neurofibromin 2

..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...

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

..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...

..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...

....

..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...

....

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

..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...

....

....

..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...

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

..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...

..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...

..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...

..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...

....

....

..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...

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

..We also propose a model that could account for the intricacies of Merlin function across model organisms...

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

....

..These findings provide direct insight into protein function and tumorigenesis in NF2 and indicate a unique treatment paradigm for this disorder...

..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...

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

..Sciatic nerves from these mice and sural nerve biopsies from NF2 patients revealed reduced phosphorylation of the neurofilament H subunit, decreased interfilament spacings and irregularly shaped axons...

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

..Depletion of Angiomotin in Nf2(-/-) Schwann cells attenuates the Ras-MAPK signaling pathway, impedes cellular proliferation in vitro and tumorigenesis in vivo...

..We thus provide evidence that merlin plays a pivotal role in controlling the neuronal wiring in the developing CNS...

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

..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...

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

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

..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...

..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...

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

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

..Thus, Rac1-mediated canonical Wnt signaling is essential for the loss of contact inhibition in NF2-deficient cells...

..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...

..We aimed to establish the contribution of the SMARCB1 and the NF2 genes to sporadic and familial schwannomatosis in our cohort...

..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 data support the significance of regulated Rac signaling in mediating Schwann cell-axon interaction and suggest that controlling Rac activity as a possible therapy for schwannomas...

....

..Upon phosphorylation or interaction with an effector protein, merlin undergoes a subtle conformational change, suggesting a novel mechanism that modulates the interaction between the FERM domain and the CTD...

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

..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...

....

..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...

..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...

..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...

..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...

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

....

..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...

..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...

..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...

..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...

..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...

..These results provide evidence that mutations in the NF2 gene play an important role in the development of sporadic meningiomas as well as indicating a different tumorigenesis of these meningioma variants...

..These data strongly support the notion that NF2 is the sole target of 22q LOH in meningiomas and that loss of merlin expression is always caused by genetic alteration of NF2, following the classic "two hit" theory...

..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...

..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...

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

..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...

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

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

....

..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...

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

..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...

..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...

..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...

..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...

..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...

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

..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 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...

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

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

..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...

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

..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...

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

....

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

....

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

..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 results of these studies will provide insights into the fundamental mechanisms contributing to VS cell growth and radiosensitivity and will likely contribute to the development of novel therapies for VSs. ..

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

..g. DDW and FASEB), and receive guidance from a selected Career Development Research Advisory Committee. ..

..These studies are initial steps in validating LIMK and/or cofilin as drug targets for development of an effective treatment for NF2 aimed at preserving hearing. ..

..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 unprecedented opportunities to leverage developmental neurobiology to identify new drug targets for the treatment of these CNS cancers. ..

..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. ..

..These studies will have impact not only on NF2, but also on sporadic meningiomas and schwannomas, which are quite common in the general population. ..

....

..We also plan to determine whether Merlin controls the surface availability of ErbB3 via a similar mechanism. ..

..The identification of an effective medical therapy for VS and meningiomas would represent a breakthrough in neuro-oncology and enhance the quality of life and survival in patients with these tumors. ..

..abstract_text> ..

..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 ..

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

..It is light, inexpensive, has high utility, and can be retrofitted easily to most wheelchairs. It also reduces the risk of turnovers while propelling up ramps, and lessens the upper extremity stresses imposed by the manual propulsion. ..

..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. ..

..This will in turn benefit the health of human beings. Furthermore, the developed computational techniques can be applicable to a wide range of multi-color bio-imaging problems, thereby having a broad impact on the biomedical community. ..

..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. ..

....

..Based on nucleolar localization of schwannomin in STS26T Schwann cells, its effect on RNA polymerase I transcription will be assayed in vitro using nuclear extracts, purified transcription factors and recombinant proteins. ..

....

..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. ..

..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. ..

..abstract_text> ..

....

..Our ability to design rational therapies for schwannomas and meningiomas is dependent on an improved understanding of the mechanisms by which loss of merlin expression and function promotes tumor formation. ..

..and (3) analyzing the ability of DAL-1 to impair cell growth and motility. These studies are collectively designed to define the role of this novel family of growth regulators in meningioma tumorigenesis and progression. ..

..abstract_text> ..

..unreadable] [unreadable] [unreadable]..

..abstract_text> ..

..unreadable] [unreadable] [unreadable] [unreadable]..

..unreadable] [unreadable] [unreadable]..

..unreadable] [unreadable] [unreadable]..

..unreadable] [unreadable] [unreadable] [unreadable]..

..abstract_text> ..

....

..The resulting data, together with genotype data from at least two other genome-wide association scans, will allow us to evaluate and calibrate our methods for association mapping. [unreadable] [unreadable] [unreadable] [unreadable]..

..Here, we propose to develop efficient methods for analyzing high-throughput sequence data and to distribute software tools that allow others to extract maximum benefit from our methods. ..

..Finally, the families recruited for this study will serve as a valuable resource for future genetic epidemiology studies of SLE. Therefore, the efforts of this project represent an important investment for the future. ..

..The information obtained here will elucidate the physiological functions of these tumor suppressors, which will aid in designing better therapies. ..

..By the end of the project, which will coincide with the completion of the human genome project, they will be able to analyze all of the specific candidate genes that map to linked markers. ..

..abstract_text> ..

....

..My postdoctoral training proposal is illustrative of this interdisciplinary approach, with specific application to the area of alcohol use and abuse. ..

....

..If there are resources left over, we plan to genotype 400 normal controls and perform a case-control analysis using a chi-squared test to confirm any suggestive findings. ..

..This will promote to the research community at large the status of NF research, the link with other cancers and neurological disorders and the key barriers to be addressed. [unreadable] [unreadable] [unreadable]..

..2). Taken together, these studies should clarify the mechanisms by which the loss of Syk(L) and aberrant expression of Syk(S) promotes breast cancer progression. [unreadable] [unreadable]..

..abstract_text> ..

..As AREA grant, this project has been designed to accommodate the training and education of undergraduate researchers. [unreadable] [unreadable] [unreadable]..

..cholerae or due to natural causes. [unreadable] [unreadable] [unreadable]..

..The meeting will take place in December of 2007 and be attended by scientists from academia, government, and industry. [unreadable] [unreadable] [unreadable]..

..abstract_text> ..

..abstract_text> ..

..Successful completion of this study should further elucidate important pathways of vestibular schwannoma formation with good potential for future development of pharmaco-therapeutics. ..

..abstract_text> ..

..Finally, due to the clinical and apparent genetic heterogeneity of RA, we will study specific RA phenotypes as secondary outcomes. ..