The Experts below are selected from a list of 564 Experts worldwide ranked by ideXlab platform

Nailing Zhang - One of the best experts on this subject based on the ideXlab platform.

  • spatial organization of hippo signaling at the plasma membrane mediated by the tumor suppressor merlin nf2
    Cell, 2013
    Co-Authors: Jianzhong Yu, Yonggang Zheng, Qian Chen, Nailing Zhang
    Abstract:

    Summary Although Merlin/NF2 was discovered two decades ago as a tumor suppressor underlying Neurofibromatosis Type II, its precise molecular mechanism remains poorly understood. Recent studies in Drosophila revealed a potential link between Merlin and the Hippo pathway by placing Merlin genetically upstream of the kinase Hpo/Mst. In contrast to the commonly depicted linear model of Merlin functioning through Hpo/Mst, here we show that in both Drosophila and mammals, Merlin promotes downstream Hippo signaling without activating the intrinsic kinase activity of Hpo/Mst. Instead, Merlin directly binds and recruits the effector kinase Wts/Lats to the plasma membrane. Membrane recruitment, in turn, promotes Wts phosphorylation by the Hpo-Sav kinase complex. We further show that disruption of the actin cytoskeleton promotes Merlin-Wts interactions, which implicates Merlin in actin-mediated regulation of Hippo signaling. Our findings elucidate an important molecular function of Merlin and highlight the plasma membrane as a critical subcellular compartment for Hippo signal transduction.

  • Spatial Organization of Hippo Signaling at the Plasma Membrane Mediated by the Tumor Suppressor Merlin/NF2
    Cell, 2013
    Co-Authors: Feng Yin, Yonggang Zheng, Nailing Zhang, Qian Chen, Duojia Pan
    Abstract:

    Although Merlin/NF2 was discovered two decades ago as a tumor suppressor underlying Neurofibromatosis Type II, its precise molecular mechanism remains poorly understood. Recent studies in Drosophila revealed a potential link between Merlin and the Hippo pathway by placing Merlin genetically upstream of the kinase Hpo/Mst. In contrast to the commonly depicted linear model of Merlin functioning through Hpo/Mst, here we show that in both Drosophila and mammals, Merlin promotes downstream Hippo signaling without activating the intrinsic kinase activity of Hpo/Mst. Instead, Merlin directly binds and recruits the effector kinase Wts/Lats to the plasma membrane. Membrane recruitment, in turn, promotes Wts phosphorylation by the Hpo-Sav kinase complex. We further show that disruption of the actin cytoskeleton promotes Merlin-Wts interactions, which implicates Merlin in actin-mediated regulation of Hippo signaling. Our findings elucidate an important molecular function of Merlin and highlight the plasma membrane as a critical subcellular compartment for Hippo signal transduction.

Nancy Ratner - One of the best experts on this subject based on the ideXlab platform.

  • The Nf2 Tumor Suppressor, Merlin, Functions in Rac-Dependent Signaling
    Developmental Cell, 2001
    Co-Authors: Reuben J. Shaw, J. Guillermo Paez, Marcello Curto, Ann Yaktine, Wendy M. Pruitt, Ichiko Saotome, John P. O'bryan, Vikas Gupta, Nancy Ratner, Channing J. Der
    Abstract:

    Abstract Mutations in the Neurofibromatosis Type II ( NF2 ) tumor suppressor predispose humans and mice to tumor development. The study of Nf2 +/− mice has demonstrated an additional effect of Nf2 loss on tumor metastasis. The NF2 -encoded protein, merlin, belongs to the ERM (ezrin, radixin, and moesin) family of cytoskeleton:membrane linkers. However, the molecular basis for the tumor- and metastasis- suppressing activity of merlin is unknown. We have now placed merlin in a signaling pathway downstream of the small GTPase Rac. Expression of activated Rac induces phosphorylation and decreased association of merlin with the cytoskeleton. Furthermore, merlin overexpression inhibits Rac-induced signaling in a phosphorylation-dependent manner. 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.

  • Interaction between two isoforms of the NF2 tumor suppressor protein, merlin, and between merlin and ezrin, suggests modulation of ERM proteins by merlin.
    Journal of neuroscience research, 2000
    Co-Authors: Jin-jun Meng, D.j. Lowrie, Hao Sun, Emily Dorsey, Patricia D. Pelton, Anne-marie Bashour, Joanna Groden, Nancy Ratner
    Abstract:

    The product of the Neurofibromatosis Type II (NF2) tumor suppressor gene, merlin, is closely related to the ezrin-radixin-moesin (ERM) family, a group of proteins believed to link the cytoskeleton to the plasma membrane. Mutation in the NF2 locus is associated with Schwann cell tumors (schwannomas). The two predominant merlin isoforms, I and II, differ only in the carboxy-terminal 16 residues and only isoform I is anti-proliferative. Merlin lacks an actin-binding domain conserved among ezrin, radixin and moesin. Because merlin, ezrin and moesin are co-expressed in Schwann cells, and all homodimerize, we have examined whether merlin and ezrin dimerize with one another. We found by immunoprecipitation and yeast two-hybrid assays that both merlin isoforms interact with ezrin. The interaction occurs in a head-to-tail orientation, with the amino-terminal half of one protein interacting with the carboxy-terminal half of the other. The two merlin isoforms behave differently in their interaction with ezrin. Isoform I binds only ezrin whose carboxy-terminus is exposed, whereas isoform II binds ezrin regardless of whether ezrin is in the open or closed conformation. The heterodimerization of merlin is a much stronger interaction than the interaction between either merlin isoform and ezrin, and can inhibit merlin-ezrin binding. This suggests that, in vivo, merlin dimerization could regulate merlin-ERM protein interaction, and could thus indirectly regulate other interactions involving ERM proteins. J. Neurosci. Res. 62:491–502, 2000. © 2000 Wiley-Liss, Inc.

Duojia Pan - One of the best experts on this subject based on the ideXlab platform.

  • Spatial Organization of Hippo Signaling at the Plasma Membrane Mediated by the Tumor Suppressor Merlin/NF2
    Cell, 2013
    Co-Authors: Feng Yin, Yonggang Zheng, Nailing Zhang, Qian Chen, Duojia Pan
    Abstract:

    Although Merlin/NF2 was discovered two decades ago as a tumor suppressor underlying Neurofibromatosis Type II, its precise molecular mechanism remains poorly understood. Recent studies in Drosophila revealed a potential link between Merlin and the Hippo pathway by placing Merlin genetically upstream of the kinase Hpo/Mst. In contrast to the commonly depicted linear model of Merlin functioning through Hpo/Mst, here we show that in both Drosophila and mammals, Merlin promotes downstream Hippo signaling without activating the intrinsic kinase activity of Hpo/Mst. Instead, Merlin directly binds and recruits the effector kinase Wts/Lats to the plasma membrane. Membrane recruitment, in turn, promotes Wts phosphorylation by the Hpo-Sav kinase complex. We further show that disruption of the actin cytoskeleton promotes Merlin-Wts interactions, which implicates Merlin in actin-mediated regulation of Hippo signaling. Our findings elucidate an important molecular function of Merlin and highlight the plasma membrane as a critical subcellular compartment for Hippo signal transduction.

Helen Morrison - One of the best experts on this subject based on the ideXlab platform.

  • RESEARCH ARTICLE Merlin Isoforms 1 and 2 Both Act as Tumour Suppressors and Are Required for Optimal Sperm Maturation
    2016
    Co-Authors: Ansgar Zoch, Steffen Mayerl, Thomas Greither, Juliane Rübsam, Heike Heuer, Marco Giovannini, Er Schulz, Helen Morrison
    Abstract:

    The tumour suppressor Merlin, encoded by the gene NF2, is frequently mutated in the auto-somal dominant disorder Neurofibromatosis Type II, characterised primarily by the develop-ment of schwannoma and other glial cell tumours. However, NF2 is expressed in virtually all analysed human and rodent organs, and its deletion in mice causes early embryonic lethality. Additionally, NF2 encodes for two major isoforms of Merlin of unknown functional-ity. Specifically, the tumour suppressor potential of isoform 2 remains controversial. In this study, we used Nf2 isoform-specific knockout mouse models to analyse the function of each isoform during development and organ homeostasis. We found that both isoforms carry full tumour suppressor functionality and can completely compensate the loss of the other isoform during development and in most adult organs. Surprisingly, we discovered that spermatogenesis is strictly dependent on the presence of both isoforms. While the tes-tis primarily expresses isoform 1, we noticed an enrichment of isoform 2 in spermatogonial stem cells. Deletion of either isoform was found to cause decreased sperm quality as observed by maturation defects and head/midpiece abnormalities. These defects led to impaired sperm functionality as assessed by decreased sperm capacitation. Thus, we describe spermatogenesis as a new Nf2-dependent process. Additionally, we provide for the first time in vivo evidence for equal tumour suppressor potentials of Merlin isoform 1 and isoform 2

  • Merlin Isoforms 1 and 2 Both Act as Tumour Suppressors and Are Required for Optimal Sperm Maturation
    PLOS ONE, 2015
    Co-Authors: Ansgar Zoch, Steffen Mayerl, Alexander Schulz, Thomas Greither, Lucien Frappart, Juliane Rübsam, Heike Heuer, Marco Giovannini, Helen Morrison
    Abstract:

    The tumour suppressor Merlin, encoded by the gene NF2, is frequently mutated in the autosomal dominant disorder Neurofibromatosis Type II, characterised primarily by the development of schwannoma and other glial cell tumours. However, NF2 is expressed in virtually all analysed human and rodent organs, and its deletion in mice causes early embryonic lethality. Additionally, NF2 encodes for two major isoforms of Merlin of unknown functionality. Specifically, the tumour suppressor potential of isoform 2 remains controversial. In this study, we used Nf2 isoform-specific knockout mouse models to analyse the function of each isoform during development and organ homeostasis. We found that both isoforms carry full tumour suppressor functionality and can completely compensate the loss of the other isoform during development and in most adult organs. Surprisingly, we discovered that spermatogenesis is strictly dependent on the presence of both isoforms. While the testis primarily expresses isoform 1, we noticed an enrichment of isoform 2 in spermatogonial stem cells. Deletion of either isoform was found to cause decreased sperm quality as observed by maturation defects and head/midpiece abnormalities. These defects led to impaired sperm functionality as assessed by decreased sperm capacitation. Thus, we describe spermatogenesis as a new Nf2-dependent process. Additionally, we provide for the first time in vivo evidence for equal tumour suppressor potentials of Merlin isoform 1 and isoform 2.

Yonggang Zheng - One of the best experts on this subject based on the ideXlab platform.

  • spatial organization of hippo signaling at the plasma membrane mediated by the tumor suppressor merlin nf2
    Cell, 2013
    Co-Authors: Jianzhong Yu, Yonggang Zheng, Qian Chen, Nailing Zhang
    Abstract:

    Summary Although Merlin/NF2 was discovered two decades ago as a tumor suppressor underlying Neurofibromatosis Type II, its precise molecular mechanism remains poorly understood. Recent studies in Drosophila revealed a potential link between Merlin and the Hippo pathway by placing Merlin genetically upstream of the kinase Hpo/Mst. In contrast to the commonly depicted linear model of Merlin functioning through Hpo/Mst, here we show that in both Drosophila and mammals, Merlin promotes downstream Hippo signaling without activating the intrinsic kinase activity of Hpo/Mst. Instead, Merlin directly binds and recruits the effector kinase Wts/Lats to the plasma membrane. Membrane recruitment, in turn, promotes Wts phosphorylation by the Hpo-Sav kinase complex. We further show that disruption of the actin cytoskeleton promotes Merlin-Wts interactions, which implicates Merlin in actin-mediated regulation of Hippo signaling. Our findings elucidate an important molecular function of Merlin and highlight the plasma membrane as a critical subcellular compartment for Hippo signal transduction.

  • Spatial Organization of Hippo Signaling at the Plasma Membrane Mediated by the Tumor Suppressor Merlin/NF2
    Cell, 2013
    Co-Authors: Feng Yin, Yonggang Zheng, Nailing Zhang, Qian Chen, Duojia Pan
    Abstract:

    Although Merlin/NF2 was discovered two decades ago as a tumor suppressor underlying Neurofibromatosis Type II, its precise molecular mechanism remains poorly understood. Recent studies in Drosophila revealed a potential link between Merlin and the Hippo pathway by placing Merlin genetically upstream of the kinase Hpo/Mst. In contrast to the commonly depicted linear model of Merlin functioning through Hpo/Mst, here we show that in both Drosophila and mammals, Merlin promotes downstream Hippo signaling without activating the intrinsic kinase activity of Hpo/Mst. Instead, Merlin directly binds and recruits the effector kinase Wts/Lats to the plasma membrane. Membrane recruitment, in turn, promotes Wts phosphorylation by the Hpo-Sav kinase complex. We further show that disruption of the actin cytoskeleton promotes Merlin-Wts interactions, which implicates Merlin in actin-mediated regulation of Hippo signaling. Our findings elucidate an important molecular function of Merlin and highlight the plasma membrane as a critical subcellular compartment for Hippo signal transduction.