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John Watrous - One of the best experts on this subject based on the ideXlab platform.
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Quantum Arthur-Merlin Games
arXiv: Computational Complexity, 2005Co-Authors: Chris Marriott, John WatrousAbstract:This paper studies quantum Arthur-Merlin games, which are Arthur-Merlin games in which Arthur and Merlin can perform quantum computations and Merlin can send Arthur quantum information. As in the classical case, messages from Arthur to Merlin are restricted to be strings of uniformly generated random bits. It is proved that for one-message quantum Arthur-Merlin games, which correspond to the complexity class QMA, completeness and soundness errors can be reduced exponentially without increasing the length of Merlin's message. Previous constructions for reducing error required a polynomial increase in the length of Merlin's message. Applications of this fact include a proof that logarithmic length quantum certificates yield no increase in power over BQP and a simple proof that QMA is contained in PP. Other facts that are proved include the equivalence of three (or more) message quantum Arthur-Merlin games with ordinary quantum interactive proof systems and some basic properties concerning two-message quantum Arthur-Merlin games.
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Quantum Arthur---Merlin games
computational complexity, 2005Co-Authors: Chris Marriott, John WatrousAbstract:This paper studies quantum Arthur---Merlin games, which are Arthur---Merlin games in which Arthur and Merlin can perform quantum computations and Merlin can send Arthur quantum information. As in the classical case, messages from Arthur to Merlin are restricted to be strings of uniformly generated random bits. It is proved that for one-message quantum Arthur---Merlin games, which correspond to the complexity class QMA, completeness and soundness errors can be reduced exponentially without increasing the length of Merlin's message. Previous constructions for reducing error required a polynomial increase in the length of Merlin's message. Applications of this fact include a proof that logarithmic length quantum certificates yield no increase in power over BQP and a simple proof that $$ {\text{QMA}} \subseteq {\text{PP}}. $$ Other facts that are proved include the equivalence of three (or more) message quantum Arthur---Merlin games with ordinary quantum interactive proof systems and some basic properties concerning two-message quantum Arthur---Merlin games.
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quantum arthur Merlin games
Conference on Computational Complexity, 2004Co-Authors: Chris Marriott, John WatrousAbstract:This paper studies quantum Arthur-Merlin games, which are a restricted form of quantum interactive proof system in which the verifier's messages are given by unbiased coin-flips. The following results are proved. For one-message quantum Arthur-Merlin games, which correspond to the complexity class QMA, completeness and soundness errors can be reduced exponentially without increasing the length of Merlin's message. Previous constructions for reducing error required a polynomial increase in the length of Merlin's message. Applications of this fact include a proof that logarithmic length quantum certificates yield no increase in power over BQP and a simple proof that QMA /spl sube/ PP. In the case of three or more messages, quantum Arthur-Merlin games are equivalent in power to ordinary quantum interactive proof systems. In fact, for any language having a quantum interactive proof system there exists a three-message quantum Arthur-Merlin game in which Arthur's only message consists of just a single coin-flip that achieves perfect completeness and soundness error exponentially close to 1/2. Any language having a two-message quantum Arthur-Merlin game is contained in BP /spl middot/ PP. This gives some suggestion that three messages are stronger than two in the quantum Arthur-Merlin setting.
Helen Morrison - One of the best experts on this subject based on the ideXlab platform.
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Merlin cooperates with neurofibromin and Spred1 to suppress the Ras-Erk pathway
Human molecular genetics, 2020Co-Authors: Yan Cui, Hongchuan Jin, Stephan Schacke, Jiani C Yin, Yi-ping Hsueh, Helen MorrisonAbstract:The Ras-Erk pathway is frequently over-activated in human tumors. Neurofibromatosis type 1 and 2 (NF1, NF2) are characterized by multiple tumors of Schwann cell origin. The NF1 tumor suppressor neurofibromin is a principal Ras-GAP accelerating Ras inactivation, whereas the NF2 tumor suppressor Merlin is a scaffold protein coordinating multiple signaling pathways. We have previously reported that Merlin interacts with Ras and p120RasGAP. Here, we show that Merlin can also interact with the neurofibromin/Spred1 complex via Merlin-binding sites present on both proteins. Further, Merlin can directly bind to the Ras-binding domain and the kinase domain of Raf1. As the third component of the neurofibromin/Spred1 complex, Merlin cannot increase the Ras-GAP activity; rather, it blocks Ras binding to Raf1 by functioning as a 'selective Ras barrier'. Merlin-deficient Schwann cells require the Ras-Erk pathway activity for proliferation. Accordingly, suppression of the Ras-Erk pathway likely contributes to Merlin's tumor suppressor activity. Taken together, our results, and studies by others, support targeting or co-targeting of this pathway as a therapy for NF2 inactivation-related tumors.
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the nf2 tumor suppressor Merlin interacts with ras and rasgap which may modulate ras signaling
Oncogene, 2019Co-Authors: Yan Cui, Susann Groth, Scott Troutman, Annemarie Carlstedt, Tobias Sperka, Lars Bjorn Riecken, Joseph L Kissil, Hongchuan Jin, Helen MorrisonAbstract:Inactivation of the tumor suppressor NF2/Merlin underlies neurofibromatosis type 2 (NF2) and some sporadic tumors. Previous studies have established that Merlin mediates contact inhibition of proliferation; however, the exact mechanisms remain obscure and multiple pathways have been implicated. We have previously reported that Merlin inhibits Ras and Rac activity during contact inhibition, but how Merlin regulates Ras activity has remained elusive. Here we demonstrate that Merlin can directly interact with both Ras and p120RasGAP (also named RasGAP). While Merlin does not increase the catalytic activity of RasGAP, the interactions with Ras and RasGAP may fine-tune Ras signaling. In vivo, loss of RasGAP in Schwann cells, unlike the loss of Merlin, failed to promote tumorigenic growth in an orthotopic model. Therefore, modulation of Ras signaling through RasGAP likely contributes to, but is not sufficient to account for, Merlin's tumor suppressor activity. Our study provides new insight into the mechanisms of Merlin-dependent Ras regulation and may have additional implications for Merlin-dependent regulation of other small GTPases.
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Expression of Merlin and phospho-Merlin in oligodendrocyte cell lines.
2018Co-Authors: Andrea Toledo, Elena Grieger, Khalad Karram, Helen Morrison, Stephan L. BaaderAbstract:RT4, OLN93 and TC620 cell lines were stably transfected with pcNF2hflag (Merlin) and pcDNA3.1 (control). Representative Western blots of gels loaded with 15 μg of total protein extracts are shown in A. The densitometric determination of Merlin and phospho-Merlin in the cell lines was performed by normalizing with cyclophilin B (mean ± SEM, n = 3, ***p < 0.001, Wilcoxon rank-sum test). Immunofluorescent staining of Merlin and phalloidin staining of actin in Nf2 stably transfected cell lines demonstrates the preferred localization of Merlin in the cytoplasm (B). Single confocal planes of transfected cells are shown using the same microscope parameters. Scale bars: 10μm.
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Merlin Inhibits Neurite Outgrowth in the CNS
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010Co-Authors: Alexander Schulz, Helen Morrison, Katja J. Geissler, Sujeet Kumar, Gregor Leichsenring, Stephan L. BaaderAbstract:The neurofibromatosis type 2 gene product Merlin is known to provoke gliogenic tumors as a result of its mutagenic loss. Merlin's physiological anti-mitogenic function makes it unique among its ezrin-radixin-moesin (ERM) family members. Although ERM proteins and Merlin are known to be expressed in glial cells of the peripheral nervous system and CNS, the neuronal expression pattern and function of Merlin have been less well investigated. We report here expression of Merlin in developing and mature neurons of the murine CNS. Within cerebellar Purkinje cells (PCs), Merlin was localized in the soma, sprouting dendrites and axons. Merlin expression in PCs was high during the period of initial dendrite regression and declined during later phases of dendrite elongation. Consistently, Merlin expression in vivo was increased in Engrailed-2-overexpressing PCs, which are characterized by a reduced dendritic extension. Furthermore, overexpression of Merlin in dissociated cerebellar cultures and in neurogenic P19 cells caused a significant decline in neurite outgrowth, while, conversely, inhibition of Merlin expression increased process formation. This effect was dependent on phosphorylation of serine 518 and involved the inactivation of the growth-promoting GTPase Rac. We thus provide evidence that Merlin plays a pivotal role in controlling the neuronal wiring in the developing CNS.
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Merlin neurofibromatosis type 2 suppresses growth by inhibiting the activation of ras and rac
Cancer Research, 2007Co-Authors: Helen Morrison, Tobias Sperka, Marco Giovannini, Jan Manent, Helmut Ponta, Peter HerrlichAbstract:The small G-protein Ras is a tightly controlled regulator of cell fate. Prolonged or persistent arrest in the activated GTP-loaded state by mutation of Ras as in lung cancer or in a Ras-GTPase-activating protein as in neurofibromatosis type 1 promotes tumorigenesis. We now show that the tumor-suppressor protein Merlin (mutated in neurofibromatosis type 2) also controls Ras activity. Systematic analysis of growth factor signaling located the step of Merlin interference to the activation of Ras and Rac. Merlin independently uncouples both Ras and Rac from growth factor signals. In the case of Ras, Merlin acts downstream of the receptor tyrosine kinase-growth factor receptor binding protein 2 (Grb2)-SOS complex. However, Merlin does not bind either SOS or Ras, but it counteracts the ERM (ezrin, radixin, moesin)-dependent activation of Ras, which correlates with the formation of a complex comprising ERM proteins, Grb2, SOS, Ras, and filamentous actin. Because efficient signaling from Ras requires Rac-p21-activated kinase-dependent phosphorylations of Raf and mitogen-activated protein/extracellular signal-regulated kinase kinase, Merlin can also inhibit signal transfer from dominantly active Ras mutants. We propose that the interference of Merlin with Ras- and Rac-dependent signal transfer represents part of the tumor-suppressive action of Merlin.
David H. Gutmann - One of the best experts on this subject based on the ideXlab platform.
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the neurofibromatosis 2 protein Merlin regulates glial cell growth in an erbb2 and src dependent manner
Molecular and Cellular Biology, 2009Co-Authors: Sean S Houshmandi, Marco Giovannini, Ryan J Emnett, David H. GutmannAbstract:Individuals with the inherited cancer predisposition syndrome neurofibromatosis 2 (NF2) develop several central nervous system (CNS) malignancies, including glial cell neoplasms (ependymomas). Recent studies have suggested that the NF2 protein, Merlin (or schwannomin), may regulate receptor tyrosine kinase signaling, intracellular mitogenic growth control pathways, or adherens junction organization in non-nervous-system cell types. For this report, we used glial fibrillary acidic protein conditional knockout mice and derivative glia to determine how Merlin regulates CNS glial cell proliferation. We show that the loss of Merlin in glial cells results in increased proliferation in vitro and in vivo. Merlin regulation of glial cell growth reflects deregulated Src activity, such that pharmacologic or genetic inhibition of Src activation reduces Nf2(-/-) glial cell growth to wild-type levels. We further show that Src regulates Nf2(-/-) glial cell growth by sequentially regulating FAK and paxillin phosphorylation/activity. Next, we demonstrate that Src activation results from Merlin regulation of ErbB2 activation and that genetic or pharmacologic ErbB2 inhibition reduces Nf2(-/-) glial cell Src/Src effector activation and proliferation to wild-type levels. 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.
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the neurofibromatosis 2 tumor suppressor gene product Merlin regulates human meningioma cell growth by signaling through yap
Neoplasia, 2008Co-Authors: Katherine Striedinger, David H. Gutmann, Gilson S. Baia, Scott R Vandenberg, Michael W Mcdermott, Anita LalAbstract:Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by the occurrence of schwannomas and meningiomas. Several studies have examined the ability of the NF2 gene product, Merlin, to function as a tumor suppressor in diverse cell types; however, little is known about Merlin growth regulation in meningiomas. In Drosophila, Merlin controls cell proliferation and apoptosis by signaling through the Hippo pathway to inhibit the function of the transcriptional coactivator Yorkie. The Hippo pathway is conserved in mammals. On the basis of these observations, we developed human meningioma cell lines matched for Merlin expression to evaluate Merlin growth regulation and investigate the relationship between NF2 status and Yes-associated protein (YAP), the mammalian homolog of Yorkie. NF2 loss in meningioma cells was associated with loss of contact-dependent growth inhibition, enhanced anchorage-independent growth and increased cell proliferation due to increased S-phase entry. In addition, Merlin loss in both meningioma cell lines and primary tumors resulted in increased YAP expression and nuclear localization. Finally, siRNA-mediated reduction of YAP in NF2-deficient meningioma cells rescued the effects of Merlin loss on cell proliferation and S-phase entry. Collectively, these results represent the first demonstration that Merlin regulates cell growth in human cancer cells by suppressing YAP.
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Merlin Is a Potent Inhibitor of Glioma Growth
Cancer research, 2008Co-Authors: Ying-ka Ingar Lau, Lucas B. Murray, S. Sean Houshmandi, David H. GutmannAbstract:Neurofibromatosis 2 (NF2) is an inherited cancer syndrome in which affected individuals develop nervous system tumors, including schwannomas, meningiomas, and ependymomas. The NF2 protein Merlin (or schwannomin) is a member of the Band 4.1 superfamily of proteins, which serve as linkers between transmembrane proteins and the actin cytoskeleton. In addition to mutational inactivation of the NF2 gene in NF2-associated tumors, mutations and loss of Merlin expression have also been reported in other types of cancers. In the present study, we show that Merlin expression is dramatically reduced in human malignant gliomas and that reexpression of functional Merlin dramatically inhibits both subcutaneous and intracranial growth of human glioma cells in mice. We further show that Merlin reexpression inhibits glioma cell proliferation and promotes apoptosis in vivo . Using microarray analysis, we identify altered expression of specific molecules that play key roles in cell proliferation, survival, and motility. These Merlin-induced changes of gene expression were confirmed by real-time quantitative PCR, Western blotting, and functional assays. These results indicate that reexpression of Merlin correlates with activation of mammalian sterile 20-like 1/2–large tumor suppressor 2 signaling pathway and inhibition of canonical and noncanonical Wnt signals. Collectively, our results show that Merlin is a potent inhibitor of high-grade human glioma. [Cancer Res 2008;68(14):5733–42]
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Akt phosphorylation regulates the tumour-suppressor Merlin through ubiquitination and degradation
Nature cell biology, 2007Co-Authors: Xiaoling Tang, Sung-wuk Jang, Xuerong Wang, Zhixue Liu, Scott Bahr, Shi-yong Sun, Daniel J. Brat, David H. GutmannAbstract:The neurofibromatosis-2 (NF2) tumour-suppressor gene encodes an intracellular membrane-associated protein, called Merlin, whose growth-suppressive function is dependent on its ability to form interactions through its intramolecular amino-terminal domain (NTD) and carboxy-terminal domain (CTD). Merlin phosphorylation plays a critical part in dictating Merlin NTD/CTD interactions as well as in controlling binding to its effector proteins. Merlin is partially regulated by phosphorylation of Ser 518, such that hyperphosphorylated Merlin is inactive and fails to form productive intramolecular and intermolecular interactions. Here, we show that the protein kinase Akt directly binds to and phosphorylates Merlin on residues Thr 230 and Ser 315, which abolishes Merlin NTD/CTD interactions and binding to Merlin's effector protein PIKE-L and other binding partners. 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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neurofibromatosis 2 nf2 tumor suppressor Merlin inhibits phosphatidylinositol 3 kinase through binding to pike l
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Rong Rong, Xiaoling Tang, David H. GutmannAbstract:Neurofibromatosis 2 (NF2) is a tumor suppressor, although the molecular mechanism accounting for this effect remains unknown. Here, we show that Merlin exerts its activity by inhibiting phosphatidylinositol 3-kinase (PI3-kinase), through binding to PIKE-L. Wild-type Merlin, but not patient-derived mutant (L64P), binds PIKE-L and inhibits PI3-kinase activity. This suppression of PI3-kinase activity results from Merlin disrupting the binding of PIKE-L to PI3-kinase. In addition, Merlin suppression of PI3-kinase activity as well as schwannoma cell growth is abrogated by a single PIKE-L point mutation (P187L) that cannot bind Merlin but can still activate PI3-kinase. 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.
Andrea I. Mcclatchey - One of the best experts on this subject based on the ideXlab platform.
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the nf2 tumor suppressor Merlin regulates epidermal development through the establishment of a junctional polarity complex
Developmental Cell, 2010Co-Authors: Andrew B Gladden, Alan M Hebert, Eveline E Schneeberger, Andrea I. McclatcheyAbstract:The neurofibromatosis type 2 (NF2) tumor suppressor, Merlin, is a FERM (Four point one, Ezrin, Radixin, Moesin) domain-containing protein whose loss results in defective morphogenesis and tumorigenesis in multiple tissues. Like the closely related ERM proteins (Ezrin, Radixin, and Moesin), Merlin may organize the plasma membrane by assembling membrane protein complexes and linking them to the cortical actin cytoskeleton. We previously found that Merlin is a critical mediator of contact-dependent inhibition of proliferation and is required for the establishment of stable adherens junctions (AJs) in cultured cells. Here, we delineate the molecular function of Merlin in AJ establishment in epidermal keratinocytes in vitro and confirm that a role in AJ establishment is an essential function of Merlin in vivo. Our studies reveal that Merlin can associate directly with α-catenin and link it to Par3, thereby providing an essential link between the AJ and the Par3 polarity complex during junctional maturation.
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localization to the cortical cytoskeleton is necessary for nf2 Merlin dependent epidermal growth factor receptor silencing
Molecular and Cellular Biology, 2008Co-Authors: Banumathi K Cole, Marcello Curto, Annie W Chan, Andrea I. McclatcheyAbstract: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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nf2 Merlin a coordinator of receptor signalling and intercellular contact
British Journal of Cancer, 2008Co-Authors: Marcello Curto, Andrea I. McclatcheyAbstract:This review explores possible mechanisms by which the neurofibromatosis type-2 tumour suppressor Merlin regulates contact-dependent inhibition of proliferation. Starting from an evolutionary perspective, the concurrent emergence of intercellular contacts and proliferation control in multicellular organisms is first considered. Following a brief survey of the molecular and subcellular milieus in which Merlin performs its function, the importance of different cellular and biological contexts in defining the function of Merlin is discussed. Finally, an integrated model for Merlin and the Ezrin, Radixin, and Moesin (ERM) proteins functioning in the regulation of cellular interfaces is proposed.
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Nf2/Merlin: a coordinator of receptor signalling and intercellular contact
British journal of cancer, 2007Co-Authors: Marcello Curto, Andrea I. McclatcheyAbstract:This review explores possible mechanisms by which the neurofibromatosis type-2 tumour suppressor Merlin regulates contact-dependent inhibition of proliferation. Starting from an evolutionary perspective, the concurrent emergence of intercellular contacts and proliferation control in multicellular organisms is first considered. Following a brief survey of the molecular and subcellular milieus in which Merlin performs its function, the importance of different cellular and biological contexts in defining the function of Merlin is discussed. Finally, an integrated model for Merlin and the Ezrin, Radixin, and Moesin (ERM) proteins functioning in the regulation of cellular interfaces is proposed.
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Merlin and ERM proteins: unappreciated roles in cancer development?
Nature reviews. Cancer, 2003Co-Authors: Andrea I. McclatcheyAbstract:Merlin is closely related to ezrin, radixin and moesin (ERMs) — membrane–cytoskeleton-associated proteins that belong to the protein 4.1 superfamily. Although Merlin is the only member of the Merlin/ERM subfamily that is known to function as a tumour suppressor, common subcellular localization, shared interacting partners and physical interaction between Merlin and the ERMs indicate that functional overlap exists. Mouse models indicate that Merlin inactivation might have an unappreciated role in human cancer aetiology. So, could the ERM proteins also have a role in cancer development?
Chris Marriott - One of the best experts on this subject based on the ideXlab platform.
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Quantum Arthur-Merlin Games
arXiv: Computational Complexity, 2005Co-Authors: Chris Marriott, John WatrousAbstract:This paper studies quantum Arthur-Merlin games, which are Arthur-Merlin games in which Arthur and Merlin can perform quantum computations and Merlin can send Arthur quantum information. As in the classical case, messages from Arthur to Merlin are restricted to be strings of uniformly generated random bits. It is proved that for one-message quantum Arthur-Merlin games, which correspond to the complexity class QMA, completeness and soundness errors can be reduced exponentially without increasing the length of Merlin's message. Previous constructions for reducing error required a polynomial increase in the length of Merlin's message. Applications of this fact include a proof that logarithmic length quantum certificates yield no increase in power over BQP and a simple proof that QMA is contained in PP. Other facts that are proved include the equivalence of three (or more) message quantum Arthur-Merlin games with ordinary quantum interactive proof systems and some basic properties concerning two-message quantum Arthur-Merlin games.
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Quantum Arthur---Merlin games
computational complexity, 2005Co-Authors: Chris Marriott, John WatrousAbstract:This paper studies quantum Arthur---Merlin games, which are Arthur---Merlin games in which Arthur and Merlin can perform quantum computations and Merlin can send Arthur quantum information. As in the classical case, messages from Arthur to Merlin are restricted to be strings of uniformly generated random bits. It is proved that for one-message quantum Arthur---Merlin games, which correspond to the complexity class QMA, completeness and soundness errors can be reduced exponentially without increasing the length of Merlin's message. Previous constructions for reducing error required a polynomial increase in the length of Merlin's message. Applications of this fact include a proof that logarithmic length quantum certificates yield no increase in power over BQP and a simple proof that $$ {\text{QMA}} \subseteq {\text{PP}}. $$ Other facts that are proved include the equivalence of three (or more) message quantum Arthur---Merlin games with ordinary quantum interactive proof systems and some basic properties concerning two-message quantum Arthur---Merlin games.
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quantum arthur Merlin games
Conference on Computational Complexity, 2004Co-Authors: Chris Marriott, John WatrousAbstract:This paper studies quantum Arthur-Merlin games, which are a restricted form of quantum interactive proof system in which the verifier's messages are given by unbiased coin-flips. The following results are proved. For one-message quantum Arthur-Merlin games, which correspond to the complexity class QMA, completeness and soundness errors can be reduced exponentially without increasing the length of Merlin's message. Previous constructions for reducing error required a polynomial increase in the length of Merlin's message. Applications of this fact include a proof that logarithmic length quantum certificates yield no increase in power over BQP and a simple proof that QMA /spl sube/ PP. In the case of three or more messages, quantum Arthur-Merlin games are equivalent in power to ordinary quantum interactive proof systems. In fact, for any language having a quantum interactive proof system there exists a three-message quantum Arthur-Merlin game in which Arthur's only message consists of just a single coin-flip that achieves perfect completeness and soundness error exponentially close to 1/2. Any language having a two-message quantum Arthur-Merlin game is contained in BP /spl middot/ PP. This gives some suggestion that three messages are stronger than two in the quantum Arthur-Merlin setting.