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Pesquisa : D12.776.526.600 [Categoria DeCS]
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[PMID]:28467818
[Au] Autor:Janda CY; Dang LT; You C; Chang J; de Lau W; Zhong ZA; Yan KS; Marecic O; Siepe D; Li X; Moody JD; Williams BO; Clevers H; Piehler J; Baker D; Kuo CJ; Garcia KC
[Ad] Endereço:Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, and Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
[Ti] Título:Surrogate Wnt agonists that phenocopy canonical Wnt and ß-catenin signalling.
[So] Source:Nature;545(7653):234-237, 2017 05 11.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Wnt proteins modulate cell proliferation and differentiation and the self-renewal of stem cells by inducing ß-catenin-dependent signalling through the Wnt receptor frizzled (FZD) and the co-receptors LRP5 and LRP6 to regulate cell fate decisions and the growth and repair of several tissues. The 19 mammalian Wnt proteins are cross-reactive with the 10 FZD receptors, and this has complicated the attribution of distinct biological functions to specific FZD and Wnt subtype interactions. Furthermore, Wnt proteins are modified post-translationally by palmitoylation, which is essential for their secretion, function and interaction with FZD receptors. As a result of their acylation, Wnt proteins are very hydrophobic and require detergents for purification, which presents major obstacles to the preparation and application of recombinant Wnt proteins. This hydrophobicity has hindered the determination of the molecular mechanisms of Wnt signalling activation and the functional importance of FZD subtypes, and the use of Wnt proteins as therapeutic agents. Here we develop surrogate Wnt agonists, water-soluble FZD-LRP5/LRP6 heterodimerizers, with FZD5/FZD8-specific and broadly FZD-reactive binding domains. Similar to WNT3A, these Wnt agonists elicit a characteristic ß-catenin signalling response in a FZD-selective fashion, enhance the osteogenic lineage commitment of primary mouse and human mesenchymal stem cells, and support the growth of a broad range of primary human organoid cultures. In addition, the surrogates can be systemically expressed and exhibit Wnt activity in vivo in the mouse liver, regulating metabolic liver zonation and promoting hepatocyte proliferation, resulting in hepatomegaly. These surrogates demonstrate that canonical Wnt signalling can be activated by bi-specific ligands that induce receptor heterodimerization. Furthermore, these easily produced, non-lipidated Wnt surrogate agonists facilitate functional studies of Wnt signalling and the exploration of Wnt agonists for translational applications in regenerative medicine.
[Mh] Termos MeSH primário: Transdução de Sinais
Proteínas Wnt/agonistas
Proteínas Wnt/metabolismo
Via de Sinalização Wnt
beta Catenina/metabolismo
[Mh] Termos MeSH secundário: Animais
Diferenciação Celular
Linhagem da Célula
Proliferação Celular
Receptores Frizzled/metabolismo
Células HEK293
Hepatócitos/citologia
Hepatomegalia/metabolismo
Hepatomegalia/patologia
Seres Humanos
Interações Hidrofóbicas e Hidrofílicas
Intestinos/citologia
Ligantes
Fígado/metabolismo
Fígado/patologia
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Células Mesenquimais Estromais/citologia
Células Mesenquimais Estromais/metabolismo
Camundongos
Modelos Moleculares
Organoides/citologia
Organoides/metabolismo
Multimerização Proteica
Solubilidade
Técnicas de Cultura de Tecidos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Frizzled Receptors); 0 (Ligands); 0 (Low Density Lipoprotein Receptor-Related Protein-5); 0 (Low Density Lipoprotein Receptor-Related Protein-6); 0 (Wnt Proteins); 0 (beta Catenin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180217
[Lr] Data última revisão:
180217
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1038/nature22306


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[PMID]:29176883
[Au] Autor:Sebastian A; Hum NR; Murugesh DK; Hatsell S; Economides AN; Loots GG
[Ad] Endereço:Lawrence Livermore National Laboratories, Physical and Life Sciences Directorate, Livermore, CA, United States of America.
[Ti] Título:Wnt co-receptors Lrp5 and Lrp6 differentially mediate Wnt3a signaling in osteoblasts.
[So] Source:PLoS One;12(11):e0188264, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Wnt3a is a major regulator of bone metabolism however, very few of its target genes are known in bone. Wnt3a preferentially signals through transmembrane receptors Frizzled and co-receptors Lrp5/6 to activate the canonical signaling pathway. Previous studies have shown that the canonical Wnt co-receptors Lrp5 and Lrp6 also play an essential role in normal postnatal bone homeostasis, yet, very little is known about specific contributions by these co-receptors in Wnt3a-dependent signaling. We used high-throughput sequencing technology to identify target genes regulated by Wnt3a in osteoblasts and to elucidate the role of Lrp5 and Lrp6 in mediating Wnt3a signaling. Our study identified 782 genes regulated by Wnt3a in primary calvarial osteoblasts. Wnt3a up-regulated the expression of several key regulators of osteoblast proliferation/ early stages of differentiation while inhibiting genes expressed in later stages of osteoblastogenesis. We also found that Lrp6 is the key mediator of Wnt3a signaling in osteoblasts and Lrp5 played a less significant role in mediating Wnt3a signaling.
[Mh] Termos MeSH primário: Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Osteoblastos/metabolismo
Receptores Wnt/metabolismo
Transdução de Sinais
Proteína Wnt3A/metabolismo
[Mh] Termos MeSH secundário: Animais
Osso e Ossos/metabolismo
Diferenciação Celular/genética
Regulação para Baixo/genética
Perfilação da Expressão Gênica
Ontologia Genética
Camundongos Knockout
Osteogênese/genética
Fenótipo
Transcriptoma/genética
Regulação para Cima/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Low Density Lipoprotein Receptor-Related Protein-5); 0 (Low Density Lipoprotein Receptor-Related Protein-6); 0 (Receptors, Wnt); 0 (Wnt3A Protein)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171219
[Lr] Data última revisão:
171219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0188264


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[PMID]:29017031
[Au] Autor:Kirsch N; Chang LS; Koch S; Glinka A; Dolde C; Colozza G; Benitez MDJ; De Robertis EM; Niehrs C
[Ad] Endereço:Division of Molecular Embryology, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum (DKFZ), 69120 Heidelberg, Germany.
[Ti] Título:Angiopoietin-like 4 Is a Wnt Signaling Antagonist that Promotes LRP6 Turnover.
[So] Source:Dev Cell;43(1):71-82.e6, 2017 Oct 09.
[Is] ISSN:1878-1551
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Angiopoietin-like 4 (ANGPTL4) is a secreted signaling protein that is implicated in cardiovascular disease, metabolic disorder, and cancer. Outside of its role in lipid metabolism, ANGPTL4 signaling remains poorly understood. Here, we identify ANGPTL4 as a Wnt signaling antagonist that binds to syndecans and forms a ternary complex with the Wnt co-receptor Lipoprotein receptor-related protein 6 (LRP6). This protein complex is internalized via clathrin-mediated endocytosis and degraded in lysosomes, leading to attenuation of Wnt/ß-catenin signaling. Angptl4 is expressed in the Spemann organizer of Xenopus embryos and acts as a Wnt antagonist to promote notochord formation and prevent muscle differentiation. This unexpected function of ANGPTL4 invites re-interpretation of its diverse physiological effects in light of Wnt signaling and may open therapeutic avenues for human disease.
[Mh] Termos MeSH primário: Angiopoietinas/metabolismo
Endocitose/fisiologia
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Receptores de LDL/metabolismo
Via de Sinalização Wnt/fisiologia
Proteínas de Xenopus/metabolismo
beta Catenina/metabolismo
[Mh] Termos MeSH secundário: Proteína 4 Semelhante a Angiopoietina
Angiopoietinas/genética
Animais
Seres Humanos
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
Fosforilação
Transdução de Sinais/fisiologia
Proteína Wnt3A/metabolismo
Xenopus
Proteínas de Xenopus/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ANGPTL4 protein, Xenopus); 0 (ANGPTL4 protein, human); 0 (Angiopoietin-like 4 Protein); 0 (Angiopoietins); 0 (LRP6 protein, human); 0 (Low Density Lipoprotein Receptor-Related Protein-6); 0 (Receptors, LDL); 0 (Wnt3A Protein); 0 (Xenopus Proteins); 0 (beta Catenin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171011
[St] Status:MEDLINE


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[PMID]:28694256
[Au] Autor:Ahn Y; Sims C; Murray MJ; Kuhlmann PK; Fuentes-Antrás J; Weatherbee SD; Krumlauf R
[Ad] Endereço:Stowers Institute for Medical Research, Kansas City, MO 64110, USA youngwook_ahn@brown.edu rek@stowers.org.
[Ti] Título:Multiple modes of Lrp4 function in modulation of Wnt/ß-catenin signaling during tooth development.
[So] Source:Development;144(15):2824-2836, 2017 08 01.
[Is] ISSN:1477-9129
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:During development and homeostasis, precise control of Wnt/ß-catenin signaling is in part achieved by secreted and membrane proteins that negatively control activity of the Wnt co-receptors Lrp5 and Lrp6. Lrp4 is related to Lrp5/6 and is implicated in modulation of Wnt/ß-catenin signaling, presumably through its ability to bind to the Wise (Sostdc1)/sclerostin (Sost) family of Wnt antagonists. To gain insights into the molecular mechanisms of Lrp4 function in modulating Wnt signaling, we performed an array of genetic analyses in murine tooth development, where Lrp4 and Wise play important roles. We provide genetic evidence that Lrp4 mediates the Wnt inhibitory function of Wise and also modulates Wnt/ß-catenin signaling independently of Wise. Chimeric receptor analyses raise the possibility that the Lrp4 extracellular domain interacts with Wnt ligands, as well as the Wnt antagonists. Diverse modes of Lrp4 function are supported by severe tooth phenotypes of mice carrying a human mutation known to abolish Lrp4 binding to Sost. Our data suggest a model whereby Lrp4 modulates Wnt/ß-catenin signaling via interaction with Wnt ligands and antagonists in a context-dependent manner.
[Mh] Termos MeSH primário: Receptores de LDL/metabolismo
Dente/embriologia
Dente/metabolismo
beta Catenina/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteínas Morfogenéticas Ósseas/deficiência
Proteínas Morfogenéticas Ósseas/genética
Proteínas Morfogenéticas Ósseas/metabolismo
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Camundongos
Camundongos Mutantes
Receptores de LDL/deficiência
Receptores de LDL/genética
Dente/patologia
Via de Sinalização Wnt/genética
Via de Sinalização Wnt/fisiologia
beta Catenina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bone Morphogenetic Proteins); 0 (Low Density Lipoprotein Receptor-Related Protein-5); 0 (Low Density Lipoprotein Receptor-Related Protein-6); 0 (Lrp4 protein, mouse); 0 (Lrp5 protein, mouse); 0 (Lrp6 protein, mouse); 0 (Receptors, LDL); 0 (Sostdc1 protein, mouse); 0 (beta Catenin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171126
[Lr] Data última revisão:
171126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170712
[St] Status:MEDLINE
[do] DOI:10.1242/dev.150680


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[PMID]:28626941
[Au] Autor:Sezgin E; Azbazdar Y; Ng XW; Teh C; Simons K; Weidinger G; Wohland T; Eggeling C; Ozhan G
[Ad] Endereço:MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, UK.
[Ti] Título:Binding of canonical Wnt ligands to their receptor complexes occurs in ordered plasma membrane environments.
[So] Source:FEBS J;284(15):2513-2526, 2017 Aug.
[Is] ISSN:1742-4658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:While the cytosolic events of Wnt/ß-catenin signaling (canonical Wnt signaling) pathway have been widely studied, only little is known about the molecular mechanisms involved in Wnt binding to its receptors at the plasma membrane. Here, we reveal the influence of the immediate plasma membrane environment on the canonical Wnt-receptor interaction. While the receptors are distributed both in ordered and disordered environments, Wnt binding to its receptors selectively occurs in more ordered membrane environments which appear to cointernalize with the Wnt-receptor complex. Moreover, Wnt/ß-catenin signaling is significantly reduced when the membrane order is disturbed by specific inhibitors of certain lipids that prefer to localize at the ordered environments. Similarly, a reduction in Wnt signaling activity is observed in Niemann-Pick Type C disease cells where trafficking of ordered membrane lipid components to the plasma membrane is genetically impaired. We thus conclude that ordered plasma membrane environments are essential for binding of canonical Wnts to their receptor complexes and downstream signaling activity.
[Mh] Termos MeSH primário: Membrana Celular/metabolismo
Proteínas do Citoesqueleto/metabolismo
Microdomínios da Membrana/metabolismo
Receptores Wnt/agonistas
Proteínas Wnt/metabolismo
Via de Sinalização Wnt
Proteína Wnt3/metabolismo
Proteína Wnt3A/metabolismo
Proteínas de Peixe-Zebra/metabolismo
[Mh] Termos MeSH secundário: Animais
Animais Geneticamente Modificados
Células CHO
Linhagem Celular Tumoral
Células Cultivadas
Cricetulus
Proteínas do Citoesqueleto/genética
Embrião não Mamífero/metabolismo
Genes Reporter
Células HEK293
Seres Humanos
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/agonistas
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Proteínas Luminescentes/genética
Proteínas Luminescentes/metabolismo
Doenças de Niemann-Pick/metabolismo
Doenças de Niemann-Pick/patologia
Receptores Wnt/metabolismo
Proteínas Recombinantes de Fusão/metabolismo
Proteínas Wnt/genética
Proteína Wnt3/genética
Proteína Wnt3A/genética
Peixe-Zebra/genética
Peixe-Zebra/metabolismo
Proteínas de Peixe-Zebra/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytoskeletal Proteins); 0 (Low Density Lipoprotein Receptor-Related Protein-6); 0 (Luminescent Proteins); 0 (Receptors, Wnt); 0 (Recombinant Fusion Proteins); 0 (Wnt Proteins); 0 (Wnt3 Protein); 0 (Wnt3A Protein); 0 (Wnt3a protein, zebrafish); 0 (Zebrafish Proteins); 0 (wnt8a protein, zebrafish)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170620
[St] Status:MEDLINE
[do] DOI:10.1111/febs.14139


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[PMID]:28425175
[Au] Autor:Seo T; Sakon T; Nakazawa S; Nishioka A; Watanabe K; Matsumoto K; Akasaka M; Shioi N; Sawada H; Araki S
[Ad] Endereço:Sugashima Marine Biological Laboratory, Graduate School of Science, Nagoya University, Japan.
[Ti] Título:Haemorrhagic snake venom metalloproteases and human ADAMs cleave LRP5/6, which disrupts cell-cell adhesions in vitro and induces haemorrhage in vivo.
[So] Source:FEBS J;284(11):1657-1671, 2017 Jun.
[Is] ISSN:1742-4658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Snake venom metalloproteases (SVMPs) are members of the a disintegrin and metalloprotease (ADAM) family of proteins, as they possess similar domains. SVMPs are known to elicit snake venom-induced haemorrhage; however, the target proteins and cleavage sites are not known. In this work, we identified a target protein of vascular apoptosis-inducing protein 1 (VAP1), an SVMP, relevant to its ability to induce haemorrhage. VAP1 disrupted cell-cell adhesions by relocating VE-cadherin and γ-catenin from the cell-cell junction to the cytosol, without inducing proteolysis of VE-cadherin. The Wnt receptors low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) are known to promote catenin relocation, and are rendered constitutively active in Wnt signalling by truncation. Thus, we examined whether VAP1 cleaves LRP5/6 to induce catenin relocation. Indeed, we found that VAP1 cleaved the extracellular region of LRP6 and LRP5. This cleavage removes four inhibitory ß-propeller structures, resulting in activation of LRP5/6. Recombinant human ADAM8 and ADAM12 also cleaved LRP6 at the same site. An antibody against a peptide including the LRP6-cleavage site inhibited VAP1-induced VE-cadherin relocation and disruption of cell-cell adhesions in cultured cells, and blocked haemorrhage in mice in vivo. Intriguingly, animals resistant to the effects of haemorrhagic snake venom express variants of LRP5/6 that lack the VAP1-cleavage site, or low-density lipoprotein receptor domain class A domains involved in formation of the constitutively active form. The results validate LRP5/6 as physiological targets of ADAMs. Furthermore, they indicate that SVMP-induced cleavage of LRP5/6 causes disruption of cell-cell adhesion and haemorrhage, potentially opening new avenues for the treatment of snake bites.
[Mh] Termos MeSH primário: Proteínas ADAM/metabolismo
Proteínas Reguladoras de Apoptose/metabolismo
Venenos de Crotalídeos/metabolismo
Hemorragia/induzido quimicamente
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/fisiologia
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/fisiologia
Metaloendopeptidases/metabolismo
[Mh] Termos MeSH secundário: Proteínas ADAM/farmacologia
Proteína ADAM12/metabolismo
Proteína ADAM12/farmacologia
Sequência de Aminoácidos
Animais
Anticorpos Neutralizantes/farmacologia
Adesão Celular/efeitos dos fármacos
Adesão Celular/fisiologia
Resistência a Medicamentos
Fibrinogênio/metabolismo
Fibronectinas/metabolismo
Células HeLa
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Interações Hidrofóbicas e Hidrofílicas
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/química
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/química
Masculino
Proteínas de Membrana/metabolismo
Proteínas de Membrana/farmacologia
Camundongos
Modelos Moleculares
Simulação de Acoplamento Molecular
Domínios Proteicos
Estrutura Secundária de Proteína/efeitos dos fármacos
Proteínas Recombinantes/metabolismo
Alinhamento de Sequência
Homologia de Sequência de Aminoácidos
Especificidade da Espécie
Vertebrados/metabolismo
Via de Sinalização Wnt/efeitos dos fármacos
Via de Sinalização Wnt/fisiologia
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Neutralizing); 0 (Apoptosis Regulatory Proteins); 0 (Crotalid Venoms); 0 (Fibronectins); 0 (LRP5 protein, human); 0 (LRP6 protein, human); 0 (Low Density Lipoprotein Receptor-Related Protein-5); 0 (Low Density Lipoprotein Receptor-Related Protein-6); 0 (Lrp5 protein, mouse); 0 (Lrp6 protein, mouse); 0 (Membrane Proteins); 0 (Recombinant Proteins); 0 (fibrinogen Aalpha); 9001-32-5 (Fibrinogen); EC 3.4.24.- (ADAM Proteins); EC 3.4.24.- (ADAM12 Protein); EC 3.4.24.- (ADAM12 protein, human); EC 3.4.24.- (ADAM8 protein, human); EC 3.4.24.- (Metalloendopeptidases); EC 3.4.24.- (VAP2 protein, Crotalus atrox); EC 3.4.24.- (vascular apoptosis-inducing protein 1, Crotalus atrox)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170421
[St] Status:MEDLINE
[do] DOI:10.1111/febs.14066


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[PMID]:28359679
[Au] Autor:Zhang Y; Seid K; Obermayr F; Just L; Neckel PH
[Ad] Endereço:Institute of Clinical Anatomy and Cell Analysis, University of Tübingen, Tübingen, Germany.
[Ti] Título:Activation of Wnt Signaling Increases Numbers of Enteric Neurons Derived From Neonatal Mouse and Human Progenitor Cells.
[So] Source:Gastroenterology;153(1):154-165.e9, 2017 Jul.
[Is] ISSN:1528-0012
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND & AIMS: Neural stem and progenitor cells from the enteric nervous system (ENS) might serve as a source of cells for treatment of neurogastrointestinal disorders. Before we can use these cells, we must increase our understanding of the signaling mechanisms that regulate proliferation and differentiation. We systematically evaluated the effects of canonical Wnt signaling on proliferation and differentiation of cultured ENS progenitor cells from neonatal mice and humans. METHODS: We isolated ENS progenitors from tunica muscularis of the small intestine of newborn (postnatal day 0) wild-type C57BL/6 mice as well as from Wnt1-Cre2 reporter mice. We also obtained intestinal tissue samples from infants (2 and 7 months old) undergoing surgery for imperforate anus or focal intestinal perforation and isolated ENS cells. ENS cells were cultured under proliferation conditions leading to formation of 3-dimensional spheres, which we activated with Wnt3a and SB216763 in order to activate the ß-catenin-dependent canonical Wnt pathway. We used immunoblot and quantitative polymerase chain reaction to evaluate the molecular response to Wnt stimuli and immunohistochemistry, proliferation, and cell death assays to identify new neurons. RESULTS: In proliferating enterospheres derived from ENS progenitor cells, we verified the expression of Wnt receptors frizzled 1-10 and the co-receptors low-density lipoprotein receptor-related proteins 5 and 6. Pharmacologic stimulation with Wnt agonists led to intracellular accumulation of Wnt-dependent ß-catenin and up-regulated expression of known Wnt target genes axin2, lef1, and lgr5. Activation of the canonical Wnt pathway promoted growth of ENS cell spheres during cell expansion and increased the number of newborn neurons derived from mouse and human progenitor cells. CONCLUSIONS: In studies of human and mouse ENS progenitors, we found activation of the Wnt signaling pathway to promote neurogenesis of the ENS in vitro. The neurogenic effect of Wnt agonists on ENS progenitors supports their use in generation of cell pools for autologous cell replacement therapies.
[Mh] Termos MeSH primário: Diferenciação Celular
Proliferação Celular
Sistema Nervoso Entérico/citologia
Neurônios
RNA Mensageiro/análise
Via de Sinalização Wnt
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Proteína Axina/genética
Contagem de Células
Morte Celular
Proliferação Celular/efeitos dos fármacos
Feminino
Receptores Frizzled/genética
Receptores Frizzled/metabolismo
Expressão Gênica/efeitos dos fármacos
Seres Humanos
Indóis/farmacologia
Lactente
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Fator 1 de Ligação ao Facilitador Linfoide/genética
Masculino
Maleimidas/farmacologia
Camundongos
Camundongos Endogâmicos C57BL
Receptores Acoplados a Proteínas-G/genética
Esferoides Celulares/metabolismo
Células-Tronco
Regulação para Cima
Via de Sinalização Wnt/efeitos dos fármacos
Proteína Wnt3A/farmacologia
beta Catenina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AXIN2 protein, human); 0 (Axin Protein); 0 (Axin2 protein, mouse); 0 (Frizzled Receptors); 0 (Indoles); 0 (LGR5 protein, human); 0 (Lgr5 protein, mouse); 0 (Low Density Lipoprotein Receptor-Related Protein-5); 0 (Low Density Lipoprotein Receptor-Related Protein-6); 0 (Lymphoid Enhancer-Binding Factor 1); 0 (Maleimides); 0 (RNA, Messenger); 0 (Receptors, G-Protein-Coupled); 0 (SB 216763); 0 (Wnt3A Protein); 0 (beta Catenin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170401
[St] Status:MEDLINE


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[PMID]:28234935
[Au] Autor:Poorebrahim M; Sadeghi S; Rahimi H; Karimipoor M; Azadmanesh K; Mazlomi MA; Teimoori-Toolabi L
[Ad] Endereço:Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
[Ti] Título:Rational design of DKK3 structure-based small peptides as antagonists of Wnt signaling pathway and in silico evaluation of their efficiency.
[So] Source:PLoS One;12(2):e0172217, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Dysregulated Wnt signaling pathway is highly associated with the pathogenesis of several human cancers. Dickkopf proteins (DKKs) are thought to inhibit Wnt signaling pathway through binding to lipoprotein receptor-related protein (LRP) 5/6. In this study, based on the 3-dimensional (3D) structure of DKK3 Cys-rich domain 2 (CRD2), we have designed and developed several peptide inhibitors of Wnt signaling pathway. Modeller 9.15 package was used to predict 3D structure of CRD2 based on the Homology modeling (HM) protocol. After refinement and minimization with GalaxyRefine and NOMAD-REF servers, the quality of selected models was evaluated utilizing VADAR, SAVES and ProSA servers. Molecular docking studies as well as literature-based information revealed two distinct boxes located at CRD2 which are actively involved in the DKK3-LRP5/6 interaction. A peptide library was constructed conducting the backrub sequence tolerance scanning protocol in Rosetta3.5 according to the DKK3-LRP5/6 binding sites. Seven tolerated peptides were chosen and their binding affinity and stability were improved by some logical amino acid substitutions. Molecular dynamics (MD) simulations of peptide-LRP5/6 complexes were carried out using GROMACS package. After evaluation of binding free energies, stability, electrostatic potential and some physicochemical properties utilizing computational approaches, three peptides (PEP-I1, PEP-I3 and PEP-II2) demonstrated desirable features. However, all seven improved peptides could sufficiently block the Wnt-binding site of LRP6 in silico. In conclusion, we have designed and improved several small peptides based on the LRP6-binding site of CRD2 of DKK3. These peptides are highly capable of binding to LRP6 in silico, and may prevent the formation of active Wnt-LRP6-Fz complex.
[Mh] Termos MeSH primário: Desenho de Drogas
Peptídeos e Proteínas de Sinalização Intercelular/química
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/química
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/química
Engenharia de Proteínas/métodos
Proteínas Wnt/química
Via de Sinalização Wnt/efeitos dos fármacos
[Mh] Termos MeSH secundário: Antineoplásicos/química
Sítios de Ligação
Simulação por Computador
Seres Humanos
Imagem Tridimensional
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/antagonistas & inibidores
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/antagonistas & inibidores
Simulação de Acoplamento Molecular
Simulação de Dinâmica Molecular
Biblioteca de Peptídeos
Ligação Proteica
Domínios Proteicos
Transdução de Sinais
Eletricidade Estática
Termodinâmica
Proteínas Wnt/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (DKK3 protein, human); 0 (Intercellular Signaling Peptides and Proteins); 0 (LRP5 protein, human); 0 (LRP6 protein, human); 0 (Low Density Lipoprotein Receptor-Related Protein-5); 0 (Low Density Lipoprotein Receptor-Related Protein-6); 0 (Peptide Library); 0 (Wnt Proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170225
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0172217


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[PMID]:28187755
[Au] Autor:Xia S; Ji R; Zhan W
[Ad] Endereço:Ultrasound Department, Rui Jin Hospital Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Huang Pu District, Shanghai, Zip code: 200025, People's Republic of China.
[Ti] Título:Long noncoding RNA papillary thyroid carcinoma susceptibility candidate 3 (PTCSC3) inhibits proliferation and invasion of glioma cells by suppressing the Wnt/ß-catenin signaling pathway.
[So] Source:BMC Neurol;17(1):30, 2017 Feb 10.
[Is] ISSN:1471-2377
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The dysregulation of long noncoding RNAs (lncRNAs) has been identified in a variety of cancers. An increasing number of studies have found the critical role of lncRNAs in the regulation of cellular processes, such as proliferation, invasion and differentiation. Long noncoding RNA papillary thyroid carcinoma susceptibility candidate 3 (PTCSC3) is a novel lncRNA that was primarily detected in papillary thyroid carcinoma. However, the biological function and molecular mechanism of lncRNA PTCSC3 in glioma are still unknown. METHODS: The expression level of lncRNA PTCSC3 in human microglia and glioma cell lines was examined using quantitative real-time polymerase chain reaction (qRT-PCR). The influence of lncRNA PTCSC3 on cell proliferation were studied using the cell counting kit-8, and cell cycle and apoptosis were analyzed by flow cytometry assays. The migration and invasion abilities were investigated by transwell and wound healing assays. The target genes of lncRNA PTCSC3 were explored by qRT-PCR, immunofluorescence and western blot. RESULTS: LncRNA PTCSC3 was significantly downregulated in glioma cell lines. The overexpression of lncRNA PTCSC3 suppressed proliferation and induced apoptosis in U87 and U251 cells. Additionally, the overexpression of lncRNA PTCSC3 inhibited the migration and invasion of U87 and U251 cells. Moreover, lncRNA PTCSC3 inhibited the epithelial-mesenchymal transition of U87 cells. The study also demonstrated that LRP6, as a receptor of the Wnt/ß-catenin pathway, was a target of lncRNA PTCSC3. By evaluating the expression levels of Axin1, active ß-catenin, c-myc, and cyclin D1, the study indicated that lncRNA PTCSC3 inhibited the activation of the Wnt/ß-cateninpathway through targeting LRP6. CONCLUSIONS: LncRNA PTCSC3 inhibits the proliferation and migration of glioma cells and suppresses Wnt/ß-catenin signaling pathway by targeting LRP6. LncRNA PTCSC3 is a potential therapeutic target for treatment of glioma.
[Mh] Termos MeSH primário: Regulação Neoplásica da Expressão Gênica/genética
Glioma/patologia
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/biossíntese
RNA não Traduzido/biossíntese
[Mh] Termos MeSH secundário: Apoptose/genética
Western Blotting
Linhagem Celular Tumoral
Movimento Celular/genética
Proliferação Celular/genética
Imunofluorescência
Glioma/genética
Glioma/metabolismo
Seres Humanos
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
RNA não Traduzido/análise
Reação em Cadeia da Polimerase em Tempo Real
Via de Sinalização Wnt/genética
beta Catenina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CTNNB1 protein, human); 0 (LRP6 protein, human); 0 (Low Density Lipoprotein Receptor-Related Protein-6); 0 (Ptcsc3 untranslated RNA, human); 0 (RNA, Untranslated); 0 (beta Catenin)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170306
[Lr] Data última revisão:
170306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170212
[St] Status:MEDLINE
[do] DOI:10.1186/s12883-017-0813-6


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[PMID]:28180900
[Au] Autor:Sopko R; Mugford JW; Lehmann A; Shapiro RI; Rushe M; Kulkarni A; Worrall J; Amatucci J; Wen D; Pederson NE; Minesinger BK; Arndt JW; Pepinsky B
[Ad] Endereço:Department of Cell and Protein Sciences, Biogen, Cambridge, MA 02142, USA.
[Ti] Título:Engineering potent long-acting variants of the Wnt inhibitor DKK2.
[So] Source:Protein Eng Des Sel;30(5):359-372, 2017 May 01.
[Is] ISSN:1741-0134
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Wnt signaling pathways are required for a wide variety of biological processes ranging from embryonic development to tissue repair and regeneration. Dickkopf-2 (DKK2) is classically defined as a canonical Wnt inhibitor, though it may play a role in activating non-canonical Wnt pathways in the context of endothelial network formation after acute injury. Here we report the discovery of a fusion partner for a DKK2 polypeptide that significantly improves the expression, biochemical properties and pharmacokinetics (PK) of the DKK2 polypeptide. Specifically, human serum albumin (HSA) was identified as a highly effective fusion partner. Substitution of selected amino acid residues in DKK2 designed to decrease heparan sulfate binding by HSA-DKK2 variants, further improved the PK properties of the molecule in rodents. The HSA-DKK2 variants were monomeric, as thermally stable as wild type, and active as measured by their ability to bind to and prevent phosphorylation of the Wnt coreceptor LRP6. Our engineering efforts resulted in potent long-lived variants of the canonical Wnt inhibitor DKK2, applicable for Wnt pathway manipulation either by systematic delivery or focused administration at sites of tissue injury.
[Mh] Termos MeSH primário: Peptídeos e Proteínas de Sinalização Intercelular
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/antagonistas & inibidores
Engenharia de Proteínas
Proteínas Recombinantes de Fusão
Albumina Sérica
Proteínas Wnt/antagonistas & inibidores
Via de Sinalização Wnt/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Peptídeos e Proteínas de Sinalização Intercelular/biossíntese
Peptídeos e Proteínas de Sinalização Intercelular/química
Peptídeos e Proteínas de Sinalização Intercelular/isolamento & purificação
Peptídeos e Proteínas de Sinalização Intercelular/farmacologia
Camundongos
Proteínas Recombinantes de Fusão/biossíntese
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/isolamento & purificação
Proteínas Recombinantes de Fusão/farmacologia
Albumina Sérica/biossíntese
Albumina Sérica/química
Albumina Sérica/isolamento & purificação
Albumina Sérica/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Dkk2 protein, mouse); 0 (Intercellular Signaling Peptides and Proteins); 0 (Low Density Lipoprotein Receptor-Related Protein-6); 0 (Lrp6 protein, mouse); 0 (Recombinant Fusion Proteins); 0 (Serum Albumin); 0 (Wnt Proteins)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170717
[Lr] Data última revisão:
170717
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170210
[St] Status:MEDLINE
[do] DOI:10.1093/protein/gzx007



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