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Pesquisa : D08.811.277.040.330.300.400.475 [Categoria DeCS]
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[PMID]:28691643
[Au] Autor:Di J; Gao K; Qu D; Yang J; Zheng J
[Ad] Endereço:1 Cancer Institute, Xuzhou Medical College, Xuzhou, P.R. China.
[Ti] Título:Rap2B promotes angiogenesis via PI3K/AKT/VEGF signaling pathway in human renal cell carcinoma.
[So] Source:Tumour Biol;39(7):1010428317701653, 2017 Jul.
[Is] ISSN:1423-0380
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human renal cell carcinoma which is a highly vascular tumor is the leading cause of death from urologic cancers. Angiogenesis has a pivotal role in oncogenesis and in the viability and expansion of renal cell carcinoma. Rap2B, as a small guanosine triphosphate-binding protein of the Ras family, was first discovered in the early 1990s during the screening of a platelet complementary DNA library. Previous studies have shown that Rap2B aberrantly expressed in human carcinogenesis and promoted the development of tumors via multiple signaling pathways. However, the function of Rap2B in tumor angiogenesis that is necessary for tumor growth and metastasis remains unknown. In this study, we examined the role of Rap2B in angiogenesis in renal cell carcinoma by Western blot, quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, human umbilical vascular endothelial cells growth assay, and endothelial cell tube formation assay. We found that Rap2B promoted angiogenesis in vitro and in vivo. Moreover, our data illustrated that phosphoinositide 3-kinase/AKT signaling pathway is involved in Rap2B-mediated upregulation of vascular endothelial growth factor and renal cell carcinoma angiogenesis. Taken together, these results revealed that Rap2B promotes renal cell carcinoma angiogenesis via phosphoinositide 3-kinase/AKT/vascular endothelial growth factor signaling pathway, which suggests that Rap2B is a novel therapeutic target for renal cell carcinoma anti-angiogenesis therapy.
[Mh] Termos MeSH primário: Carcinoma de Células Renais/genética
Proliferação Celular/genética
Neovascularização Patológica/genética
Proteínas rap de Ligação ao GTP/genética
[Mh] Termos MeSH secundário: Carcinoma de Células Renais/tratamento farmacológico
Carcinoma de Células Renais/patologia
Linhagem Celular Tumoral
Movimento Celular/genética
Regulação Neoplásica da Expressão Gênica
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Terapia de Alvo Molecular
Metástase Neoplásica
Neovascularização Patológica/tratamento farmacológico
Neovascularização Patológica/patologia
Proteína Oncogênica v-akt/genética
Fosfatidilinositol 3-Quinases/genética
Transdução de Sinais/genética
Fator A de Crescimento do Endotélio Vascular/genética
Proteínas rap de Ligação ao GTP/biossíntese
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (VEGFA protein, human); 0 (Vascular Endothelial Growth Factor A); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (Oncogene Protein v-akt); EC 3.6.1.- (RAP2B protein, human); EC 3.6.5.2 (rap GTP-Binding Proteins)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170726
[Lr] Data última revisão:
170726
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170711
[St] Status:MEDLINE
[do] DOI:10.1177/1010428317701653


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[PMID]:28591224
[Au] Autor:Lin KT; Sun SP; Wu JI; Wang LH
[Ad] Endereço:Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
[Ti] Título:Low-dose glucocorticoids suppresses ovarian tumor growth and metastasis in an immunocompetent syngeneic mouse model.
[So] Source:PLoS One;12(6):e0178937, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ovarian cancer has the highest mortality rate among gynecologic malignancies. Despite chemotherapy and surgical debulking options, ovarian cancer recurs and disseminates frequently with a poor prognosis. We previously reported a novel role of glucocorticoids (GCs) in metastatic ovarian cancer by upregulating microRNA-708. In this study, we used an immunocompetent syngeneic mouse model and further evaluated the effect and optimal dosages of GCs in treating metastatic ovarian cancer. The treatment of C57BL/6-derived ovarian cancer ID-8 cells with a synthetic GC, dexamethasone (DEX), induced the expression of microRNA-708, leading to decreased cell migration and invasion through targeting Rap1B. Administration of DEX at a low dose, as low as 5 µg/kg body weight, inhibited the primary tumor size and abdominal metastasis in mice bearing ID-8 cell-derived ovarian tumors. In the treated primary tumors, microRNA-708 was upregulated, whereas some proinflammatory cytokines, namely interleukin (IL)-1ß and IL-18, were downregulated. The number of tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment were reduced. Overall, our study shows that low-dose GCs can suppress ovarian cancer progression and metastasis likely through not only the upregulation of the metastasis suppressor microRNA-708, but also the modulation of TAMs and MDSCs in the tumor microenvironment.
[Mh] Termos MeSH primário: Glucocorticoides/farmacologia
Imunocompetência/efeitos dos fármacos
Neoplasias Ovarianas/patologia
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Movimento Celular/genética
Proliferação Celular/efeitos dos fármacos
Citocinas/metabolismo
Dexametasona/farmacologia
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Regulação para Baixo/efeitos dos fármacos
Regulação para Baixo/genética
Feminino
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Glucocorticoides/uso terapêutico
Mediadores da Inflamação/metabolismo
Macrófagos/efeitos dos fármacos
Macrófagos/metabolismo
Macrófagos/patologia
Camundongos Endogâmicos C57BL
MicroRNAs/genética
MicroRNAs/metabolismo
Modelos Biológicos
Células Supressoras Mieloides/metabolismo
Células Supressoras Mieloides/patologia
Invasividade Neoplásica
Metástase Neoplásica
Neoplasias Ovarianas/tratamento farmacológico
Neoplasias Ovarianas/genética
Transdução de Sinais/efeitos dos fármacos
Transcrição Genética/efeitos dos fármacos
Regulação para Cima/efeitos dos fármacos
Regulação para Cima/genética
Proteínas rap de Ligação ao GTP/genética
Proteínas rap de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytokines); 0 (Glucocorticoids); 0 (Inflammation Mediators); 0 (MicroRNAs); 7S5I7G3JQL (Dexamethasone); EC 3.6.1.- (Rap1b protein, mouse); EC 3.6.5.2 (rap GTP-Binding Proteins)
[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:170608
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0178937


  3 / 715 MEDLINE  
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[PMID]:28546426
[Au] Autor:Emery AC; Xu W; Eiden MV; Eiden LE
[Ad] Endereço:From the Section on Molecular Neuroscience and.
[Ti] Título:Guanine nucleotide exchange factor Epac2-dependent activation of the GTP-binding protein Rap2A mediates cAMP-dependent growth arrest in neuroendocrine cells.
[So] Source:J Biol Chem;292(29):12220-12231, 2017 Jul 21.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:First messenger-dependent activation of MAP kinases in neuronal and endocrine cells is critical for cell differentiation and function and requires guanine nucleotide exchange factor (GEF)-mediated activation of downstream Ras family small GTPases, which ultimately lead to ERK, JNK, and p38 phosphorylation. Because there are numerous GEFs and also a host of Ras family small GTPases, it is important to know which specific GEF-small GTPase dyad functions in a given cellular process. Here we investigated the upstream activators and downstream effectors of signaling via the GEF Epac2 in the neuroendocrine NS-1 cell line. Three cAMP sensors, Epac2, PKA, and neuritogenic cAMP sensor-Rapgef2, mediate distinct cellular outputs: p38-dependent growth arrest, cAMP response element-binding protein-dependent cell survival, and ERK-dependent neuritogenesis, respectively, in these cells. Previously, we found that cAMP-induced growth arrest of PC12 and NS-1 cells requires Epac2-dependent activation of p38 MAP kinase, which posed the important question of how Epac2 engages p38 without simultaneously activating other MAP kinases in neuronal and endocrine cells. We now show that the small GTP-binding protein Rap2A is the obligate effector for, and GEF substrate of, Epac2 in mediating growth arrest through p38 activation in NS-1 cells. This new pathway is distinctly parcellated from the G protein-coupled receptor → G → adenylate cyclase → cAMP → PKA → cAMP response element-binding protein pathway mediating cell survival and the G protein-coupled receptor → G → adenylate cyclase → cAMP → neuritogenic cAMP sensor-Rapgef2 → B-Raf → MEK → ERK pathway mediating neuritogenesis in NS-1 cells.
[Mh] Termos MeSH primário: AMP Cíclico/metabolismo
Fatores de Troca do Nucleotídeo Guanina/metabolismo
Sistema de Sinalização das MAP Quinases
Células Neuroendócrinas/metabolismo
Processamento de Proteína Pós-Traducional
Proteínas rap de Ligação ao GTP/agonistas
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Ativação Enzimática
Proteínas de Ligação ao GTP/química
Proteínas de Ligação ao GTP/genética
Proteínas de Ligação ao GTP/metabolismo
Proteínas de Fluorescência Verde/genética
Proteínas de Fluorescência Verde/metabolismo
Ligantes
Proteínas Monoméricas de Ligação ao GTP/antagonistas & inibidores
Proteínas Monoméricas de Ligação ao GTP/genética
Proteínas Monoméricas de Ligação ao GTP/metabolismo
Proteínas do Tecido Nervoso/agonistas
Proteínas do Tecido Nervoso/antagonistas & inibidores
Proteínas do Tecido Nervoso/genética
Proteínas do Tecido Nervoso/metabolismo
Neuritos/metabolismo
Células Neuroendócrinas/citologia
Neurogênese
Fosforilação
Prenilação de Proteína
Interferência de RNA
Ratos
Proteínas Recombinantes/metabolismo
Proteínas rap de Ligação ao GTP/antagonistas & inibidores
Proteínas rap de Ligação ao GTP/genética
Proteínas rap de Ligação ao GTP/metabolismo
Proteínas ras/antagonistas & inibidores
Proteínas ras/genética
Proteínas ras/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Epac-2 protein, rat); 0 (Guanine Nucleotide Exchange Factors); 0 (Ligands); 0 (Nerve Tissue Proteins); 0 (Rap2a protein, rat); 0 (Recombinant Proteins); 147336-22-9 (Green Fluorescent Proteins); E0399OZS9N (Cyclic AMP); EC 3.6.1.- (GTP-Binding Proteins); EC 3.6.5.2 (Monomeric GTP-Binding Proteins); EC 3.6.5.2 (Rit1 protein, rat); EC 3.6.5.2 (rap GTP-Binding Proteins); EC 3.6.5.2 (ras Proteins)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170808
[Lr] Data última revisão:
170808
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170527
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.790329


  4 / 715 MEDLINE  
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[PMID]:28423503
[Au] Autor:Ding L; Sun R; Zhang X
[Ad] Endereço:College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, Jiangsu 225009, China.
[Ti] Título:Rap2b siRNA significantly enhances the anticancer therapeutic efficacy of adriamycin in a gold nanoshell-based drug/gene co-delivery system.
[So] Source:Oncotarget;8(13):21200-21211, 2017 Mar 28.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Rap2b is a novel p53 target we have identified recently. Knockdown of Rap2b sensitizes HCT116 cells to adriamycin-induced apoptosis, indicating that Rap2b promotes adriamycin resistance in cancer cells. In the present study, we designed a nanostructure-based drug/gene delivery system to evaluate the potential of Rap2b siRNA as a therapeutic agent against human cancers. Specifically, after co-incubated with HCT116 cells, adriamycin- and Rap2b siRNA-loaded gold nanoshells were internalized. Subsequent laser irradiation promoted release of adriamycin and Rap2b siRNA from the nanoparticles. The laser-induced release of Rap2b siRNA decreased cellular expression of Rap2b and significantly enhanced the anticancer therapeutic efficacy of adriamycin in vitro and in vivo. In addition, laser irradiation of the nanoparticles might exert an additional thermal killing effect on cancer cells and further improved the anticancer efficacy of adriamycin. In summary, Rap2b siRNA is a potential enhancing agent for adriamycin-based anticancer therapeutics and the gold nanoshell-based drug/gene delivery system carrying both adriamycin and Rap2b siRNA provides a promising anticancer therapeutic strategy.
[Mh] Termos MeSH primário: Doxorrubicina/administração & dosagem
Técnicas de Transferência de Genes
Terapia Genética/métodos
Neoplasias Experimentais/terapia
RNA Interferente Pequeno/administração & dosagem
Proteínas rap de Ligação ao GTP/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Western Blotting
Sistemas de Liberação de Medicamentos/métodos
Ouro
Células HCT116
Seres Humanos
Camundongos
Camundongos Nus
Microscopia Confocal
Nanoconchas
Nanotecnologia
Reação em Cadeia da Polimerase
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Small Interfering); 7440-57-5 (Gold); 80168379AG (Doxorubicin); EC 3.6.1.- (RAP2B protein, human); EC 3.6.5.2 (rap GTP-Binding Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170421
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15508


  5 / 715 MEDLINE  
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[PMID]:28405688
[Au] Autor:Wang L; Zhu B; Wang S; Wu Y; Zhan W; Xie S; Shi H; Yu R
[Ad] Endereço:Insitute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, P.R. China.
[Ti] Título:Regulation of glioma migration and invasion via modification of Rap2a activity by the ubiquitin ligase Nedd4-1.
[So] Source:Oncol Rep;37(5):2565-2574, 2017 May.
[Is] ISSN:1791-2431
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:Νeuronal precursor cell expressed and developmentally downregulated protein (Nedd4-1) is an E3 ubiquitin ligase with critical roles in the pathogenesis of cancer. Herein, we demonstrated that Nedd4-1 protein was upregulated in glioma tissues vs. that in non-cancerous tissues by western blotting and immunohistochemistry. Scratch migration and Transwell chamber assays indicated that downregulation of Nedd4-1 significantly reduced the migration and invasion of the glioma cell lines U251 and U87. Conversely, overexpression of Nedd4-1 obviously enhanced the migratory and invasive capacities in both cell lines. To investigate the role of Nedd4-1 and the intracellular pathways involved, we performed pull-down and co-immunoprecipitation assays, and recognized that Nedd4-1, TNIK and Rap2a formed a complex. Moreover, Nedd4-1 selectively ubiquitinated its specific substrates, the wild-type Rap2a (WT-Rap2a) and dominant-active Rap2a (DA-Rap2a) rather than the dominant-negative Rap2a (DN-Rap2a) in the U251 cells. Subsequently, we demonstrated that Rap2a was robustly ubiquitinated by Nedd4-1 along with the K63-linked, but not the K48-linked ubiquitin chain, which significantly inhibited GTP-Rap2a activity by GST-RalGDS pull-down assay. To further verify whether the ubiquitination of Rap2a by Nedd4-1 regulated the migration and invasion of glioma cells, Nedd4-1, HA-tagged ubiquitin and its mutants as well as WT-Rap2a were co-transfected in the U251 and U87 cell lines. The results confirmed that Nedd4-1 inhibited GTP-Rap2a activity, and promoted the migration and invasion of glioma cells. In brief, our findings demonstrated the important role of Nedd4-1 in regulating the migration and invasion of glioma cells via the Nedd4-1/Rap2a pathway, which may qualify Nedd4-1 as a viable therapeutic target for glioma.
[Mh] Termos MeSH primário: Neoplasias Encefálicas/patologia
Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo
Glioma/patologia
Ubiquitina-Proteína Ligases/metabolismo
Proteínas rap de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Neoplasias Encefálicas/metabolismo
Linhagem Celular Tumoral
Movimento Celular
Complexos Endossomais de Distribuição Requeridos para Transporte/genética
Glioma/metabolismo
Seres Humanos
Ubiquitina-Proteína Ligases Nedd4
Ubiquitina-Proteína Ligases/genética
Ubiquitinação
Proteínas rap de Ligação ao GTP/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Endosomal Sorting Complexes Required for Transport); EC 2.3.2.26 (Nedd4 Ubiquitin Protein Ligases); EC 2.3.2.26 (Nedd4 protein, human); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 3.6.1.- (RAP2A protein, human); EC 3.6.5.2 (rap GTP-Binding Proteins)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170414
[St] Status:MEDLINE
[do] DOI:10.3892/or.2017.5572


  6 / 715 MEDLINE  
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[PMID]:28119087
[Au] Autor:Jia Z; Yang Y; Dengyan Z; Chunyang Z; Donglei L; Kai W; Song Z
[Ad] Endereço:Department of Thoracic Surgery, The First Affiliated Hospital, Zhengzhou University, Henan province, PR China; Department of Key Thoracic Tumour Experimental Laboratory of Zhengzhou, PR China.
[Ti] Título:RAP1B, a DVL2 binding protein, activates Wnt/beta-catenin signaling in esophageal squamous cell carcinoma.
[So] Source:Gene;611:15-20, 2017 May 05.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:RAP1B is a small GTPase, which regulates multiple cellular processes. Up-regulation of RAP1B has been observed in several cancer types. Although previous study has shown that miR-518 inhibited the proliferation and invasion of esophageal squamous cell carcinoma (ESCC) cells possibly by targeting RAP1B, the expression pattern and the functions of RAP1B in ESCC are not fully understood. Here, we have fund that the expression of RAP1B was up-regulated in ESCC clinical samples. Gain-of-function and loss-of-function assays demonstrated that RAP1B promoted the growth, migration and metastasis of the ESCC cells. Moreover, the mechanism study showed that RAP1B interacted with DVL2, an important upstream regulator for beta-catenin/TCF signaling, and activated beta-catenin/TCF signaling. Taken together, our study demonstrated the oncogenic roles of RAP1B in ESCC, and suggested that RAP1B might be a therapeutic target.
[Mh] Termos MeSH primário: Carcinoma de Células Escamosas/metabolismo
Proteínas Desgrenhadas/metabolismo
Neoplasias Esofágicas/metabolismo
Via de Sinalização Wnt
beta Catenina/metabolismo
Proteínas rap de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Animais
Western Blotting
Carcinoma de Células Escamosas/genética
Carcinoma de Células Escamosas/patologia
Linhagem Celular Tumoral
Movimento Celular/genética
Proliferação Celular/genética
Proteínas Desgrenhadas/genética
Neoplasias Esofágicas/genética
Neoplasias Esofágicas/patologia
Regulação Neoplásica da Expressão Gênica
Seres Humanos
Imuno-Histoquímica
Camundongos Nus
Metástase Neoplásica
Ligação Proteica
Interferência de RNA
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Transplante Heterólogo
beta Catenina/genética
Proteínas rap de Ligação ao GTP/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DVL2 protein, human); 0 (Dishevelled Proteins); 0 (beta Catenin); EC 3.6.1.- (RAP1B protein, human); EC 3.6.5.2 (rap GTP-Binding Proteins)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170411
[Lr] Data última revisão:
170411
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170126
[St] Status:MEDLINE


  7 / 715 MEDLINE  
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[PMID]:28081729
[Au] Autor:Zhang L; Duan HB; Yang YS
[Ti] Título:Knockdown of Rap2B Inhibits the Proliferation and Invasion in Hepatocellular Carcinoma Cells.
[So] Source:Oncol Res;25(1):19-27, 2017 Jan 02.
[Is] ISSN:1555-3906
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Rap2B, a member of the Ras family of small GTP-binding proteins, was found to be highly expressed in various human tumors and plays an important role in the development of tumors. However, the function of Rap2B in hepatocellular carcinoma (HCC) remains unclear. Therefore, in this study, we investigated the biological functions of Rap2B in HCC and the potential underlying mechanisms. Our results indicated that Rap2B was highly expressed in HCC tissues and cell lines. Rap2B silencing obviously inhibited the proliferation, migration, and invasion of HCC cells, as well as attenuated xenografted tumor growth in vivo. Furthermore, Rap2B silencing greatly reduced the expression levels of phosphorylated focal adhesion kinase (p-FAK), matrix metalloproteinase-2 (MMP-2), and MMP-9 in HCC cells. In conclusion, our data suggest that Rap2B silencing inhibits the proliferation and invasion in HCC cells. Thus, Rap2B may have potential as a treatment for HCC.
[Mh] Termos MeSH primário: Carcinoma Hepatocelular/genética
Inativação Gênica
Neoplasias Hepáticas/genética
Proteínas rap de Ligação ao GTP/genética
[Mh] Termos MeSH secundário: Animais
Carcinoma Hepatocelular/metabolismo
Carcinoma Hepatocelular/patologia
Linhagem Celular Tumoral
Movimento Celular
Proliferação Celular
Modelos Animais de Doenças
Quinase 1 de Adesão Focal/metabolismo
Regulação da Expressão Gênica
Técnicas de Silenciamento de Genes
Seres Humanos
Neoplasias Hepáticas/metabolismo
Neoplasias Hepáticas/patologia
Camundongos
RNA Mensageiro/genética
RNA Interferente Pequeno/genética
Transdução de Sinais
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Messenger); 0 (RNA, Small Interfering); EC 2.7.10.2 (Focal Adhesion Kinase 1); EC 3.6.1.- (RAP2B protein, human); EC 3.6.5.2 (rap GTP-Binding Proteins)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170314
[Lr] Data última revisão:
170314
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170114
[St] Status:MEDLINE
[do] DOI:10.3727/096504016X14685034103914


  8 / 715 MEDLINE  
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[PMID]:28052935
[Au] Autor:Witte A; Meineke B; Sticht J; Philipsen L; Kuropka B; Müller AJ; Freund C; Schraven B; Kliche S
[Ad] Endereço:Otto von Guericke University, Institute of Molecular and Clinical Immunology, Health Campus Immunology, Infectiology and Inflammation, Magdeburg, Germany.
[Ti] Título:D120 and K152 within the PH Domain of T Cell Adapter SKAP55 Regulate Plasma Membrane Targeting of SKAP55 and LFA-1 Affinity Modulation in Human T Lymphocytes.
[So] Source:Mol Cell Biol;37(7), 2017 Apr 01.
[Is] ISSN:1098-5549
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The ß2-integrin lymphocyte function-associated antigen 1 (LFA-1) is needed for the T cell receptor (TCR)-induced activation of LFA-1 to promote T cell adhesion and interaction with antigen-presenting cells (APCs). LFA-1-mediated cell-cell interactions are critical for proper T cell differentiation and proliferation. The Src kinase-associated phosphoprotein of 55 kDa (SKAP55) is a key regulator of TCR-mediated LFA-1 signaling (inside-out/outside-in signaling). To gain an understanding of how SKAP55 controls TCR-mediated LFA-1 activation, we assessed the functional role of its pleckstrin homology (PH) domain. We identified two critical amino acid residues within the PH domain of SKAP55, aspartic acid 120 (D120) and lysine 152 (K152). D120 facilitates the retention of SKAP55 in the cytoplasm of nonstimulated T cells, while K152 promotes SKAP55 membrane recruitment via actin binding upon TCR triggering. Importantly, the K152-dependent interaction of the PH domain with actin promotes the binding of talin to LFA-1, thus facilitating LFA-1 activation. These data suggest that K152 and D120 within the PH domain of SKAP55 regulate plasma membrane targeting and TCR-mediated activation of LFA-1.
[Mh] Termos MeSH primário: Ácido Aspártico/metabolismo
Membrana Celular/metabolismo
Antígeno-1 Associado à Função Linfocitária/metabolismo
Lisina/metabolismo
Fosfoproteínas/química
Fosfoproteínas/metabolismo
Linfócitos T/metabolismo
[Mh] Termos MeSH secundário: Actinas/metabolismo
Adesão Celular
Seres Humanos
Células Jurkat
Lipídeos/química
Proteínas Mutantes/metabolismo
Mutação/genética
Fosfatos de Fosfatidilinositol/metabolismo
Domínios Proteicos
Receptores de Antígenos de Linfócitos T/metabolismo
Relação Estrutura-Atividade
Talina/metabolismo
Proteínas rap de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (Lipids); 0 (Lymphocyte Function-Associated Antigen-1); 0 (Mutant Proteins); 0 (Phosphatidylinositol Phosphates); 0 (Phosphoproteins); 0 (Receptors, Antigen, T-Cell); 0 (SKAP1 protein, human); 0 (Talin); 0 (phosphatidylinositol 3,4,5-triphosphate); 30KYC7MIAI (Aspartic Acid); EC 3.6.5.2 (rap GTP-Binding Proteins); K3Z4F929H6 (Lysine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170917
[Lr] Data última revisão:
170917
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170106
[St] Status:MEDLINE


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[PMID]:28003362
[Au] Autor:Takahashi M; Li Y; Dillon TJ; Stork PJ
[Ad] Endereço:From the Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239-3098.
[Ti] Título:Phosphorylation of Rap1 by cAMP-dependent Protein Kinase (PKA) Creates a Binding Site for KSR to Sustain ERK Activation by cAMP.
[So] Source:J Biol Chem;292(4):1449-1461, 2017 Jan 27.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cyclic adenosine monophosphate (cAMP) is an important mediator of hormonal stimulation of cell growth and differentiation through its activation of the extracellular signal-regulated kinase (ERK) cascade. Two small G proteins, Ras and Rap1 have been proposed to mediate this activation. Using HEK293 cells as a model system, we have recently shown that both Ras and Rap1 are required for cAMP signaling to ERKs. However, cAMP-dependent Ras signaling to ERKs is transient and rapidly terminated by PKA phosphorylation of the Raf isoforms C-Raf and B-Raf. In contrast, cAMP-dependent Rap1 signaling to ERKs and Rap1 is potentiated by PKA. We show that this is due to sustained binding of B-Raf to Rap1. One of the targets of PKA is Rap1 itself, directly phosphorylating Rap1a on serine 180 and Rap1b on serine 179. We show that these phosphorylations create potential binding sites for the adaptor protein 14-3-3 that links Rap1 to the scaffold protein KSR. These results suggest that Rap1 activation of ERKs requires PKA phosphorylation and KSR binding. Because KSR and B-Raf exist as heterodimers within the cell, this binding also brings B-Raf to Rap1, allowing Rap1 to couple to ERKs through B-Raf binding to Rap1 independently of its Ras-binding domain.
[Mh] Termos MeSH primário: Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
AMP Cíclico/metabolismo
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Lisina-tRNA Ligase/metabolismo
Proteínas rap de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Animais
AMP Cíclico/genética
Proteínas Quinases Dependentes de AMP Cíclico/genética
Ativação Enzimática/genética
MAP Quinases Reguladas por Sinal Extracelular/genética
Células HEK293
Seres Humanos
Lisina-tRNA Ligase/genética
Camundongos
Camundongos Knockout
Proteínas Proto-Oncogênicas B-raf/genética
Proteínas Proto-Oncogênicas B-raf/metabolismo
Proteínas rap de Ligação ao GTP/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
E0399OZS9N (Cyclic AMP); EC 2.7.11.1 (BRAF protein, human); EC 2.7.11.1 (Braf protein, mouse); EC 2.7.11.1 (Proto-Oncogene Proteins B-raf); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); EC 3.6.5.2 (rap GTP-Binding Proteins); EC 6.1.1.6 (KRS protein, human); EC 6.1.1.6 (Lysine-tRNA Ligase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170619
[Lr] Data última revisão:
170619
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161223
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.768986


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[PMID]:27493245
[Au] Autor:Gera N; Swanson KD; Jin T
[Ad] Endereço:Chemotaxis Signal Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA; and nidhi_gera@hms.harvard.edu.
[Ti] Título:ß-Arrestin 1-dependent regulation of Rap2 is required for fMLP-stimulated chemotaxis in neutrophil-like HL-60 cells.
[So] Source:J Leukoc Biol;101(1):239-251, 2017 Jan.
[Is] ISSN:1938-3673
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:ß-Arrestins have emerged as key regulators of cytoskeletal rearrangement that are required for directed cell migration. Whereas it is known that ß-arrestins are required for formyl-Met-Leu-Phe receptor (FPR) recycling, less is known about their role in regulating FPR-mediated neutrophil chemotaxis. Here, we show that ß-arrestin 1 (ArrB1) coaccumulated with F-actin within the leading edge of neutrophil-like HL-60 cells during chemotaxis, and its knockdown resulted in markedly reduced migration within fMLP gradients. The small GTPase Ras-related protein 2 (Rap2) was found to bind ArrB1 under resting conditions but dissociated upon fMLP stimulation. The FPR-dependent activation of Rap2 required ArrB1 but was independent of Gα activity. Significantly, depletion of either ArrB1 or Rap2 resulted in reduced chemotaxis and defects in cellular repolarization within fMLP gradients. These data strongly suggest a model in which FPR is able to direct ArrB1 and other bound proteins that are required for lamellipodial extension to the leading edge in migrating neutrophils, thereby orientating and directing cell migration.
[Mh] Termos MeSH primário: Quimiotaxia/efeitos dos fármacos
N-Formilmetionina Leucil-Fenilalanina/farmacologia
Neutrófilos/citologia
Neutrófilos/metabolismo
beta-Arrestina 1/metabolismo
Proteínas rap de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Adesão Celular/efeitos dos fármacos
Membrana Celular/efeitos dos fármacos
Membrana Celular/metabolismo
Fatores Quimiotáticos/farmacologia
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo
Técnicas de Silenciamento de Genes
Células HL-60
Seres Humanos
Modelos Biológicos
Neutrófilos/efeitos dos fármacos
Pseudópodes/efeitos dos fármacos
Pseudópodes/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chemotactic Factors); 0 (beta-Arrestin 1); 59880-97-6 (N-Formylmethionine Leucyl-Phenylalanine); EC 3.6.1.- (RAP2A protein, human); EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go); EC 3.6.5.2 (rap GTP-Binding Proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170901
[Lr] Data última revisão:
170901
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160806
[St] Status:MEDLINE
[do] DOI:10.1189/jlb.2A1215-572R



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