neurofibromin 2

..We propose that Merlin suppresses tumorigenesis by translocating to the nucleus to inhibit CRL4(DCAF1)...

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..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...

..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...

..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...

..At low cell density, merlin is phosphorylated, growth permissive, and exists in a complex with ezrin, moesin, and CD44. These data indicate that merlin and CD44 form a molecular switch that specifies cell growth arrest or proliferation...

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..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...

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..For a subset of VS without detectable gene alterations, promoter inactivation by hypermethylation has been suggested. However, published data are very limited and contradictory...

..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...

..Its deduced product has homology with proteins at the plasma membrane and cytoskeleton interface, a previously unknown site of action of tumour suppressor genes in humans...

..Knocking down PIKE-L with RNA interference abolishes merlin's tumor-suppressive activity. Our data support the hypothesis that PIKE-L is an important mediator of merlin growth suppression...

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..The NF2 gene may thus constitute a tumour suppressor gene of more general importance in tumorigenesis...

..However, components acting upstream of Expanded and Merlin, such as transmembrane receptors, have not yet been identified...

..Collectively, our results show that merlin is a potent inhibitor of high-grade human glioma...

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..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...

..melanogaster tumor suppressors, establish a basic framework for Fat signaling from receptor to transcription factor and implicate Warts as an integrator of multiple growth control signals...

..We conclude that merlin regulates Rac activation, and suggest that this is important for human schwannoma cell dedifferentiation...

..This study provides further evidence on the connection between merlin and cAMP/PKA signaling and suggests a role for merlin in the cAMP/PKA transduction pathway...

..Furthermore, Akt-mediated phosphorylation leads to merlin degradation by ubiquitination. These studies demonstrate that Akt-mediated merlin phosphorylation regulates the function of merlin in the absence of an inactivating mutation...

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..By understanding the function of these tumor suppressors, we have a unique opportunity to develop targeted pharmacotherapeutic interventions for these disorders...

..Lastly, we identify NF2 patient mutations that dramatically reduce each of these interactions in vitro. Based on these findings, we propose a model for merlin folding critical to its ability to function as a tumor suppressor protein...

..The results obtained provide a causal link between the reorganization/changes to the cell surface HSGAGs by the overexpression of Merlin and the inhibition of the metastatic activity of the mouse melanoma B16F10 cells in vivo...

..We propose that Merlin mediates contact inhibition and suppresses tumorigenesis by translocating to the nucleus to inhibit CRL4(DCAF1)...

..These results suggest that schwannomin isoforms have distinct functional roles and predict the existence of human mutations involving the C-terminus of schwannomin...

..Thus, schwannomin is a tumour suppressor directly involved in actin-cytoskeleton organization, which suggests that alterations in the cytoskeleton are an early event in the pathogenesis of some tumour types...

..PI3K is relevant for both IGF-IR and previously described PDGFR-β signaling in schwannoma...

..These results suggest that the NF2 gene might be involved in the differentiation of Schwann cells...

..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...

..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...

..These data indicate that the specific loss of merlin is universal to schwannomas and is not linked to loss of ezrin, radixin, or moesin expression...

..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...

..NF2 can inhibit Ras-induced malignant transformation. However, the primary (signaling) target of NF2 in the oncogenic pathway has not been previously identified...

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..These results biochemically connect merlin to the cortical cytoskeleton and indicate differential regulation of merlin from ERM proteins...

..NF2 contributes as a tumor suppressor in a small subset of GIST. These abnormalities are presumably followed by increased genetic instability...

..We suggest that therapy with nilotinib or combinational therapy that  simultaneously inhibits PDGFR and the downstream Raf/MEK1/2/ERK1/2 pathway could represent an effective treatment for schwannomas and other merlin-deficient tumors...

..These mutants illustrate the utility of zebrafish as a model for studying liver development and disease, and provide valuable tools for investigating the molecular pathogenesis of congenital biliary disorders and fatty liver disease...

..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...

..Collectively, these data indicate that erbin regulates MAP kinase activation in Schwann cells and suggest that erbin links merlin to both adherens junction protein complexes and the MAP kinase signaling pathway...

..We propose that the interference of merlin with Ras- and Rac-dependent signal transfer represents part of the tumor-suppressive action of merlin...

..Together, our results suggest an important role for the NF2 tumor suppressor, and perhaps the ERM family in tumor formation and metastasis...

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..NF2 gene mRNA expression was assessed in fresh tissue of stomach from 5 consecutive patients. We detected no alterations in NF2 gene expression in the quantitative analyses of the 5 tumors...

..Finally, I will discuss how loss of merlin leads to tumourigenesis in order to understand the rationale for emerging new therapeutic targets...

..These biochemical investigations provide insights into the regulation of merlin function and establish a framework for elucidating tumorigenic mechanisms involved in neoplasms associated with merlin inactivation...

..These data indicate that merlin may function to maintain normal cytoskeletal organization, and suggest that merlin's influence on cell growth depends on specific cytoskeletal rearrangements...

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..More interestingly, a negatively charged peptide binds to the inositol site in a crystal contact and causes a greater conformational change in the structure than inositol...

..These results suggest the possibility that merlin and HRS may regulate cell growth in schwannoma cells through interacting pathways...

..These results suggest that loss of activity of several naturally occurring schwannomin mutants is due to disruption of the fold of the N-terminal domain, leading to loss of both membrane localization and actin association...

..Thus, the interaction of betaPDGFR with NHERF may provide an essential link between the cell membrane and the cortical actin cytoskeleton independent of receptor activity...

..Our studies indicate that merlin functions as a tumor and metastasis suppressor by controlling cadherin-mediated cell:cell contact...

..These results suggest the existence of a novel mechanism for coordinate regulation of cell proliferation and epithelial integrity in developing tissues...

..Thus, MLK3 is part of a multiprotein complex and is required for ERK activation. The levels of this complex may be negatively regulated by merlin...

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..Finally, fibroblasts that express this mutant Nf2 allele form tumors when injected into nude mice...

..The closely related tumour suppressor merlin shares many properties with ERM proteins, yet also provides a distinct and essential function...

..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...

..It defines a pathogenic mechanism for the development of NF2 in humans with mutations in exon 2 of NF2...

..This link provides a possible mechanism for the effect of loss of merlin expression in tumorigenesis...

..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...

..These results provide insights into the functions and functional organization of a novel tumor suppressor gene...

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..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...

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..While merlin's functional activity has been examined in mammalian and Drosophila models, little is understood about its evolution, diversity, and overall distribution among different taxa...

..These observations suggest that merlin S518 phosphorylation directly modulates merlin intramolecular and intermolecular associations important for the ability of merlin to function as a tumor suppressor...

..Finally, ex has a role in regulating Wingless protein levels in the eye that is not obviously shared by either mer or hpo. Taken together, our data suggest that Mer and Ex differentially regulate multiple downstream pathways...

..Varying use of this organizing activity by different types of cells could provide an explanation for the unique spectrum of tumors associated with NF2 deficiency in mammals...

..These microtubule association results confirm the notion that merlin exists in "open" and "closed" conformations relevant to its function as a negative growth regulator...

..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...

..Finally, Nf2-/- cells exhibit characteristics of cells expressing activated alleles of Rac. These studies provide insight into the normal cellular function of merlin and how Nf2 mutation contributes to tumor initiation and progression...

..The structure also is consistent with inactivation mechanisms caused by the pathogenic mutations associated with NF2...

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..These results suggest that Merlin, blistered, and scribbler function together in a common pathway to regulate Drosophila wing epithelial development...

..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...

..Comparison of these findings with those reported for ERM proteins reveal a distinct role for merlin in actin filament dynamics...

..E3KARP binds tightly to the ezrin N-ERMAD but has little affinity for the merlin N-ERMAD. The implications of these associations and the hierarchies of binding for the function and regulation of merlin and ERM proteins are discussed...

..Here, we review these recent findings and their relevance to the tumor suppressor function of Merlin...

..We propose that Merlin acts in response to the Gurken signal by apically targeting the signal that initiates axis specification in the oocyte...

..Recent studies have revealed that ERM proteins transduce growth signals, and have shed new light on how merlin links cell growth to the cytoskeleton...

..MYPT-1-PP1delta and its substrate merlin are part of a previously undescribed tumour suppressor cascade that can be hindered in two ways, by mutation of the NF2 gene and by upregulation of the oncoprotein CPI-17...

..This first mouse model initiated with a genetic lesion found in human meningiomas provides a powerful tool for investigating tumor progression and for the preclinical evaluation of therapeutic interventions...

..The results show that merlin plays a key role in the regulation of the Schwann cell microtubule cytoskeleton and suggest a mechanism by which loss of merlin leads to cytoskeletal defects observed in human schwannomas...

..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...

..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...

..This extended binding mode suggests a novel mechanism for how different signals could produce varying levels of activation. Sequence conservation suggests a similar regulation of the tumor suppressor merlin...

..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...

..Although the NF2 protein is known as a cytoskeletal linker, additional functions in a cytoplasmic compartment and in the nucleus may exist...

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..They also should be considered in studies investigating mutations of this gene in members of NF2 families and in tumor analyses...

..These studies seek to identify the underlying cellular abnormalities that lead to tumor formation and to identify novel therapies that specifically limit schwannoma growth. ..

..Furthermore, the development of a quantitative tumor model allows for the assessment of small molecule therapeutics in a pre-clinical setting. ..

..It is expected that a mechanistic understanding of Merlin's function will shed light on contact inhibition and on the pathogenesis of NF2 mutant tumors. ..

..Collectively these studies provide a concerted effort towards understanding the neurologic functions of NF2 and TSC genes and treating disease manifestations associated with these diseases. ..

..Alternatively, merlin could repress the recruitment of MLK3 by Rho family GTPases. In Aim 3, we will use biochemical and molecular biological methods to explore these possibilities. ..

..Alternatively, merlin could repress the recruitment of MLK3 by Rho family GTPases. In Aim 3, we will use biochemical and molecular biological methods to explore these possibilities. ..

..Overall, these studies are expected to provide insights regarding mechanisms by which specific TSGs contribute to the pathogenesis of MM and delineate potential avenues for therapeutic intervention. ..

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..Such insights may facilitate the therapeutic interventions of relevant human diseases, including diseases of the retina. ..

..abstract_text> ..

..Treatment is limited to surgery or radiation. The proposed project investigates the molecular events that cause vestibular schwannomas with the goal of developing a new medical treatment alternative. ..

..Finally, these studies should contribute to work on the mechanisms by which cellular interactions function to control cell growth and determine cell fate during development. ..

..Mouse lenses from animals with one defective NF2 gene will be used to determine whether accumulated DNA damage is the cause of several kinds of cataracts. ..

..The proposed studies are expected to provide insight into regulation of normal axon-glial interactions, and to lead to strategies to understand and ultimately treat human schwannomas. ..

..The proposed studies are expected to provide insight into regulation of normal axon-glial interactions, and to lead to strategies to understand and ultimately treat human schwannomas. ..

..We anticipate that these studies will shed new light on pathways involved in merlin-mediated tumor suppression, and may suggest possible molecular targets for therapeutic strategies for tumors that arise from loss of merlin function. ..

..Therefore, this proposal has high biological and clinical relevance ..

..Finally, these studies should contribute to work on the mechanisms by which cellular interactions function to control cell growth and determine cell fate during development. ..

..Finally, these studies should contribute to work on the mechanisms by which cellular interactions function to control cell growth and determine cell fate during development ..

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..With the identification, replication and characterization of the association for BP and 8q24 we will be in a strong positionto pursue further gene and functional studies. ..

..This should lead to a better understanding of merlin function in normal cells and the consequences of its loss in tumor development. Such information will directly assist in the search for effective therapies. ..

..The validation of Paks as potential targets for inhibition, stemming from these studies, will point directly at approaches for the development of therapeutics towards the treatment of neurofibromatosis type 2. ..