neurofibromin 2

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

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

..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...

..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...

..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...

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

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

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

....

....

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

..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...

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

..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...

..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...

..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...

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

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

..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...

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

....

....

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

..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...

..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...

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

..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...

..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...

..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...

..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...

..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 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...

..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...

..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...

..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...

....

..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...

....

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

..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...

..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...

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

..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...

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

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

....

..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...

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

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

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

..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...

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

..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...

....

..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...

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

....

....

..Together, our data revealed a novel regulatory mechanism for the tumor suppressor function of Merlin...

..These data are consistent with the hypothesis that schwannomin requires HRS interaction to be fully functionally active and to inhibit STAT activation...

..Ultimately, a better understanding of exactly how Ezrin confers metastatic advantage will provide important insight into this key problem in cancer biology...

....

..These findings imply that merlin has widespread and specific functions in the human central nervous system...

..In this article, we propose a molecular model for NF2 protein (merlin) function in the light of these and related new findings...

....

....

..In this review, we summarize the involvement of NF2 inactivation in tumorigenesis. We also discuss observations implicating merlin in cell motility and cell proliferation, with a focus on recent findings linking merlin to Rac signaling...

..These results identify merlin as the first neuronal binding partner for PKA-RIbeta and suggest a novel function for merlin in connecting neuronal cytoskeleton to PKA signaling...

....

..Recent evidence of post-translational regulatory mechanisms which offer hope for new drug intervention strategies to help alleviate this debilitating disease are asses sed...

..Only cells in the intermediate zone expressed schwannomin, indicating that schwannomin may play an important role in cellular migration...

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

....

..These results suggest that merlin is an as yet unknown regulator of neurite outgrowth through the interaction with paxillin, providing a possibly common mechanism regulating neurite formation...

..Future studies will include building more comprehensive libraries and comparing libraries from various vestibular schwannoma phenotypes to identify useful diagnostic or prognostic markers, and targets for therapeutic intervention...

..It is likely, therefore, that the tumorigenesis of meningothelial meningiomas is the result of deleterious alterations of genes that have final phenotypical effects similar to inactivation of the NF2 gene...

....

..Our gene dosage assay will detect deletions of one or more exons as well as gross deletions of the whole coding region of the gene. It can complement the existing screening methods because it is faster and easier...

..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...

..Subsequent investigations have confirmed merlin's role in tumor formation, but have yet to reveal its mechanism of action...

..These results show that the NF2 gene is highly conserved and suggests that the analysis of the mouse NF2 gene might yield insights into the function of the human gene...

..These data indicate that loss of NF2 protein function is a necessary step in schwannoma pathogenesis and that the NF2 gene functions as a recessive tumor suppressor gene...

..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...

..An important outcome of the study of neurofibromatosis-associated tumorigenesis has been insight into the more general molecular and cellular bases of nervous system tumors...

..The authors recommend surgery for symptomatic lesions. Asymptomatic tumours can be monitored. Regular follow up is essential as they may develop fresh lesions at any time. The relevant literature is discussed...

..This study suggests a role for merlin in mediating PKA-induced changes of the actin cytoskeleton...

..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...

....

..Together, these results provide evidence that merlin interacts with beta1 integrin and that merlin localization changes from a cytosolic to cytoskeletal compartment during SC differentiation...

..A single patient carried a 3-bp deletion removing a phenylalanine residue. We conclude that the majority of NF2 patients carry an inactivating mutation of the NF2 gene and that neutral polymorphism in the gene is rare...

..Together, these results provide the first functional clue to the existence of schwannomin isoforms and could unravel novel pathways for the transport and subcellular localization of schwannomin in vivo...

..The ability to develop schwannoma growth with a noninvasive imaging technique will allow assessment of therapeutic interventions...

..From two tumors no protein was precipitated. Truncated NF2 proteins were not observed. The authors conclude that mutant NF2 proteins are unstable and undergo accelerated degradation...

..These results are consistent with tight spatial regulation of S518 phosphorylation at the plasma membrane in a paxillin and Cdc42-Pak dependent manner that leads to local reorganization of the SC cytoskeleton...

..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. ..

....

..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. ..

..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. ..

..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. ..

..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. ..