex and Mer function and implicate Kibra as a potential tumor suppressor with relevance to neurofibromatosis. ..
- Fehon R, Oren T, LaJeunesse D, Melby T, McCartney B. Isolation of mutations in the Drosophila homologues of the human Neurofibromatosis 2 and yeast CDC42 genes using a simple and efficient reverse-genetic method. Genetics. 1997;146:245-52 pubmed
- Meng J, Lowrie D, Sun H, Dorsey E, Pelton P, Bashour A, et al. Interaction between two isoforms of the NF2 tumor suppressor protein, merlin, and between merlin and ezrin, suggests modulation of ERM proteins by merlin. J Neurosci Res. 2000;62:491-502 pubmed..This suggests that, in vivo, merlin dimerization could regulate merlin-ERM protein interaction, and could thus indirectly regulate other interactions involving ERM proteins. ..
- Huynh D, Nechiporuk T, Pulst S. Alternative transcripts in the mouse neurofibromatosis type 2 (NF2) gene are conserved and code for schwannomins with distinct C-terminal domains. Hum Mol Genet. 1994;3:1075-9 pubmed..These results suggest that schwannomin isoforms have distinct functional roles and predict the existence of human mutations involving the C-terminus of schwannomin. ..
- Ramesh V. Merlin and the ERM proteins in Schwann cells, neurons and growth cones. Nat Rev Neurosci. 2004;5:462-70 pubmed
- Jacoby L, MacCollin M, Louis D, Mohney T, Rubio M, Pulaski K, et al. Exon scanning for mutation of the NF2 gene in schwannomas. Hum Mol Genet. 1994;3:413-9 pubmed..Thus, inactivation of merlin is a common feature underlying both inherited and sporadic forms of schwannoma. ..
- Chen Y, Yu P, Lu D, Tagle D, Cai T. A novel isoform of beta-spectrin II localizes to cerebellar Purkinje-cell bodies and interacts with neurofibromatosis type 2 gene product schwannomin. J Mol Neurosci. 2001;17:59-70 pubmed
- Lee J, Moon H, Lee W, Chun H, Han C, Jeon Y, et al. Merlin facilitates ubiquitination and degradation of transactivation-responsive RNA-binding protein. Oncogene. 2006;25:1143-52 pubmed..These results suggest that merlin is involved in the regulation of TRBP protein level by facilitating its ubiquitination in response to such cues as cell-cell contacts. ..
- Hanemann C. Magic but treatable? Tumours due to loss of merlin. Brain. 2008;131:606-15 pubmed..Finally, I will discuss how loss of merlin leads to tumourigenesis in order to understand the rationale for emerging new therapeutic targets...
- Xu H, Gutmann D. Merlin differentially associates with the microtubule and actin cytoskeleton. J Neurosci Res. 1998;51:403-15 pubmed..These microtubule association results confirm the notion that merlin exists in "open" and "closed" conformations relevant to its function as a negative growth regulator. ..
- Maitra S, Kulikauskas R, Gavilan H, Fehon R. The tumor suppressors Merlin and Expanded function cooperatively to modulate receptor endocytosis and signaling. Curr Biol. 2006;16:702-9 pubmed..We propose that these proteins control proliferation by regulating the abundance, localization, and turnover of cell-surface receptors and that misregulation of these processes may be a key component of tumorigenesis. ..
- Okada T, Lopez Lago M, Giancotti F. Merlin/NF-2 mediates contact inhibition of growth by suppressing recruitment of Rac to the plasma membrane. J Cell Biol. 2005;171:361-71 pubmed..These results provide a framework for understanding the tumor suppressor function of Merlin and indicate that Merlin mediates contact inhibition of growth by suppressing recruitment of Rac to matrix adhesions. ..
- Chen Y, Gutmann D, Haipek C, Martinsen B, Bronner Fraser M, Krull C. Characterization of chicken Nf2/merlin indicates regulatory roles in cell proliferation and migration. Dev Dyn. 2004;229:541-54 pubmed..Collectively, these results demonstrate that c-merlin is developmentally regulated in migrating and differentiating myogenic cells, where it functions as a negative regulator of both muscle growth and motility. ..
- Jacoby L, MacCollin M, Barone R, Ramesh V, Gusella J. Frequency and distribution of NF2 mutations in schwannomas. Genes Chromosomes Cancer. 1996;17:45-55 pubmed..However, the absence of mutations in exons 16 and 17 suggests that an inactivating mutation affecting only one of the merlin's alternative termini may not be sufficient to eliminate tumor suppressor function. ..
- Gautreau A, Fievet B, Brault E, Antony C, Houdusse A, Louvard D, et al. Isolation and characterization of an aggresome determinant in the NF2 tumor suppressor. J Biol Chem. 2003;278:6235-42 pubmed
- Genevet A, Wehr M, Brain R, Thompson B, Tapon N. Kibra is a regulator of the Salvador/Warts/Hippo signaling network. Dev Cell. 2010;18:300-8 pubmed publisher..We suggest that Kibra is part of an apical scaffold that promotes SWH pathway activity. ..
- Kaempchen K, Mielke K, Utermark T, Langmesser S, Hanemann C. Upregulation of the Rac1/JNK signaling pathway in primary human schwannoma cells. Hum Mol Genet. 2003;12:1211-21 pubmed..We conclude that merlin regulates Rac activation, and suggest that this is important for human schwannoma cell dedifferentiation. ..
- Xiao G, Gallagher R, Shetler J, Skele K, Altomare D, Pestell R, et al. The NF2 tumor suppressor gene product, merlin, inhibits cell proliferation and cell cycle progression by repressing cyclin D1 expression. Mol Cell Biol. 2005;25:2384-94 pubmed
- Kissil J, Johnson K, Eckman M, Jacks T. Merlin phosphorylation by p21-activated kinase 2 and effects of phosphorylation on merlin localization. J Biol Chem. 2002;277:10394-9 pubmed..By using wild-type and mutated forms of merlin and phospho-directed antibodies, we show that phosphorylation of merlin at serine 518 leads to dramatic protein relocalization. ..
- Zhang N, Bai H, David K, Dong J, Zheng Y, Cai J, et al. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev Cell. 2010;19:27-38 pubmed publisher..Our studies link Merlin/NF2 to mammalian Hippo signaling and implicate YAP activation as a mediator of pathologies relevant to Neurofibromatosis 2...