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Pesquisa : D08.811.277.040.330.300.400.700.100 [Categoria DeCS]
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[PMID]:29242061
[Au] Autor:Kaito Y; Kataoka R; Mihara T; Takechi K; Takahira A; Watanabe S; Han F; Tamura M
[Ad] Endereço:Department of Applied Chemistry, Graduate School of Science and Engineering, Ehime University, 3 Bunkyo-cho, Matsuyama, Ehime 790-8577, Japan.
[Ti] Título:Phosphorylation of Ser-525 in ßPix impairs Nox1-activating ability in Caco-2 cells.
[So] Source:Arch Biochem Biophys;638:58-65, 2018 01 15.
[Is] ISSN:1096-0384
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:ßPix activates Nox1, an O -generating NADPH oxidase, through Rac activation. In this study, we found that S525E mutation of ßPix eliminated its Nox1-activating ability in transfected Caco-2 cells. Unexpectedly, affinity for Rac was not diminished but rather enhanced by S525E mutation, and guanine nucleotide exchange factor (GEF) activity was not altered. The N-terminal fragment (amino acids 1-400) showed similar Rac-binding and GEF activity to wild-type ßPix. In contrast, the C-terminal fragment (amino acids 408-646) had higher Rac-binding activity, particularly for Rac-GTP, than wild-type ßPix, and showed no GEF activity. These data suggest that a second Rac-binding site within the C-terminal region is opened by phosphorylation of Ser-525. The site may bind not only Rac-GDP but also Rac-GTP released from the N-terminal catalytic region, which interrupts Rac-GTP translocation to the membrane where Nox1 resides. If one considers that S340E mutation enhances Nox1 activation (Kaito et al., 2014), the present study suggests that ßPix can also play an inhibitory role in O production, depending on the sites of phosphorylation.
[Mh] Termos MeSH primário: Mutação de Sentido Incorreto
NADPH Oxidase 1/metabolismo
Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo
Superóxidos/metabolismo
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Células CACO-2
Ativação Enzimática/genética
Seres Humanos
NADPH Oxidase 1/genética
Fosforilação/genética
Domínios Proteicos
Fatores de Troca de Nucleotídeo Guanina Rho/genética
Proteínas rac de Ligação ao GTP/genética
Proteínas rac de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Rho Guanine Nucleotide Exchange Factors); 11062-77-4 (Superoxides); EC 1.6.3.- (NADPH Oxidase 1); EC 1.6.3.- (NOX1 protein, human); EC 3.6.5.2 (rac GTP-Binding Proteins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171216
[St] Status:MEDLINE


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[PMID]:28467910
[Au] Autor:Tajiri H; Uruno T; Shirai T; Takaya D; Matsunaga S; Setoyama D; Watanabe M; Kukimoto-Niino M; Oisaki K; Ushijima M; Sanematsu F; Honma T; Terada T; Oki E; Shirasawa S; Maehara Y; Kang D; Côté JF; Yokoyama S; Kanai M; Fukui Y
[Ad] Endereço:Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan; Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
[Ti] Título:Targeting Ras-Driven Cancer Cell Survival and Invasion through Selective Inhibition of DOCK1.
[So] Source:Cell Rep;19(5):969-980, 2017 May 02.
[Is] ISSN:2211-1247
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Oncogenic Ras plays a key role in cancer initiation but also contributes to malignant phenotypes by stimulating nutrient uptake and promoting invasive migration. Because these latter cellular responses require Rac-mediated remodeling of the actin cytoskeleton, we hypothesized that molecules involved in Rac activation may be valuable targets for cancer therapy. We report that genetic inactivation of the Rac-specific guanine nucleotide exchange factor DOCK1 ablates both macropinocytosis-dependent nutrient uptake and cellular invasion in Ras-transformed cells. By screening chemical libraries, we have identified 1-(2-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-2-oxoethyl)-5-pyrrolidinylsulfonyl-2(1H)-pyridone (TBOPP) as a selective inhibitor of DOCK1. TBOPP dampened DOCK1-mediated invasion, macropinocytosis, and survival under the condition of glutamine deprivation without impairing the biological functions of the closely related DOCK2 and DOCK5 proteins. Furthermore, TBOPP treatment suppressed cancer metastasis and growth in vivo in mice. Our results demonstrate that selective pharmacological inhibition of DOCK1 could be a therapeutic approach to target cancer cell survival and invasion.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Movimento Celular/efeitos dos fármacos
Piridonas/farmacologia
Proteínas rac de Ligação ao GTP/efeitos adversos
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/uso terapêutico
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos C57BL
Neoplasias Experimentais/tratamento farmacológico
Pinocitose/efeitos dos fármacos
Piridonas/uso terapêutico
Bibliotecas de Moléculas Pequenas/farmacologia
Bibliotecas de Moléculas Pequenas/uso terapêutico
Proteínas rac de Ligação ao GTP/genética
Proteínas rac de Ligação ao GTP/metabolismo
Proteínas ras/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (DOCK1 protein, mouse); 0 (Pyridones); 0 (Small Molecule Libraries); EC 3.6.5.2 (rac GTP-Binding Proteins); EC 3.6.5.2 (ras Proteins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE


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[PMID]:29190756
[Au] Autor:Shao S; Xiang C; Qin K; Ur Rehman Aziz A; Liao X; Liu B
[Ad] Endereço:Department of Biomedical Engineering, Faculty of Electronic Information and Electrical Engineering, Dalian University of Technology, Dalian, China.
[Ti] Título:Visualizing the spatiotemporal map of Rac activation in bovine aortic endothelial cells under laminar and disturbed flows.
[So] Source:PLoS One;12(11):e0189088, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Disturbed flow can eliminate the alignment of endothelial cells in the direction of laminar flow, and significantly impacts on atherosclerosis in collateral arteries near the bifurcation and high curvature regions. While shear stress induced Rac polarity has been shown to play crucial roles in cell polarity and migration, little is known about the spatiotemporal map of Rac under disturbed flow, and the mechanism of flow-induced cell polarity still needs to be elucidated. In this paper, disturbed flow or laminar flow with 15 dyn/cm2 of average shear stress was applied on bovine aortic endothelial cells (BAECs) for 30 minutes. A genetically-encoded PAK-PBD-GFP reporter was transfected into BAECs to visualize the real-time activation of Rac in living cell under fluorescence microscope. The imaging of the fluorescence intensity was analyzed by Matlab and the normalized data was converted into 3D spatiotemporal map. Then the changes of data upon chemical interference were fitted with logistic curve to explore the rule and mechanism of Rac polarity under laminar or disturbed flow. A polarized Rac activation was observed at the downstream edge along the laminar flow, which was enhanced by benzol alcohol-enhanced membrane fluidity but inhibited by nocodazole-disrupted microtubules or cholesterol-inhibited membrane fluidity, while no obvious polarized Rac activation could be found upon disturbed flow application. It is concluded that disturbed flow inhibits the flow-induced Rac polarized activation, which is related to the interaction of cell membrane and cytoskeleton, especially the microtubules.
[Mh] Termos MeSH primário: Aorta/citologia
Endotélio Vascular/citologia
Proteínas rac de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Animais
Aorta/metabolismo
Bovinos
Endotélio Vascular/metabolismo
Fluidez de Membrana
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.6.5.2 (rac GTP-Binding Proteins)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180101
[Lr] Data última revisão:
180101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171201
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189088


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[PMID]:28886159
[Au] Autor:Park S; Jang H; Kim BS; Hwang C; Jeong GS; Park Y
[Ad] Endereço:Department of Biomedical Engineering, Biomedical Science of Brain Korea 21, College of Medicine, Korea University, Seoul, Korea.
[Ti] Título:Directional migration of mesenchymal stem cells under an SDF-1α gradient on a microfluidic device.
[So] Source:PLoS One;12(9):e0184595, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Homing of peripheral stem cells is regulated by one of the most representative homing factors, stromal cell-derived factor 1 alpha (SDF-1α), which specifically binds to the plasma membrane receptor CXCR4 of mesenchymal stem cells (MSCs) in order to initiate the signaling pathways that lead to directional migration and homing of stem cells. This complex homing process and directional migration of stem cells have been mimicked on a microfluidic device that is capable of generating a chemokine gradient within the collagen matrix and embedding endothelial cell (EC) monolayers to mimic blood vessels. On the microfluidic device, stem cells showed directional migration toward the higher concentration of SDF-1α, whereas treatment with the CXCR4 antagonist AMD3100 caused loss of directionality of stem cells. Furthermore, inhibition of stem cell's main migratory signaling pathways, Rho-ROCK and Rac pathways, caused blockage of actomyosin and lamellipodia formation, decreasing the migration distance but maintaining directionality. Stem cell homing regulated by SDF-1α caused directional migration of stem cells, while the migratory ability was affected by the activation of migration-related signaling pathways.
[Mh] Termos MeSH primário: Quimiocina CXCL12/química
Dispositivos Lab-On-A-Chip
Células Mesenquimais Estromais/citologia
[Mh] Termos MeSH secundário: Amidas/farmacologia
Aminoquinolinas/farmacologia
Movimento Celular/efeitos dos fármacos
Compostos Heterocíclicos/farmacologia
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Imuno-Histoquímica
Células Mesenquimais Estromais/efeitos dos fármacos
Microscopia Confocal
Piridinas/farmacologia
Pirimidinas/farmacologia
Transdução de Sinais/efeitos dos fármacos
Proteínas rac de Ligação ao GTP/antagonistas & inibidores
Proteínas rac de Ligação ao GTP/metabolismo
Proteínas rho de Ligação ao GTP/antagonistas & inibidores
Proteínas rho de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amides); 0 (Aminoquinolines); 0 (Chemokine CXCL12); 0 (Heterocyclic Compounds); 0 (NSC 23766); 0 (Pyridines); 0 (Pyrimidines); 138381-45-0 (Y 27632); 155148-31-5 (JM 3100); EC 3.6.5.2 (rac GTP-Binding Proteins); EC 3.6.5.2 (rho GTP-Binding Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170909
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184595


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[PMID]:28859089
[Au] Autor:Gujar MR; Stricker AM; Lundquist EA
[Ad] Endereço:Department of Molecular Biosciences, Program in Molecular, Cellular, and Developmental Biology, The University of Kansas, Lawrence, KS, United States of America.
[Ti] Título:Flavin monooxygenases regulate Caenorhabditis elegans axon guidance and growth cone protrusion with UNC-6/Netrin signaling and Rac GTPases.
[So] Source:PLoS Genet;13(8):e1006998, 2017 Aug.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The guidance cue UNC-6/Netrin regulates both attractive and repulsive axon guidance. Our previous work showed that in C. elegans, the attractive UNC-6/Netrin receptor UNC-40/DCC stimulates growth cone protrusion, and that the repulsive receptor, an UNC-5:UNC-40 heterodimer, inhibits growth cone protrusion. We have also shown that inhibition of growth cone protrusion downstream of the UNC-5:UNC-40 repulsive receptor involves Rac GTPases, the Rac GTP exchange factor UNC-73/Trio, and the cytoskeletal regulator UNC-33/CRMP, which mediates Semaphorin-induced growth cone collapse in other systems. The multidomain flavoprotein monooxygenase (FMO) MICAL (Molecule Interacting with CasL) also mediates growth cone collapse in response to Semaphorin by directly oxidizing F-actin, resulting in depolymerization. The C. elegans genome does not encode a multidomain MICAL-like molecule, but does encode five flavin monooxygenases (FMO-1, -2, -3, -4, and 5) and another molecule, EHBP-1, similar to the non-FMO portion of MICAL. Here we show that FMO-1, FMO-4, FMO-5, and EHBP-1 may play a role in UNC-6/Netrin directed repulsive guidance mediated through UNC-40 and UNC-5 receptors. Mutations in fmo-1, fmo-4, fmo-5, and ehbp-1 showed VD/DD axon guidance and branching defects, and variably enhanced unc-40 and unc-5 VD/DD axon guidance defects. Developing growth cones in vivo of fmo-1, fmo-4, fmo-5, and ehbp-1 mutants displayed excessive filopodial protrusion, and transgenic expression of FMO-5 inhibited growth cone protrusion. Mutations suppressed growth cone inhibition caused by activated UNC-40 and UNC-5 signaling, and activated Rac GTPase CED-10 and MIG-2, suggesting that these molecules are required downstream of UNC-6/Netrin receptors and Rac GTPases. From these studies we conclude that FMO-1, FMO-4, FMO-5, and EHBP-1 represent new players downstream of UNC-6/Netrin receptors and Rac GTPases that inhibit growth cone filopodial protrusion in repulsive axon guidance.
[Mh] Termos MeSH primário: Orientação de Axônios/genética
Proteínas de Caenorhabditis elegans/genética
Caenorhabditis elegans/genética
Oxigenases de Função Mista/genética
Proteínas do Tecido Nervoso/genética
[Mh] Termos MeSH secundário: Animais
Animais Geneticamente Modificados
Caenorhabditis elegans/crescimento & desenvolvimento
Dinitrocresóis/metabolismo
Mutação
Netrinas
Pseudópodes/genética
Pseudópodes/metabolismo
Transdução de Sinais
Proteínas rac de Ligação ao GTP/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Caenorhabditis elegans Proteins); 0 (Dinitrocresols); 0 (Nerve Tissue Proteins); 0 (Netrins); 0 (UNC-6 protein, C elegans); 1604ZJR09T (4,6-dinitro-o-cresol); EC 1.- (Mixed Function Oxygenases); EC 3.6.5.2 (rac GTP-Binding Proteins)
[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:170901
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1006998


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[PMID]:28817691
[Au] Autor:Joshi S; Singh AR; Wong SS; Zulcic M; Jiang M; Pardo A; Selman M; Hagood JS; Durden DL
[Ad] Endereço:UCSD Department of Pediatrics, Moores UCSD Cancer Center, University of California, San Diego, United States of America.
[Ti] Título:Rac2 is required for alternative macrophage activation and bleomycin induced pulmonary fibrosis; a macrophage autonomous phenotype.
[So] Source:PLoS One;12(8):e0182851, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by cellular phenotype alterations and deposition of extracellular matrix proteins. The alternative activation of macrophages in the lungs has been associated as a major factor promoting pulmonary fibrosis, however the mechanisms underlying this phenomenon are poorly understood. In the present study, we have defined a molecular mechanism by which signals transmitted from the extracellular matrix via the α4ß1 integrin lead to the activation of Rac2 which regulates alternative macrophage differentiation, a signaling axis within the pulmonary macrophage compartment required for bleomycin induced pulmonary fibrosis. Mice deficient in Rac2 were protected against bleomycin-induced fibrosis and displayed diminished collagen deposition in association with lower expression of alternatively activated profibrotic macrophage markers. We have demonstrated a macrophage autonomous process by which the injection of M2 and not M1 macrophages restored the bleomycin induced pulmonary fibrosis susceptibility in Rac2-/- mice, establishing a critical role for a macrophage Rac2 signaling axis in the regulation of macrophage differentiation and lung fibrosis in vivo. We also demonstrate that markers of alternative macrophage activation are increased in patients with IPF. Taken together, these studies define an important role for an integrin-driven Rac2 signaling axis in macrophages, and reveal that Rac2 activation is required for polarization of macrophages towards a profibrotic phenotype and progression of pulmonary fibrosis in vivo.
[Mh] Termos MeSH primário: Fibrose Pulmonar Idiopática/imunologia
Ativação de Macrófagos
Macrófagos/imunologia
Proteínas rac de Ligação ao GTP/genética
[Mh] Termos MeSH secundário: Animais
Bleomicina/toxicidade
Células Cultivadas
Colágeno/metabolismo
Seres Humanos
Fibrose Pulmonar Idiopática/etiologia
Fibrose Pulmonar Idiopática/genética
Camundongos
Camundongos Endogâmicos C57BL
Fenótipo
Proteínas rac de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
11056-06-7 (Bleomycin); 9007-34-5 (Collagen); EC 3.6.1.- (rac2 GTP-binding protein); EC 3.6.5.2 (rac GTP-Binding Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170818
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182851


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[PMID]:28800782
[Au] Autor:Chiu JH; Chen FP; Tsai YF; Lin MT; Tseng LM; Shyr YM
[Ad] Endereço:Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China. chiujh@mailsrv.ym.edu.tw.
[Ti] Título:Effects of Chinese medicinal herbs on expression of brain-derived Neurotrophic factor (BDNF) and its interaction with human breast cancer MDA-MB-231 cells and endothelial HUVECs.
[So] Source:BMC Complement Altern Med;17(1):401, 2017 Aug 12.
[Is] ISSN:1472-6882
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Our previous study demonstrated that an up-regulation of the Brain-Derived Neurotrophic Factor (BDNF) signaling pathway is involved the mechanism causing the recurrence of triple negative breast cancer. The aim of this study is to investigate the effects of commonly used Chinese medicinal herbs on MDA-MB-231 and HUVEC cells and how they interact with BDNF. METHODS: Human TNBC MDA-MB-231 cells and human endothelial HUVEC cells were used to explore the effect of commonly used Chinese herbal medicines on cancer cells alone, on endothelial cells alone and on cancer cell/endothelial cell interactions; this was done via functional studies, including migration and invasion assays. Furthermore, Western blot analysis and real-time PCR investigations were also used to investigate migration signal transduction, invasion signal transduction, and angiogenic signal transduction in these systems. Finally, the effect of the Chinese medicinal herbs on cancer cell/endothelial cell interactions was assessed using co-culture and ELISA. RESULTS: In terms of autoregulation, BDNF up-regulated TrkB gene expression in both MDA-MB-231 and HUVEC cells. Furthermore, BDNF enhanced migration by MDA-MB-231 cells via Rac, Cdc42 and MMP, while also increasing the migration of HUVEC cells via MMP and COX-2 expression. As measured by ELISA, the Chinese herbal medicinal herbs A. membranaceus, P. lactiflora, L. chuanxiong, P. suffruticosa and L. lucidum increased BDNF secretion by MDA-MB-231 cells. Similarly, using a co-culture system with MDA-MB-231 cells, A. membranaceus and L. lucidum modulated BDNF-TrkB signaling by HUVEC cells. CONCLUSION: We conclude that BDNF plays an important role in the metastatic interaction between MDA-MB-231 and HUVEC cells. Some Chinese medicinal herbs are able to enhance the BDNF-related metastatic potential of the interaction between cancer cells and endothelial cells. These findings provide important information that should help with the development of integrated medical therapies for breast cancer patients.
[Mh] Termos MeSH primário: Fator Neurotrófico Derivado do Encéfalo/metabolismo
Neoplasias da Mama
Medicamentos de Ervas Chinesas/efeitos adversos
Células Endoteliais/efeitos dos fármacos
Recidiva Local de Neoplasia/etiologia
Fitoterapia/efeitos adversos
Plantas Medicinais/efeitos adversos
[Mh] Termos MeSH secundário: Neoplasias da Mama/metabolismo
Neoplasias da Mama/patologia
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Ciclo-Oxigenase 2/metabolismo
Células Endoteliais/metabolismo
Células Endoteliais/patologia
Feminino
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Magnoliopsida/efeitos adversos
Metaloproteinase 2 da Matriz/metabolismo
Metaloproteinase 9 da Matriz/metabolismo
Glicoproteínas de Membrana/metabolismo
Proteínas Tirosina Quinases/metabolismo
Receptor trkB
Transdução de Sinais
Regulação para Cima
Proteína cdc42 de Ligação ao GTP/metabolismo
Proteínas rac de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Brain-Derived Neurotrophic Factor); 0 (Drugs, Chinese Herbal); 0 (Membrane Glycoproteins); 0 (brain-derived neurotrophic factor, human); EC 1.14.99.1 (Cyclooxygenase 2); EC 2.7.10.1 (Protein-Tyrosine Kinases); EC 2.7.10.1 (Receptor, trkB); EC 2.7.10.1 (tropomyosin-related kinase-B, human); EC 3.4.24.24 (Matrix Metalloproteinase 2); EC 3.4.24.35 (Matrix Metalloproteinase 9); EC 3.6.5.2 (cdc42 GTP-Binding Protein); EC 3.6.5.2 (rac GTP-Binding Proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170813
[St] Status:MEDLINE
[do] DOI:10.1186/s12906-017-1909-7


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[PMID]:28710284
[Au] Autor:Rui M; Qian J; Liu L; Cai Y; Lv H; Han J; Jia Z; Xie W
[Ad] Endereço:From Key Laboratory of Developmental Genes and Human Disease, Institute of Life Sciences, Southeast University, Nanjing 210096, China.
[Ti] Título:The neuronal protein Neurexin directly interacts with the Scribble-Pix complex to stimulate F-actin assembly for synaptic vesicle clustering.
[So] Source:J Biol Chem;292(35):14334-14348, 2017 Sep 01.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Synaptic vesicles (SVs) form distinct pools at synaptic terminals, and this well-regulated separation is necessary for normal neurotransmission. However, how the SV cluster, in particular synaptic compartments, maintains normal neurotransmitter release remains a mystery. The presynaptic protein Neurexin (NRX) plays a significant role in synaptic architecture and function, and some evidence suggests that NRX is associated with neurological disorders, including autism spectrum disorders. However, the role of NRX in SV clustering is unclear. Here, using the neuromuscular junction at the 2-3 instar stages of larvae as a model and biochemical imaging and electrophysiology techniques, we demonstrate that NRX (DNRX) plays critical roles in regulating synaptic terminal clustering and release of SVs. We found that DNRX controls the terminal clustering and release of SVs by stimulating presynaptic F-actin. Furthermore, our results indicate that DNRX functions through the scaffold protein Scribble and the GEF protein DPix to activate the small GTPase Ras-related C3 Botulinum toxin substrate 1 (Rac1). We observed a direct interaction between the C-terminal PDZ-binding motif of DNRX and the PDZ domains of Scribble and that Scribble bridges DNRX to DPix, forming a DNRX-Scribble-DPix complex that activates Rac1 and subsequently stimulates presynaptic F-actin assembly and SV clustering. Taken together, our work provides important insights into the function of DNRX in regulating SV clustering, which could help inform further research into pathological -mediated mechanisms in neurological disorders such as autism.
[Mh] Termos MeSH primário: Transportadores de Cassetes de Ligação de ATP/metabolismo
Citoesqueleto de Actina/metabolismo
Moléculas de Adesão Celular Neuronais/metabolismo
Proteínas de Drosophila/metabolismo
Drosophila melanogaster/metabolismo
Proteínas de Membrana/metabolismo
Junção Neuromuscular/metabolismo
Vesículas Sinápticas/metabolismo
[Mh] Termos MeSH secundário: Transportadores de Cassetes de Ligação de ATP/química
Transportadores de Cassetes de Ligação de ATP/genética
Animais
Animais Geneticamente Modificados
Moléculas de Adesão Celular Neuronais/química
Moléculas de Adesão Celular Neuronais/genética
Proteínas de Drosophila/agonistas
Proteínas de Drosophila/química
Proteínas de Drosophila/genética
Drosophila melanogaster/citologia
Drosophila melanogaster/genética
Drosophila melanogaster/crescimento & desenvolvimento
Fenômenos Eletrofisiológicos
Deleção de Genes
Proteínas de Fluorescência Verde/genética
Proteínas de Fluorescência Verde/metabolismo
Células HEK293
Seres Humanos
Larva/citologia
Larva/genética
Larva/crescimento & desenvolvimento
Larva/metabolismo
Proteínas de Membrana/química
Proteínas de Membrana/genética
Mutação
Proteínas do Tecido Nervoso/química
Proteínas do Tecido Nervoso/genética
Proteínas do Tecido Nervoso/metabolismo
Junção Neuromuscular/citologia
Junção Neuromuscular/crescimento & desenvolvimento
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Domínios e Motivos de Interação entre Proteínas
Multimerização Proteica
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Proteínas rac de Ligação ao GTP/agonistas
Proteínas rac de Ligação ao GTP/química
Proteínas rac de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cell Adhesion Molecules, Neuronal); 0 (Drosophila Proteins); 0 (Membrane Proteins); 0 (Nerve Tissue Proteins); 0 (Nrx protein, Drosophila); 0 (Peptide Fragments); 0 (Rac1 protein, Drosophila); 0 (Recombinant Fusion Proteins); 0 (Scribble protein, Drosophila); 0 (pixie protein, Drosophila); 147336-22-9 (Green Fluorescent Proteins); EC 3.6.5.2 (rac GTP-Binding Proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170716
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.794040


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[PMID]:28687663
[Au] Autor:Graziano BR; Gong D; Anderson KE; Pipathsouk A; Goldberg AR; Weiner OD
[Ad] Endereço:Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA.
[Ti] Título:A module for Rac temporal signal integration revealed with optogenetics.
[So] Source:J Cell Biol;216(8):2515-2531, 2017 Aug 07.
[Is] ISSN:1540-8140
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sensory systems use adaptation to measure changes in signaling inputs rather than absolute levels of signaling inputs. Adaptation enables eukaryotic cells to directionally migrate over a large dynamic range of chemoattractant. Because of complex feedback interactions and redundancy, it has been difficult to define the portion or portions of eukaryotic chemotactic signaling networks that generate adaptation and identify the regulators of this process. In this study, we use a combination of optogenetic intracellular inputs, CRISPR-based knockouts, and pharmacological perturbations to probe the basis of neutrophil adaptation. We find that persistent, optogenetically driven phosphatidylinositol (3,4,5)-trisphosphate (PIP ) production results in only transient activation of Rac, a hallmark feature of adaptive circuits. We further identify the guanine nucleotide exchange factor P-Rex1 as the primary PIP -stimulated Rac activator, whereas actin polymerization and the GTPase-activating protein ArhGAP15 are essential for proper Rac turnoff. This circuit is masked by feedback and redundancy when chemoattractant is used as the input, highlighting the value of probing signaling networks at intermediate nodes to deconvolve complex signaling cascades.
[Mh] Termos MeSH primário: Quimiotaxia de Leucócito
Neutrófilos/enzimologia
Optogenética
Fosfatos de Fosfatidilinositol/metabolismo
Sistemas do Segundo Mensageiro
Proteínas rac de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Sistemas CRISPR-Cas
Ativação Enzimática
Retroalimentação Fisiológica
Proteínas Ativadoras de GTPase/genética
Proteínas Ativadoras de GTPase/metabolismo
Marcação de Genes
Fatores de Troca do Nucleotídeo Guanina/genética
Fatores de Troca do Nucleotídeo Guanina/metabolismo
Células HEK293
Células HL-60
Seres Humanos
Microscopia Confocal
Microscopia de Vídeo
Fosfatidilinositol 3-Quinase/metabolismo
Fosforilação
Proteínas Proto-Oncogênicas c-akt/metabolismo
Fatores de Tempo
Transfecção
Quinases Ativadas por p21/metabolismo
Proteínas rac de Ligação ao GTP/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; VIDEO-AUDIO MEDIA
[Nm] Nome de substância:
0 (GTPase-Activating Proteins); 0 (Guanine Nucleotide Exchange Factors); 0 (PREX1 protein, human); 0 (Phosphatidylinositol Phosphates); 0 (phosphatidylinositol 3,4,5-triphosphate); 0 (rho GTPase-activating protein 15, human); EC 2.7.1.137 (Phosphatidylinositol 3-Kinase); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.1 (p21-Activated Kinases); EC 3.6.5.2 (rac GTP-Binding Proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171021
[Lr] Data última revisão:
171021
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170709
[St] Status:MEDLINE
[do] DOI:10.1083/jcb.201604113


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[PMID]:28665696
[Au] Autor:Zhang XH; Shen M; Liu L; Li FM; Hu PC; Hua Q; Zhang J; Pang LN; Lu HW; Wang ZM; Chu X; Huang W
[Ad] Endereço:1 Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai, China .
[Ti] Título:Association Analysis of Single Nucleotide Polymorphisms in C1QTNF6, RAC2, and an Intergenic Region at 14q32.2 with Graves' Disease in Chinese Han Population.
[So] Source:Genet Test Mol Biomarkers;21(8):479-484, 2017 Aug.
[Is] ISSN:1945-0257
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Variation within the C1QTNF6 gene at 22q12.3, the RAC2 gene at 22q13.1, and an intergenic region at 14q32.2 were found to be associated with risk to Graves' disease (GD) in a recent study. We aimed to validate these associations with GD in an independent sample set of Han Chinese population. METHODS: We investigated these associations by genotyping the most significantly associated single nucleotide polymorphisms (SNPs) located in these three regions. Rs1456988 within the intergenic region at 14q32.2, rs229527 within C1QTNF6 at 22q12.3, and rs2284038 within RAC2 at 22q13.1 were selected for genotyping. These three SNPs were genotyped using a case-control study that included 2382 GD patients and 3092 unrelated healthy controls from Northern Han Chinese ancestry. The genotyping was performed using TaqMan assays on the ABI7900 platform. RESULTS: We found both the rs229527 allele within C1QTNF6 (odds ratio [OR] = 1.23, confidence interval [95% CI]: 1.12-1.33, p = 4.60 × 10 ) and the rs2284038 allele within RAC2 (OR = 1.10, 95% CI: 1.01-0.19, p = 3.00 × 10 ) showed significant associations with GD susceptibility. However, rs1456988 located in 14q32.2 (OR = 1.08, 95% CI: 0.99-1.16, p = 7.01 × 10 ) showed no association. Analysis of models of inheritance suggested that both the dominant and recessive models showed significant associations for rs229527 (OR = 1.24, 95% CI: 1.13-1.38, p = 9.90 × 10 ; OR = 1.49, 95% CI: 1.19-1.86, p = 3.90 × 10 ), with the dominant model being preferred. For rs2284038, the recessive model was preferred (OR = 1.18, 95% CI: 1.00-1.40, p = 4.76 × 10 ), whereas analysis of dominant model showed no association (OR = 1.10, 95% CI: 0.98-1.22, p = 0.10). CONCLUSIONS: Our findings confirmed that chromosome 22q12.3 and 22q13.1 variants are associated with GD in an independent Han Chinese population; however, 14q32.2 showed no association with GD.
[Mh] Termos MeSH primário: Colágeno/genética
Doença de Graves/genética
Proteínas rac de Ligação ao GTP/genética
[Mh] Termos MeSH secundário: Adulto
Alelos
Grupo com Ancestrais do Continente Asiático/genética
Estudos de Casos e Controles
China
Cromossomos Humanos Par 14/genética
Colágeno/metabolismo
DNA Intergênico/genética
Grupos Étnicos/genética
Feminino
Estudos de Associação Genética/métodos
Predisposição Genética para Doença
Estudo de Associação Genômica Ampla/métodos
Doença de Graves/etiologia
Seres Humanos
Masculino
Meia-Idade
Razão de Chances
Polimorfismo de Nucleotídeo Único/genética
Proteínas rac de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (C1qTNF6 protein, human); 0 (DNA, Intergenic); 9007-34-5 (Collagen); EC 3.6.1.- (rac2 GTP-binding protein); EC 3.6.5.2 (rac GTP-Binding Proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170921
[Lr] Data última revisão:
170921
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170701
[St] Status:MEDLINE
[do] DOI:10.1089/gtmb.2017.0009



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