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[PMID]:29031765
[Au] Autor:Boakye YD; Groyer L; Heiss EH
[Ad] Endereço:Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
[Ti] Título:An increased autophagic flux contributes to the anti-inflammatory potential of urolithin A in macrophages.
[So] Source:Biochim Biophys Acta;1862(1):61-70, 2018 01.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: An extract of Phyllanthus muellerianus and its constituent geraniin have been reported to exert anti-inflammatory activity in vivo. However, orally consumed geraniin, an ellagitannin, shows low bioavailability and undergoes metabolization to urolithins by gut microbiota. This study aimed at comparing geraniin and urolithin A with respect to inhibition of M1 (LPS) polarization of murine J774.1 macrophages and shedding more light on possible underlying mechanisms. METHODS: Photometric, fluorimetric as well as luminescence-based assays monitored production of reactive oxygen species (ROS) and nitric oxide (NO), cell viability or reporter gene expression. Western blot analyses and confocal microscopy showed abundance and localization of target proteins, respectively. RESULTS: Urolithin A is a stronger inhibitor of M1 (LPS) macrophage polarization (production of NO, ROS and pro-inflammatory proteins) than geraniin. Urolithin A leads to an elevated autophagic flux in macrophages. Inhibition of autophagy in M1 (LPS) macrophages overcomes the suppressed nuclear translocation of p65 (NF-kB; nuclear factor kB), the reduced expression of pro-inflammatory genes as well as the diminished NO production brought about by urolithin A. The increased autophagic flux is furthermore associated with impaired Akt/mTOR (mammalian target of rapamycin) signaling in urolithin A-treated macrophages. CONCLUSIONS AND GENERAL SIGNIFICANCE: Intestinal metabolization may boost the potential health benefit of widely consumed dietary ellagitannins, as suggested by side by side comparison of geraniin and urolithin A in M1(LPS) macrophages. Increased activity of the autophagic cellular recycling machinery aids the anti-inflammatory bioactivity of urolithin A.
[Mh] Termos MeSH primário: Anti-Inflamatórios/farmacologia
Autofagia/efeitos dos fármacos
Cumarínicos/farmacologia
Macrófagos/metabolismo
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular/efeitos dos fármacos
Animais
Células CHO
Núcleo Celular/metabolismo
Cricetinae
Cricetulus
Células HEK293
Seres Humanos
Lipopolissacarídeos/toxicidade
Camundongos
Óxido Nítrico/metabolismo
Espécies Reativas de Oxigênio/metabolismo
Fator de Transcrição RelA/metabolismo
Proteínas ral de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents); 0 (Coumarins); 0 (Lipopolysaccharides); 0 (RELA protein, human); 0 (Reactive Oxygen Species); 0 (Transcription Factor RelA); 1143-70-0 (3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one); 31C4KY9ESH (Nitric Oxide); EC 3.6.1.- (Rala protein, mouse); EC 3.6.5.2 (ral GTP-Binding Proteins)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171017
[St] Status:MEDLINE


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[PMID]:29196555
[Au] Autor:Yan C; Theodorescu D
[Ad] Endereço:State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China (C.Y.); Departments of Surgery (Urology) and Pharmacology, University of Colorado, Aurora, Colorado (D.T.); and University of Colorado Comprehensive Cancer Center, Aurora, Colorado (D.T.).
[Ti] Título:RAL GTPases: Biology and Potential as Therapeutic Targets in Cancer.
[So] Source:Pharmacol Rev;70(1):1-11, 2018 Jan.
[Is] ISSN:1521-0081
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:More than a hundred proteins comprise the RAS superfamily of small GTPases. This family can be divided into RAS, RHO, RAB, RAN, ARF, and RAD subfamilies, with each shown to play distinct roles in human cells in both health and disease. The RAS subfamily has a well-established role in human cancer with the three genes, , , and being the commonly mutated in tumors. These mutations, most often functionally activating, are especially common in pancreatic, lung, and colorectal cancers. Efforts to inhibit RAS and related GTPases have produced inhibitors targeting the downstream effectors of RAS signaling, including inhibitors of the RAF-mitogen-activated protein kinase/extracellular signal-related kinase (ERK)-ERK kinase pathway and the phosphoinositide-3-kinase-AKT-mTOR kinase pathway. A third effector arm of RAS signaling, mediated by RAL (RAS like) has emerged in recent years as a critical driver of RAS oncogenic signaling and has not been targeted until recently. RAL belongs to the RAS branch of the RAS superfamily and shares a high structural similarity with RAS. In human cells, there are two genes, and , both of which have been shown to play roles in the proliferation, survival, and metastasis of a variety of human cancers, including lung, colon, pancreatic, prostate, skin, and bladder cancers. In this review, we summarize the latest knowledge of RAL in the context of human cancer and the recent advancements in the development of cancer therapeutics targeting RAL small GTPases.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Inibidores Enzimáticos/farmacologia
Neoplasias/tratamento farmacológico
Proteínas ral de Ligação ao GTP/antagonistas & inibidores
Proteínas ral de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/química
Inibidores Enzimáticos/química
Seres Humanos
Modelos Moleculares
Terapia de Alvo Molecular
Neoplasias/enzimologia
Bibliotecas de Moléculas Pequenas/química
Bibliotecas de Moléculas Pequenas/farmacologia
Relação Estrutura-Atividade
Proteínas ral de Ligação ao GTP/química
Proteínas ral de Ligação ao GTP/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Enzyme Inhibitors); 0 (Small Molecule Libraries); EC 3.6.5.2 (ral GTP-Binding Proteins)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180102
[Lr] Data última revisão:
180102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171203
[St] Status:MEDLINE
[do] DOI:10.1124/pr.117.014415


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[PMID]:28137655
[Au] Autor:Gray CH; Konczal J; Mezna M; Ismail S; Bower J; Drysdale M
[Ad] Endereço:Drug Discovery Program, CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK. Electronic address: c.gray@beatson.gla.ac.uk.
[Ti] Título:A fully automated procedure for the parallel, multidimensional purification and nucleotide loading of the human GTPases KRas, Rac1 and RalB.
[So] Source:Protein Expr Purif;132:75-84, 2017 Apr.
[Is] ISSN:1096-0279
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Small GTPases regulate many key cellular processes and their role in human disease validates many proteins in this class as desirable targets for therapeutic intervention. Reliable recombinant production of GTPases, often in the active GTP loaded state, is a prerequisite for the prosecution of drug discovery efforts. The preparation of these active forms can be complex and often constricts the supply to the reagent intensive techniques used in structure base drug discovery. We have established a fully automated, multidimensional protein purification strategy for the parallel production of the catalytic G-domains of KRas, Rac1 and RalB GTPases in the active form. This method incorporates a four step chromatography purification with TEV protease-mediated affinity tag cleavage and a conditioning step that achieves the activation of the GTPase by exchanging GDP for the non-hydrolyzable GTP analogue GMPPnP. We also demonstrate that an automated method is efficient at loading of KRas with mantGDP for application in a SOS1 catalysed fluorescent nucleotide exchange assay. In comparison to more conventional manual workflows the automated method offers marked advantages in method run time and operator workload. This reduces the bottleneck in protein production while generating products that are highly purified and effectively loaded with nucleotide analogues.
[Mh] Termos MeSH primário: Proteínas Proto-Oncogênicas p21(ras)/isolamento & purificação
Proteínas rac1 de Ligação ao GTP/isolamento & purificação
Proteínas ral de Ligação ao GTP/isolamento & purificação
[Mh] Termos MeSH secundário: Seres Humanos
Proteínas Proto-Oncogênicas p21(ras)/química
Proteínas Proto-Oncogênicas p21(ras)/genética
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/isolamento & purificação
Proteínas rac1 de Ligação ao GTP/química
Proteínas rac1 de Ligação ao GTP/genética
Proteínas ral de Ligação ao GTP/química
Proteínas ral de Ligação ao GTP/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (KRAS protein, human); 0 (RAC1 protein, human); 0 (Ralb protein, human); 0 (Recombinant Proteins); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)); EC 3.6.5.2 (rac1 GTP-Binding Protein); EC 3.6.5.2 (ral GTP-Binding Proteins)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170703
[Lr] Data última revisão:
170703
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170201
[St] Status:MEDLINE


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[PMID]:27991934
[Au] Autor:Pomeroy EJ; Lee LA; Lee RDW; Schirm DK; Temiz NA; Ma J; Gruber TA; Diaz-Flores E; Moriarity BS; Downing JR; Shannon KM; Largaespada DA; Eckfeldt CE
[Ad] Endereço:Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota Medical School, University of Minnesota, Minneapolis, MN, USA.
[Ti] Título:Ras oncogene-independent activation of RALB signaling is a targetable mechanism of escape from NRAS(V12) oncogene addiction in acute myeloid leukemia.
[So] Source:Oncogene;36(23):3263-3273, 2017 Jun 08.
[Is] ISSN:1476-5594
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Somatic mutations that lead to constitutive activation of NRAS and KRAS proto-oncogenes are among the most common in human cancer and frequently occur in acute myeloid leukemia (AML). An inducible NRAS(V12)-driven AML mouse model has established a critical role for continued NRAS(V12) expression in leukemia maintenance. In this model genetic suppression of NRAS(V12) expression results in rapid leukemia remission, but some mice undergo spontaneous relapse with NRAS(V12)-independent (NRI) AMLs providing an opportunity to identify mechanisms that bypass the requirement for Ras oncogene activity and drive leukemia relapse. We found that relapsed NRI AMLs are devoid of NRAS(V12) expression and signaling through the major oncogenic Ras effector pathways, phosphatidylinositol-3-kinase and mitogen-activated protein kinase, but express higher levels of an alternate Ras effector, Ralb, and exhibit NRI phosphorylation of the RALB effector TBK1, implicating RALB signaling in AML relapse. Functional studies confirmed that inhibiting CDK5-mediated RALB activation with a clinically relevant experimental drug, dinaciclib, led to potent RALB-dependent antileukemic effects in human AML cell lines, induced apoptosis in patient-derived AML samples in vitro and led to a 2-log reduction in the leukemic burden in patient-derived xenograft mice. Furthermore, dinaciclib potently suppressed the clonogenic potential of relapsed NRI AMLs in vitro and prevented the development of relapsed AML in vivo. Our findings demonstrate that Ras oncogene-independent activation of RALB signaling is a therapeutically targetable mechanism of escape from NRAS oncogene addiction in AML.
[Mh] Termos MeSH primário: GTP Fosfo-Hidrolases/genética
Regulação Neoplásica da Expressão Gênica
Leucemia Experimental/patologia
Leucemia Mieloide Aguda/patologia
Proteínas de Membrana/genética
Mutação/genética
Proteínas ral de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Animais
Apoptose
Biomarcadores Tumorais/genética
Biomarcadores Tumorais/metabolismo
Proliferação Celular
Feminino
Seres Humanos
Leucemia Experimental/genética
Leucemia Experimental/metabolismo
Leucemia Mieloide Aguda/genética
Leucemia Mieloide Aguda/metabolismo
Masculino
Camundongos
Camundongos SCID
Proteínas Quinases Ativadas por Mitógeno/genética
Proteínas Quinases Ativadas por Mitógeno/metabolismo
Proteínas Monoméricas de Ligação ao GTP/genética
Proteínas Monoméricas de Ligação ao GTP/metabolismo
Invasividade Neoplásica
Oncogenes
Transdução de Sinais
Células Tumorais Cultivadas
Ensaios Antitumorais Modelo de Xenoenxerto
Proteínas ral de Ligação ao GTP/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (Membrane Proteins); 0 (Ralb protein, human); EC 2.7.11.24 (Mitogen-Activated Protein Kinases); EC 3.6.1.- (GTP Phosphohydrolases); EC 3.6.1.- (NRAS protein, human); EC 3.6.5.2 (Monomeric GTP-Binding Proteins); EC 3.6.5.2 (ral GTP-Binding Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171011
[Lr] Data última revisão:
171011
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161220
[St] Status:MEDLINE
[do] DOI:10.1038/onc.2016.471


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[PMID]:27914199
[Au] Autor:Lee G; Schwarz TL
[Ad] Endereço:The F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, United States.
[Ti] Título:Filamin, a synaptic organizer in , determines glutamate receptor composition and membrane growth.
[So] Source:Elife;5, 2016 Dec 03.
[Is] ISSN:2050-084X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Filamin is a scaffolding protein that functions in many cells as an actin-crosslinker. FLN90, an isoform of the Drosophila ortholog Filamin/cheerio that lacks the actin-binding domain, is here shown to govern the growth of postsynaptic membrane folds and the composition of glutamate receptor clusters at the larval neuromuscular junction. Genetic and biochemical analyses revealed that FLN90 is present surrounding synaptic boutons. FLN90 is required in the muscle for localization of the kinase dPak and, downstream of dPak, for localization of the GTPase Ral and the exocyst complex to this region. Consequently, Filamin is needed for growth of the subsynaptic reticulum. In addition, in the absence of filamin, type-A glutamate receptor subunits are lacking at the postsynapse, while type-B subunits cluster correctly. Receptor composition is dependent on dPak, but independent of the Ral pathway. Thus two major aspects of synapse formation, morphological plasticity and subtype-specific receptor clustering, require postsynaptic Filamin.
[Mh] Termos MeSH primário: Membrana Celular/química
Membrana Celular/metabolismo
Proteínas de Drosophila/metabolismo
Filaminas/metabolismo
Junção Neuromuscular/química
Junção Neuromuscular/metabolismo
Receptores de Glutamato/química
Receptores de Glutamato/metabolismo
[Mh] Termos MeSH secundário: Animais
Drosophila
Quinases Ativadas por p21/metabolismo
Proteínas ral de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drosophila Proteins); 0 (Filamins); 0 (Receptors, Glutamate); 0 (fln protein, Drosophila); EC 2.7.11.1 (Pak protein, Drosophila); EC 2.7.11.1 (p21-Activated Kinases); EC 3.6.5.2 (ral GTP-Binding Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161204
[St] Status:MEDLINE


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[PMID]:27825764
[Au] Autor:Yan C; Theodorescu D; Miller B; Kumar A; Kumar V; Ross D; Wempe MF
[Ad] Endereço:Department of Pharmacology, University of Colorado, Aurora, CO 80045, USA; Department of Surgery, University of Colorado, Aurora, CO 80045, USA.
[Ti] Título:Synthesis of novel Ral inhibitors: An in vitro and in vivo study.
[So] Source:Bioorg Med Chem Lett;26(23):5815-5818, 2016 12 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Chemical synthesis was performed to produce a series of 6-amino-1,3-disubstituted-4-phenyl-1,4-dihydro pyrano[2,3-c]pyrazole-5-carbonitrile compounds (14-57) which were characterized by H NMR, C NMR and LC/MS-MS. These compounds were assessed for their effect on the in vitro anchorage independent growth of human lung cancer cell line H2122 and IC values calculated. Two of the more potent compounds, BQU057 40 and BQU082 57 also displayed a dose dependent effect on RalA and RalB activity in H2122 spheroids using the common RalBP1 pull-down assay. Mouse PK and tissue distribution studies on 40 and 57 were performed and demonstrated that parent drug was present in tumor 3.0h post ip (50mg/Kg) dose.
[Mh] Termos MeSH primário: Antineoplásicos/química
Antineoplásicos/farmacologia
Neoplasias Pulmonares/tratamento farmacológico
Pirazóis/química
Pirazóis/farmacologia
Proteínas ral de Ligação ao GTP/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/farmacocinética
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Descoberta de Drogas
Seres Humanos
Pulmão/efeitos dos fármacos
Pulmão/metabolismo
Pulmão/patologia
Neoplasias Pulmonares/metabolismo
Neoplasias Pulmonares/patologia
Camundongos
Nitrilos/química
Nitrilos/farmacologia
Pirazóis/farmacocinética
Distribuição Tecidual
Proteínas ral de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Nitriles); 0 (Pyrazoles); 0 (Ralb protein, human); EC 3.6.1.- (RALA protein, human); EC 3.6.5.2 (ral GTP-Binding Proteins)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161110
[St] Status:MEDLINE


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[PMID]:27593478
[Au] Autor:Zhang Y; Tessier SN; Storey KB
[Ad] Endereço:Institute of Biochemistry and Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, ON, K1S 5B6, Canada.
[Ti] Título:Inhibition of skeletal muscle atrophy during torpor in ground squirrels occurs through downregulation of MyoG and inactivation of Foxo4.
[So] Source:Cryobiology;73(2):112-9, 2016 Oct.
[Is] ISSN:1090-2392
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Foxo4 and MyoG proteins regulate the transcription of numerous genes, including the E3 ubiquitin ligases MAFbx and MuRF1, which are activated in skeletal muscle under atrophy-inducing conditions. In the thirteen-lined ground squirrel, there is little muscle wasting that occurs during hibernation, a process characterized by bouts of torpor and arousal, despite virtual inactivity. Consequently, we were interested in studying the regulatory role of Foxo4 and MyoG on ubiquitin ligases throughout torpor-arousal cycles. Findings indicate that MAFbx and MuRF1 decreased during early torpor (ET) by 42% and 40%, respectively, relative to euthermic control (EC), although MuRF1 expression subsequently increased at late torpor (LT). The expression pattern of MyoG most closely resembled that of MAFbx, with levels decreasing during LT. In addition, the phosphorylation of Foxo4 at Thr-451 showed an initial increase during EN, followed by a decline throughout the remainder of the torpor-arousal cycle, suggesting Foxo4 inhibition. This trend was mirrored by inhibition of the Ras-Ral pathway, as the Ras and Ral proteins were decreased by 77% and 41% respectively, at ET. Foxo4 phosphorylation at S197 was depressed during entrance and torpor, suggesting Foxo4 nuclear localization, and possibly regulating the increase in MuRF1 levels at LT. These findings indicate that signaling pathways involved in regulating muscle atrophy, such as MyoG and Foxo4 through the Ras-Ral pathway, contribute to important muscle-specific changes during hibernation. Therefore, this data provides novel insight into the molecular mechanisms regulating muscle remodeling in a hibernator model.
[Mh] Termos MeSH primário: Atrofia/fisiopatologia
Hibernação/fisiologia
Músculo Esquelético/metabolismo
Miogenina/biossíntese
Sciuridae/fisiologia
Torpor/fisiologia
Fatores de Transcrição/metabolismo
[Mh] Termos MeSH secundário: Animais
Regulação para Baixo
Fosforilação
Transdução de Sinais
Transcrição Genética/genética
Ubiquitina-Proteína Ligases/metabolismo
Proteínas ral de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Myogenin); 0 (Transcription Factors); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 3.6.5.2 (ral GTP-Binding Proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160906
[St] Status:MEDLINE


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[PMID]:27510034
[Au] Autor:Jiang Y; Sverdlov MS; Toth PT; Huang LS; Du G; Liu Y; Natarajan V; Minshall RD
[Ad] Endereço:From the School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054, China, the Departments of Anesthesiology.
[Ti] Título:Phosphatidic Acid Produced by RalA-activated PLD2 Stimulates Caveolae-mediated Endocytosis and Trafficking in Endothelial Cells.
[So] Source:J Biol Chem;291(39):20729-38, 2016 Sep 23.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Caveolae are the primary route for internalization and transendothelial transport of macromolecules, such as insulin and albumin. Caveolae-mediated endocytosis is activated by Src-dependent caveolin-1 (Cav-1) phosphorylation and subsequent recruitment of dynamin-2 and filamin A (FilA), which facilitate vesicle fission and trafficking, respectively. Here, we tested the role of RalA and phospholipase D (PLD) signaling in the regulation of caveolae-mediated endocytosis and trafficking. The addition of albumin to human lung microvascular endothelial cells induced the activation of RalA within minutes, and siRNA-mediated down-regulation of RalA abolished fluorescent BSA uptake. Co-immunoprecipitation studies revealed that albumin induced the association between RalA, Cav-1, and FilA; however, RalA knockdown with siRNA did not affect FilA recruitment to Cav-1, suggesting that RalA was not required for FilA and Cav-1 complex formation. Rather, RalA probably facilitates caveolae-mediated endocytosis by activating downstream effectors. PLD2 was shown to be activated by RalA, and inhibition of PLD2 abolished Alexa-488-BSA uptake, indicating that phosphatidic acid (PA) generated by PLD2 may facilitate caveolae-mediated endocytosis. Furthermore, using a PA biosensor, GFP-PASS, we observed that BSA induced an increase in PA co-localization with Cav-1-RFP, which could be blocked by a dominant negative PLD2 mutant. Total internal reflection fluorescence microscopy studies of Cav-1-RFP also showed that fusion of caveolae with the basal plasma membrane was dependent on PLD2 activity. Thus, our results suggest that the small GTPase RalA plays an important role in promoting invagination and trafficking of caveolae, not by potentiating the association between Cav-1 and FilA but by stimulating PLD2-mediated generation of phosphatidic acid.
[Mh] Termos MeSH primário: Cavéolas/metabolismo
Endocitose/fisiologia
Células Endoteliais/metabolismo
Ácidos Fosfatídicos/biossíntese
Fosfolipase D/metabolismo
Proteínas ral de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Transporte Biológico Ativo/fisiologia
Membrana Celular/genética
Membrana Celular/metabolismo
Células Endoteliais/citologia
Seres Humanos
Mutação
Ácidos Fosfatídicos/genética
Fosfolipase D/genética
Proteínas ral de Ligação ao GTP/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Phosphatidic Acids); EC 3.1.4.- (phospholipase D2); EC 3.1.4.4 (Phospholipase D); EC 3.6.1.- (RALA protein, human); EC 3.6.5.2 (ral GTP-Binding Proteins)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170923
[Lr] Data última revisão:
170923
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160812
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.752485


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[PMID]:27334922
[Au] Autor:Thomas JC; Cooper JM; Clayton NS; Wang C; White MA; Abell C; Owen D; Mott HR
[Ad] Endereço:From the Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
[Ti] Título:Inhibition of Ral GTPases Using a Stapled Peptide Approach.
[So] Source:J Biol Chem;291(35):18310-25, 2016 08 26.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Aberrant Ras signaling drives numerous cancers, and drugs to inhibit this are urgently required. This compelling clinical need combined with recent innovations in drug discovery including the advent of biologic therapeutic agents, has propelled Ras back to the forefront of targeting efforts. Activated Ras has proved extremely difficult to target directly, and the focus has moved to the main downstream Ras-signaling pathways. In particular, the Ras-Raf and Ras-PI3K pathways have provided conspicuous enzyme therapeutic targets that were more accessible to conventional drug-discovery strategies. The Ras-RalGEF-Ral pathway is a more difficult challenge for traditional medicinal development, and there have, therefore, been few inhibitors reported that disrupt this axis. We have used our structure of a Ral-effector complex as a basis for the design and characterization of α-helical-stapled peptides that bind selectively to active, GTP-bound Ral proteins and that compete with downstream effector proteins. The peptides have been thoroughly characterized biophysically. Crucially, the lead peptide enters cells and is biologically active, inhibiting isoform-specific RalB-driven cellular processes. This, therefore, provides a starting point for therapeutic inhibition of the Ras-RalGEF-Ral pathway.
[Mh] Termos MeSH primário: Isoenzimas/antagonistas & inibidores
Peptídeos/farmacologia
Transdução de Sinais/efeitos dos fármacos
Proteínas ral de Ligação ao GTP/antagonistas & inibidores
[Mh] Termos MeSH secundário: Linhagem Celular
Seres Humanos
Isoenzimas/genética
Isoenzimas/metabolismo
Neoplasias/tratamento farmacológico
Neoplasias/enzimologia
Neoplasias/genética
Peptídeos/genética
Fosfatidilinositol 3-Quinases/genética
Fosfatidilinositol 3-Quinases/metabolismo
Proteínas ral de Ligação ao GTP/genética
Proteínas ral de Ligação ao GTP/metabolismo
Proteínas ras/genética
Proteínas ras/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Isoenzymes); 0 (Peptides); 0 (Ralb protein, human); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 3.6.5.2 (ral GTP-Binding Proteins); EC 3.6.5.2 (ras Proteins)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171121
[Lr] Data última revisão:
171121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160624
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.720243


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[PMID]:27188791
[Au] Autor:Zheng M; Zhang X; Sun N; Min C; Zhang X; Kim KM
[Ad] Endereço:Department of Pharmacology, College of Pharmacy, Drug Development Research Institute, Chonnam National University, Gwang-Ju 500-757, Republic of Korea.
[Ti] Título:RalA employs GRK2 and ß-arrestins for the filamin A-mediated regulation of trafficking and signaling of dopamine D2 and D3 receptor.
[So] Source:Biochim Biophys Acta;1863(8):2072-83, 2016 08.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Filamin A (FLNA) is known to act as platform for the signaling and intracellular trafficking of various GPCRs including dopamine D2 and D3 receptors (D2R, D3R). To understand molecular mechanisms involved in the FLNA-mediated regulation of D2R and D3R, comparative studies were conducted on the signaling and intracellular trafficking of the D2R and D3R in FLNA-knockdown cells, with a specific focus on the roles of the proteins that interact with FLNA and the D2R and D3R. Lowering the level of cellular FLNA caused an elevation in RalA activity and resulted in selective interference with the normal intracellular trafficking and signaling of the D2R and D3R, through GRK2 and ß-arrestins, respectively. Knockdown of FLNA or coexpression of active RalA interfered with the recycling of the internalized D2R and resulted in the development of receptor tolerance. Active RalA was found to interact with GRK2 to sequester it from D2R. Knockdown of FLNA or coexpression of active RalA prevented D3R from coupling with G protein. The selective involvement of GRK2- and ß-arrestins in the RalA-mediated cellular processes of the D2R and D3R was achieved via their different modes of interactions with the receptor and their distinct functional roles in receptor regulation. Our results show that FLNA is a multi-functional protein that acts as a platform on which D2R and D3R can interact with various proteins, through which selective regulation of these receptors occurs in combination with GRK2 and ß-arrestins.
[Mh] Termos MeSH primário: Filaminas/fisiologia
Quinase 2 de Receptor Acoplado a Proteína G/fisiologia
Receptores de Dopamina D2/metabolismo
Receptores de Dopamina D3/metabolismo
beta-Arrestina 1/fisiologia
beta-Arrestina 2/fisiologia
Proteínas ral de Ligação ao GTP/fisiologia
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo
Membrana Celular/metabolismo
AMP Cíclico/biossíntese
Agonistas de Dopamina/farmacologia
Genes Reporter
Células HEK293
Seres Humanos
Sistema de Sinalização das MAP Quinases/fisiologia
Transporte Proteico/fisiologia
Receptores de Dopamina D2/efeitos dos fármacos
Receptores de Dopamina D3/efeitos dos fármacos
Proteínas Recombinantes/metabolismo
Proteínas ral de Ligação ao GTP/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (DRD2 protein, human); 0 (DRD3 protein, human); 0 (Dopamine Agonists); 0 (Filamins); 0 (Receptors, Dopamine D2); 0 (Receptors, Dopamine D3); 0 (Recombinant Proteins); 0 (beta-Arrestin 1); 0 (beta-Arrestin 2); 8L70Q75FXE (Adenosine Triphosphate); E0399OZS9N (Cyclic AMP); EC 2.7.11.15 (ADRBK1 protein, human); EC 2.7.11.16 (G-Protein-Coupled Receptor Kinase 2); EC 3.6.1.- (RALA protein, human); EC 3.6.5.2 (ral GTP-Binding Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171025
[Lr] Data última revisão:
171025
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160519
[St] Status:MEDLINE



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