The Experts below are selected from a list of 1536 Experts worldwide ranked by ideXlab platform
Richard G Fehon - One of the best experts on this subject based on the ideXlab platform.
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self masking in an intact erm Merlin Protein an active role for the central α helical domain
Journal of Molecular Biology, 2007Co-Authors: Mark R Nance, Richard G Fehon, Rima Kulikauskas, Kevin G Nyberg, Andrew P Karplus, Anthony Bretscher, John J G TesmerAbstract:Ezrin/radixin/moesin (ERM) family members provide a regulated link between the cortical actin cytoskeleton and the plasma membrane to govern membrane structure and organization. Here, we report the crystal structure of intact insect moesin, revealing that its essential yet previously uncharacterized alpha-helical domain forms extensive interactions with conserved surfaces of the band four-point-one/ezrin/radixin/moesin (FERM) domain. These interdomain contacts provide a functional explanation for how PIP(2) binding and tyrosine phosphorylation of ezrin lead to activation, and provide an understanding of previously enigmatic loss-of-function missense mutations in the tumor suppressor Merlin. Sequence conservation and biochemical results indicate that this structure represents a complete model for the closed state of all ERM-Merlin Proteins, wherein the central alpha-helical domain is an active participant in an extensive set of inhibitory interactions that can be unmasked, in a rheostat-like manner, by coincident regulatory factors that help determine cell polarity and membrane structure.
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distinct cellular and subcellular patterns of expression imply distinct functions for the drosophila homologues of moesin and the neurofibromatosis 2 tumor suppressor Merlin
Journal of Cell Biology, 1996Co-Authors: Brooke M Mccartney, Richard G FehonAbstract:Interest in members of the Protein 4.1 super-family, which includes the ezrin-radixin-moesin (ERM) group, has been stimulated recently by the discovery that the human neurofibromatosis 2 (NF2) tumor suppressor gene encodes an ERM-like Protein, Merlin. Although many Proteins in this family are thought to act by linking the actin-based cytoskeleton to transmembrane Proteins, the cellular functions of Merlin have not been defined. To investigate the cellular and developmental functions of these Proteins, we have identified and characterized Drosophila homologues of moesin (Dmoesin) and of the NF2 tumor suppressor Merlin (DMerlin). Using specific antibodies, we show that although these Proteins are frequently coexpressed in developing tissues, they display distinct subcellular localizations. While Dmoesin is observed in continuous association with the plasma membrane, as is typical for an ERM family Protein, DMerlin is found in punctuate structures at the membrane and in the cytoplasm. Investigation of DMerlin cultured cells demonstrates that it is associated with endocytic compartments. 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.
Lalita A Shevde - One of the best experts on this subject based on the ideXlab platform.
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Merlin: the wizard requires Protein stability to function as a tumor suppressor.
Biochimica et biophysica acta, 2012Co-Authors: K. Adam Morrow, Lalita A ShevdeAbstract:Neurofibromatosis type 2 (NF2), characterized by tumors of the nervous system, is a result of functional loss of the NF2 gene. The NF2 gene encodes Merlin (moesin–ezrin–radixin-like Protein), an ERM (Ezrin, Radixin, Moesin) Protein family member. Merlin functions as a tumor suppressor through impacting mechanisms related to proliferation, apoptosis, survival, motility, adhesion, and invasion. Several studies have summarized the tumor intrinsic mutations in Merlin. Given the fact that tumor cells are not in isolation, but rather in an intricate, mutually sustaining synergy with their surrounding stroma, the dialog between the tumor cells and the stroma can potentially impact the molecular homeostasis and promote evolution of the malignant phenotype. This review summarizes the epigenetic modifications, transcript stability, and post-translational modifications that impact Merlin. We have reviewed the role of extrinsic factors originating from the tumor milieu that influence the availability of Merlin inside the cell. Information regarding Merlin regulation could lead to novel therapeutics by stabilizing Merlin Protein in tumors that have reduced Merlin Protein expression without displaying any NF2 genetic alterations.
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loss of tumor suppressor Merlin in advanced breast cancer is due to post translational regulation
Journal of Biological Chemistry, 2011Co-Authors: Adam K Morrow, Shamik Das, Brandon J Metge, Madhuri S Mulekar, Allan J Tucker, Rajeev S Samant, Lalita A ShevdeAbstract:Unlike malignancies of the nervous system, there have been no mutations identified in Merlin in breast cancer. As such, the role of the tumor suppressor, Merlin, has not been investigated in breast cancer. We assessed Merlin expression in breast cancer tissues by immunohistochemistry and by real-time PCR. The expression of Merlin Protein (assessed immunohistochemically) was significantly decreased in breast cancer tissues (although the transcript levels were comparable) simultaneous with increased expression of the tumor-promoting Protein, osteopontin (OPN). We further demonstrate that the loss of Merlin in breast cancer is brought about, in part, due to OPN-initiated Akt-mediated phosphorylation of Merlin leading to its proteasomal degradation. Restoring expression of Merlin resulted in reduced malignant attributes of breast cancer, characterized by reduced invasion, migration, motility, and impeded tumor (xenograft) growth in immunocompromised mice. The possibility of developing a model using the relationship between OPN and Merlin was tested with a logistic regression model applied to immunohistochemistry data. This identified consistent loss of immunohistochemical expression of Merlin in breast tumor tissues. Thus, we demonstrate for the first time a role for Merlin in impeding breast malignancy, identify a novel mechanism for the loss of Merlin Protein in breast cancer, and have developed a discriminatory model using Merlin and OPN expression in breast tumor tissues.
Brooke M Mccartney - One of the best experts on this subject based on the ideXlab platform.
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distinct cellular and subcellular patterns of expression imply distinct functions for the drosophila homologues of moesin and the neurofibromatosis 2 tumor suppressor Merlin
Journal of Cell Biology, 1996Co-Authors: Brooke M Mccartney, Richard G FehonAbstract:Interest in members of the Protein 4.1 super-family, which includes the ezrin-radixin-moesin (ERM) group, has been stimulated recently by the discovery that the human neurofibromatosis 2 (NF2) tumor suppressor gene encodes an ERM-like Protein, Merlin. Although many Proteins in this family are thought to act by linking the actin-based cytoskeleton to transmembrane Proteins, the cellular functions of Merlin have not been defined. To investigate the cellular and developmental functions of these Proteins, we have identified and characterized Drosophila homologues of moesin (Dmoesin) and of the NF2 tumor suppressor Merlin (DMerlin). Using specific antibodies, we show that although these Proteins are frequently coexpressed in developing tissues, they display distinct subcellular localizations. While Dmoesin is observed in continuous association with the plasma membrane, as is typical for an ERM family Protein, DMerlin is found in punctuate structures at the membrane and in the cytoplasm. Investigation of DMerlin cultured cells demonstrates that it is associated with endocytic compartments. 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.
Russell R Lonser - One of the best experts on this subject based on the ideXlab platform.
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missense mutations in the nf2 gene result in the quantitative loss of Merlin Protein and minimally affect Protein intrinsic function
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Chunzhang Yang, Ashok R Asthagiri, Rajiv R Iyer, Alexander Ksendzovsky, Roscoe O Brady, Zhengping Zhuang, Russell R LonserAbstract:Neurofibromatosis type 2 (NF2) is a multiple neoplasia syndrome and is caused by a mutation of the NF2 tumor suppressor gene that encodes for the tumor suppressor Protein Merlin. Biallelic NF2 gene inactivation results in the development of central nervous system tumors, including schwannomas, meningiomas, ependymomas, and astrocytomas. Although a wide variety of missense germline mutations in the coding sequences of the NF2 gene can cause loss of Merlin function, the mechanism of this functional loss is unknown. To gain insight into the mechanisms underlying loss of Merlin function in NF2, we investigated mutated Merlin homeostasis and function in NF2-associated tumors and cell lines. Quantitative Protein and RT-PCR analysis revealed that whereas Merlin Protein expression was significantly reduced in NF2-associated tumors, mRNA expression levels were unchanged. Transfection of genetic constructs of common NF2 missense mutations into NF2 gene-deficient meningioma cell lines revealed that Merlin loss of function is due to a reduction in mutant Protein half-life and increased Protein degradation. Transfection analysis also demonstrated that recovery of tumor suppressor Protein function is possible, indicating that these mutants maintain intrinsic functional capacity. Further, increased expression of mutant Protein is possible after treatment with specific proteostasis regulators, implicating Protein quality control systems in the degradative fate of mutant tumor suppressor Proteins. These findings provide direct insight into Protein function and tumorigenesis in NF2 and indicate a unique treatment paradigm for this disorder.
L. V. Omelyanchuk - One of the best experts on this subject based on the ideXlab platform.
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Drosophila melanogaster gene Merlin interacts with the clathrin adaptor Protein gene lap
Russian Journal of Genetics, 2010Co-Authors: S. A. Kopyl, N. V. Dorogova, E. M. Akhmametyeva, L. V. Omelyanchuk, L. -s. ChangAbstract:The Protein Merlin is involved in the regulation of cell proliferation and differentiation in the eyes and wings of Drosophila and is a homolog of the human Protein encoded by the Neurofibromatosis 2 ( NF2 ) gene whose mutations cause auricular nerve tumors. Recent studies show that Merlin and Expanded cooperatively regulate the recycling of membrane receptors, such as the epidermal growth factor receptor (EGFR). By performing a search for potential genetic interactions between Merlin ( Mer ) and the genes important for vesicular trafficking, we found that ectopic expression in the wing pouch of the clathrin adapter Protein Lap involved in clathrin-mediated receptor endocytosis resulted in the formation of extra vein materials. On the one hand, coexpression of wild-type Merlin and lap in the wing pouch restored normal venation, while overexpression of a dominant-negative mutant Mer ^ DBB together with lap enhanced ectopic vein formation. Using various constructs with Merlin truncated copies, we showed the C-terminal portion of the Merlin Protein to be responsible for the Merlin-lap genetic interaction. Furthermore, we showed that the Merlin and Lap Proteins colocalized at the cortex of the wing imaginal disc cells.
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evolution and origin of hrs a Protein interacting with Merlin the neurofibromatosis 2 gene product
Gene regulation and systems biology, 2009Co-Authors: L. V. Omelyanchuk, Julia A Pertseva, Sarah S Burns, Longsheng ChangAbstract:Hepatocyte growth factor receptor tyrosine kinase substrate (HRS) is an endosomal Protein required for trafficking receptor tyrosine kinases from the early endosome to the lysosome. HRS interacts with Merlin, the Neurofibromatosis 2 (NF2) gene product, and this interaction may be important for Merlin’s tumor suppressor activity. Understanding the evolution, origin, and structure of HRS may provide new insight into Merlin function. We show that HRS homologs are present across a wide range of Metazoa with the yeast Vps27 Protein as their most distant ancestor. The phylogenetic tree of the HRS family coincides with species evolution and divergence, suggesting a unique function for HRS. Sequence alignment shows that various Protein domains of HRS, including the VHS domain, the FYVE domain, the UIM domain, and the clathrin-binding domain, are conserved from yeast to multicellular organisms. The evolutionary transition from unicellular to multicellular organisms was accompanied by the appearance of a binding site for Merlin, which emerges in the early Metazoa after its separation from flatworms. In addition to the region responsible for growth suppression, the Merlin-binding and STAM-binding domains of HRS are conserved among multicellular organisms. The residue equivalent to tyrosine-377, which is phosphorylated in the human HRS Protein, is highly conserved throughout the HRS family. Three additional conserved boxes lacking assigned functions are found in the HRS Proteins of Metazoa. While boxes 1 and 3 may constitute the Eps-15- and Snx1-binding sites, respectively, box 2, containing the residue equivalent to tyrosine-377, is likely to be important for HRS phosphorylation. While several functional domains are conserved throughout the HRS family, the STAM-binding, Merlin-binding, and growth suppression domains evolved in the early Metazoa around the time the Merlin Protein emerged. As these domains appear during the transition to multicellularity, their functional roles may be related to cell-cell interaction.