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  1. Article ; Online: Pebble/ECT2 RhoGEF negatively regulates the Wingless/Wnt signaling pathway.

    Greer, Elisabeth R / Chao, Anna T / Bejsovec, Amy

    Development (Cambridge, England)

    2013  Volume 140, Issue 24, Page(s) 4937–4946

    Abstract: Wingless (Wg)/Wnt signaling is essential for patterning invertebrate and vertebrate embryos, and inappropriate Wnt activity is associated with a variety of human cancers. Despite intensive study, Wnt pathway mechanisms are not fully understood. We have ... ...

    Abstract Wingless (Wg)/Wnt signaling is essential for patterning invertebrate and vertebrate embryos, and inappropriate Wnt activity is associated with a variety of human cancers. Despite intensive study, Wnt pathway mechanisms are not fully understood. We have discovered a new mechanism for regulating the Wnt pathway: activity of a Rho guanine nucleotide exchange factor (GEF) encoded by pebble (pbl) in Drosophila and ECT2 in humans. This RhoGEF has an essential role in cytokinesis, but also plays an unexpected, conserved role in inhibiting Wg/Wnt activity. Loss and gain of pbl function in Drosophila embryos cause pattern defects that indicate altered Wg activity. Both Pbl and ECT2 repress Wg/Wnt target gene expression in cultured Drosophila and human cells. The GEF activity is required for Wnt regulation, whereas other protein domains important for cytokinesis are not. Unlike most negative regulators of Wnt activity, Pbl/ECT2 functions downstream of Armadillo (Arm)/beta-catenin stabilization. Our results indicate GTPase regulation at a novel point in Wg/Wnt signal transduction, and provide new insight into the categorization of ECT2 as a human proto-oncogene.
    MeSH term(s) Animals ; Armadillo Domain Proteins/genetics ; Body Patterning/genetics ; Cell Line ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster/metabolism ; GTP Phosphohydrolases/metabolism ; Gene Expression Regulation, Developmental ; Guanine Nucleotide Exchange Factors/genetics ; Guanine Nucleotide Exchange Factors/metabolism ; HEK293 Cells ; Humans ; Proto-Oncogene Proteins/metabolism ; RNA Interference ; RNA, Small Interfering ; Transcription Factors/genetics ; Wnt Signaling Pathway ; Wnt1 Protein/metabolism ; beta Catenin/genetics ; rho GTP-Binding Proteins/metabolism
    Chemical Substances ARM protein, Drosophila ; Armadillo Domain Proteins ; Drosophila Proteins ; ECT2 protein, human ; Guanine Nucleotide Exchange Factors ; Pbl protein, Drosophila ; Proto-Oncogene Proteins ; RNA, Small Interfering ; Transcription Factors ; Wnt1 Protein ; beta Catenin ; wg protein, Drosophila ; GTP Phosphohydrolases (EC 3.6.1.-) ; Rho1 protein, Drosophila (EC 3.6.5.2) ; rho GTP-Binding Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2013-11-06
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 90607-4
    ISSN 1477-9129 ; 0950-1991
    ISSN (online) 1477-9129
    ISSN 0950-1991
    DOI 10.1242/dev.101303
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  2. Article ; Online: Rictor/TORC2 regulates Caenorhabditis elegans fat storage, body size, and development through sgk-1.

    Jones, Kevin T / Greer, Elisabeth R / Pearce, David / Ashrafi, Kaveh

    PLoS biology

    2009  Volume 7, Issue 3, Page(s) e60

    Abstract: The target of rapamycin (TOR) kinase coordinately regulates fundamental metabolic and cellular processes to support growth, proliferation, survival, and differentiation, and consequently it has been proposed as a therapeutic target for the treatment of ... ...

    Abstract The target of rapamycin (TOR) kinase coordinately regulates fundamental metabolic and cellular processes to support growth, proliferation, survival, and differentiation, and consequently it has been proposed as a therapeutic target for the treatment of cancer, metabolic disease, and aging. The TOR kinase is found in two biochemically and functionally distinct complexes, termed TORC1 and TORC2. Aided by the compound rapamycin, which specifically inhibits TORC1, the role of TORC1 in regulating translation and cellular growth has been extensively studied. The physiological roles of TORC2 have remained largely elusive due to the lack of pharmacological inhibitors and its genetic lethality in mammals. Among potential targets of TORC2, the pro-survival kinase AKT has garnered much attention. Within the context of intact animals, however, the physiological consequences of phosphorylation of AKT by TORC2 remain poorly understood. Here we describe viable loss-of-function mutants in the Caenorhabditis elegans homolog of the TORC2-specific component, Rictor (CeRictor). These mutants display a mild developmental delay and decreased body size, but have increased lipid storage. These functions of CeRictor are not mediated through the regulation of AKT kinases or their major downstream target, the insulin-regulated FOXO transcription factor DAF-16. We found that loss of sgk-1, a homolog of the serum- and glucocorticoid-induced kinase, mimics the developmental, growth, and metabolic phenotypes of CeRictor mutants, while a novel, gain-of-function mutation in sgk-1 suppresses these phenotypes, indicating that SGK-1 is a mediator of CeRictor activity. These findings identify new physiological roles for TORC2, mediated by SGK, in regulation of C. elegans lipid accumulation and growth, and they challenge the notion that AKT is the primary effector of TORC2 function.
    MeSH term(s) Adaptor Proteins, Signal Transducing ; Animals ; Body Size ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans/growth & development ; Caenorhabditis elegans/metabolism ; Caenorhabditis elegans Proteins/genetics ; Caenorhabditis elegans Proteins/metabolism ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Gene Expression Regulation, Developmental ; Lipid Metabolism/genetics ; Mutation ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins c-akt/genetics ; Proto-Oncogene Proteins c-akt/metabolism ; Rapamycin-Insensitive Companion of mTOR Protein
    Chemical Substances Adaptor Proteins, Signal Transducing ; Caenorhabditis elegans Proteins ; Carrier Proteins ; Rapamycin-Insensitive Companion of mTOR Protein ; rict-1 protein, C elegans ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Sgk-1 protein, C elegans (EC 2.7.11.1) ; akt-1 protein, C elegans (EC 2.7.11.1)
    Language English
    Publishing date 2009-03-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2126776-5
    ISSN 1545-7885 ; 1544-9173
    ISSN (online) 1545-7885
    ISSN 1544-9173
    DOI 10.1371/journal.pbio.1000060
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 6193: Show issues Location:
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  3. Article ; Online: Neural and molecular dissection of a C. elegans sensory circuit that regulates fat and feeding.

    Greer, Elisabeth R / Pérez, Carissa L / Van Gilst, Marc R / Lee, Brian H / Ashrafi, Kaveh

    Cell metabolism

    2008  Volume 8, Issue 2, Page(s) 118–131

    Abstract: A major challenge in understanding energy balance is deciphering the neural and molecular circuits that govern behavioral, physiological, and metabolic responses of animals to fluctuating environmental conditions. The neurally expressed TGF-beta ligand ... ...

    Abstract A major challenge in understanding energy balance is deciphering the neural and molecular circuits that govern behavioral, physiological, and metabolic responses of animals to fluctuating environmental conditions. The neurally expressed TGF-beta ligand DAF-7 functions as a gauge of environmental conditions to modulate energy balance in C. elegans. We show that daf-7 signaling regulates fat metabolism and feeding behavior through a compact neural circuit that allows for integration of multiple inputs and the flexibility for differential regulation of outputs. In daf-7 mutants, perception of depleting food resources causes fat accumulation despite reduced feeding rate. This fat accumulation is mediated, in part, through neural metabotropic glutamate signaling and upregulation of peripheral endogenous biosynthetic pathways that direct energetic resources into fat reservoirs. Thus, neural perception of adverse environmental conditions can promote fat accumulation without a concomitant increase in feeding rate.
    MeSH term(s) Adaptation, Physiological/physiology ; Adipose Tissue/metabolism ; Animals ; Appetite Regulation/physiology ; Caenorhabditis elegans/cytology ; Caenorhabditis elegans/metabolism ; Caenorhabditis elegans Proteins/genetics ; Caenorhabditis elegans Proteins/metabolism ; Energy Metabolism/physiology ; Environment ; Feeding Behavior/physiology ; Lipid Metabolism/physiology ; Models, Animal ; Mutation/genetics ; Nervous System/cytology ; Nervous System/metabolism ; Neural Pathways/cytology ; Neural Pathways/metabolism ; Neurons, Afferent/cytology ; Neurons, Afferent/metabolism ; Receptors, Metabotropic Glutamate/metabolism ; Starvation/metabolism ; Transforming Growth Factor beta/genetics ; Transforming Growth Factor beta/metabolism
    Chemical Substances Caenorhabditis elegans Proteins ; DAF-7 protein, C elegans ; Receptors, Metabotropic Glutamate ; Transforming Growth Factor beta
    Language English
    Publishing date 2008-08-05
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2176834-1
    ISSN 1932-7420 ; 1550-4131
    ISSN (online) 1932-7420
    ISSN 1550-4131
    DOI 10.1016/j.cmet.2008.06.005
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 6169: Show issues Location:
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