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Pesquisa : D08.811.277.040.330.300.400.475.100 [Categoria DeCS]
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[PMID]:28459538
[Au] Autor:Biancucci M; Rabideau AE; Lu Z; Loftis AR; Pentelute BL; Satchell KJF
[Ad] Endereço:Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine , Chicago, Illinois 60611, United States.
[Ti] Título:Substrate Recognition of MARTX Ras/Rap1-Specific Endopeptidase.
[So] Source:Biochemistry;56(21):2747-2757, 2017 05 30.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ras/Rap1-specific endopeptidase (RRSP) is a cytotoxic effector domain of the multifunctional autoprocessing repeats-in-toxin (MARTX) toxin of highly virulent strains of Vibrio vulnificus. RRSP blocks RAS-MAPK kinase signaling by cleaving Ras and Rap1 within the switch I region between Y32 and D33. Although the RRSP processing site is highly conserved among small GTPases, only Ras and Rap1 have been identified as proteolytic substrates. Here we report that residues Y32 and D33 at the scissile bond play an important role in RRSP substrate recognition, while the nucleotide state of Ras has an only minimal effect. In addition, substrate specificity is generated by residues across the entire switch I region. Indeed, swapping the Ras switch I region into either RalA or RhoA, GTPases that are not recognized by RRSP, generated chimeras that are substrates of RRSP. However, a difference in the processing efficiency of Ras switch I in the context of Ras, RalA, or RhoA indicates that protein regions outside Ras switch I also contribute to efficient RRSP substrate recognition. Moreover, we show that synthetic peptides corresponding to the Ras and Rap1, but not RalA, switch I regions are cleaved by RRSP, demonstrating sequence-specific substrate recognition. In conclusion, this work demonstrates that the GTPase recognition of RRSP is independent of the nucleotide state and is mainly driven by the Ras and Rap1 switch I loop and also influenced by additional protein-protein interactions, increasing the substrate specificity of RRSP.
[Mh] Termos MeSH primário: Toxinas Bacterianas/química
Toxinas Bacterianas/metabolismo
Endopeptidases/química
Endopeptidases/metabolismo
Vibrio vulnificus/enzimologia
Proteínas rap1 de Ligação ao GTP/metabolismo
Proteínas ras/metabolismo
[Mh] Termos MeSH secundário: Seres Humanos
Modelos Moleculares
Especificidade por Substrato
Proteínas rap1 de Ligação ao GTP/química
Proteínas ras/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Toxins); EC 3.4.- (Endopeptidases); EC 3.6.5.2 (rap1 GTP-Binding Proteins); EC 3.6.5.2 (ras Proteins)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171205
[Lr] Data última revisão:
171205
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00246


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[PMID]:28550110
[Au] Autor:Genova T; Grolez GP; Camillo C; Bernardini M; Bokhobza A; Richard E; Scianna M; Lemonnier L; Valdembri D; Munaron L; Philips MR; Mattot V; Serini G; Prevarskaya N; Gkika D; Pla AF
[Ad] Endereço:Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy.
[Ti] Título:TRPM8 inhibits endothelial cell migration via a non-channel function by trapping the small GTPase Rap1.
[So] Source:J Cell Biol;216(7):2107-2130, 2017 Jul 03.
[Is] ISSN:1540-8140
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Endothelial cell adhesion and migration are critical steps of the angiogenic process, whose dysfunction is associated with tumor growth and metastasis. The TRPM8 channel has recently been proposed to play a protective role in prostate cancer by impairing cell motility. However, the mechanisms by which it could influence vascular behavior are unknown. Here, we reveal a novel non-channel function for TRPM8 that unexpectedly acts as a Rap1 GTPase inhibitor, thereby inhibiting endothelial cell motility, independently of pore function. TRPM8 retains Rap1 intracellularly through direct protein-protein interaction, thus preventing its cytoplasm-plasma membrane trafficking. In turn, this mechanism impairs the activation of a major inside-out signaling pathway that triggers the conformational activation of integrin and, consequently, cell adhesion, migration, in vitro endothelial tube formation, and spheroid sprouting. Our results bring to light a novel, pore-independent molecular mechanism by which endogenous TRPM8 expression inhibits Rap1 GTPase and thus plays a critical role in the behavior of vascular endothelial cells by inhibiting migration.
[Mh] Termos MeSH primário: Movimento Celular
Células Endoteliais/enzimologia
Neovascularização Fisiológica
Canais de Cátion TRPM/metabolismo
Proteínas rap1 de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Adesão Celular
Células HEK293
Células Endoteliais da Veia Umbilical Humana/enzimologia
Seres Humanos
Integrina beta1/metabolismo
Microscopia Confocal
Microscopia de Fluorescência
Microscopia de Vídeo
Modelos Cardiovasculares
Ligação Proteica
Transporte Proteico
Interferência de RNA
Transdução de Sinais
Canais de Cátion TRPM/genética
Fatores de Tempo
Transfecção
Proteínas rap1 de Ligação ao GTP/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; VIDEO-AUDIO MEDIA
[Nm] Nome de substância:
0 (Integrin beta1); 0 (TRPM Cation Channels); 0 (TRPM8 protein, human); EC 3.6.5.2 (rap1 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:170528
[St] Status:MEDLINE
[do] DOI:10.1083/jcb.201506024


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[PMID]:28408238
[Au] Autor:Li P; Karaczyn AA; McGlauflin R; Favreau-Lessard AJ; Jachimowicz E; Vary CP; Xu K; Wojchowski DM; Sathyanarayana P
[Ad] Endereço:Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME, USA; Department of Hematology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu Province, China.
[Ti] Título:Novel roles for podocalyxin in regulating stress myelopoiesis, Rap1a, and neutrophil migration.
[So] Source:Exp Hematol;50:77-83.e6, 2017 Jun.
[Is] ISSN:1873-2399
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Podocalyxin (Podxl) is a CD34 orthologue and cell surface sialomucin reported to have roles in renal podocyte diaphragm slit development; vascular cell integrity; and the progression of blood, breast, and prostate cancers. Roles for Podxl during nonmalignant hematopoiesis, however, are largely undefined. We have developed a Vav-Cre Podxl knockout (KO) mouse model, and report on novel roles for Podxl in governing stress myelopoiesis. At steady state, Podxl expression among hematopoietic progenitor cells was low level but was induced by granulocyte colony-stimulating factor (G-CSF) in myeloid progenitors and by thrombopoietin in human stem cells. In keeping with low-level Podxl expression at steady state, Vav-Cre deletion of Podxl did not markedly alter peripheral blood cell levels. A G-CSF challenge in Podxl-KO mice, in contrast, hyperelevated peripheral blood neutrophil and monocyte levels. Podxl-KO also substantially heightened neutrophil levels after 5-fluorouracil myeloablation. These loss-of-function phenotypes were selective, and Podxl-KO did not alter lymphocyte, basophil, or eosinophil levels. Within bone marrow (and after G-CSF challenge), Podxl deletion moderately decreased colony forming units-granulocytes, eyrthrocytes, monocyte/macrophages, megakaryocytes and CD16/32 CD11b progenitors but did not affect Gr-1 cell populations. Notably, Podxl-KO did significantly heighten peripheral blood neutrophil migration capacities. To interrogate Podxl's action mechanisms, a co-immunoprecipitation plus liquid chromatography-mass spectrometry approach was applied using hematopoietic progenitors from G-CSF-challenged mice. Rap1a, a Ras-related small GTPase, was a predominant co-retrieved Podxl partner. In bone marrow human progenitor cells, Podxl-KO led to heightened G-CSF activation of Rap1a , and Rap1a inhibition attenuated Podxl-KO neutrophil migration. Studies have revealed novel roles for Podxl as an important modulator of neutrophil and monocyte formation and of Rap1a activation during stress hematopoiesis.
[Mh] Termos MeSH primário: Mielopoese
Neutrófilos/fisiologia
Sialoglicoproteínas/genética
Estresse Fisiológico
[Mh] Termos MeSH secundário: Animais
Perfilação da Expressão Gênica
Regulação da Expressão Gênica/efeitos dos fármacos
Ordem dos Genes
Loci Gênicos
Fator Estimulador de Colônias de Granulócitos/farmacologia
Células-Tronco Hematopoéticas/citologia
Células-Tronco Hematopoéticas/efeitos dos fármacos
Células-Tronco Hematopoéticas/metabolismo
Seres Humanos
Camundongos
Camundongos Knockout
Mielopoese/genética
Sialoglicoproteínas/metabolismo
Estresse Fisiológico/genética
Proteínas rap1 de Ligação ao GTP
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Sialoglycoproteins); 0 (podocalyxin); 143011-72-7 (Granulocyte Colony-Stimulating Factor); EC 3.6.5.2 (rap1 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:170415
[St] Status:MEDLINE


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[PMID]:28378341
[Au] Autor:Liu H; Lo CM; Yeung OWH; Li CX; Liu XB; Qi X; Ng KTP; Liu J; Ma YY; Lam YF; Lian Q; Chan SC; Man K
[Ad] Endereço:Department of Surgery, Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.
[Ti] Título:NLRP3 inflammasome induced liver graft injury through activation of telomere-independent RAP1/KC axis.
[So] Source:J Pathol;242(3):284-296, 2017 Jul.
[Is] ISSN:1096-9896
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Acute-phase inflammation plays a critical role in liver graft injury. Inflammasomes, multi-molecular complexes in the cytoplasm, are responsible for initiating inflammation. Here, we aimed to explore the role of inflammasomes in liver graft injury and further to investigate the regulatory mechanism. In a clinical liver transplant cohort, we found that intragraft expression of nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes was significantly up-regulated post-transplantation. Importantly, overexpression of NLRP3 was strongly associated with poor liver function characterized by high levels of ALT, AST, and urea, as well as neutrophil infiltration after transplantation. The significant correlation between NLRP3 and IL-1ß mRNA levels led us to focus on one of the associated upstream regulators, telomere-independent repressor activator protein 1 (RAP1), which was further proved to be co-localized with NLRP3 in neutrophils. In the liver of a mouse model (hepatic ischaemia/reperfusion and hepatectomy model) and isolated neutrophils from RAP1 mice, the expression levels of NLRP3 and keratinocyte chemoattractant (KC) were significantly down-regulated in contrast to those in wild types. The levels of ALT and AST, as well as the neutrophil infiltration, were also decreased by RAP1 deficiency. In our clinical validation, intragraft KC expression was associated with NLRP3 and co-localized with RAP1 in neutrophils. Furthermore, NLRP3 inflammasomes were up-regulated by recombinant KC in the isolated neutrophils and liver of the mouse model. Our data demonstrated that NLRP3 inflammasomes, activated by the RAP1/KC axis, played a critical role in initiating inflammation during the early stage of liver graft injury. Targeting RAP1/KC/NLRP3 inflammasomes may offer a new therapeutic strategy against liver graft injury. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
[Mh] Termos MeSH primário: Inflamassomos/metabolismo
Transplante de Fígado
Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
[Mh] Termos MeSH secundário: Lesão Pulmonar Aguda/etiologia
Lesão Pulmonar Aguda/metabolismo
Adulto
Idoso
Animais
Citocinas/metabolismo
Modelos Animais de Doenças
Feminino
Técnicas de Silenciamento de Genes
Hepatectomia/métodos
Seres Humanos
Masculino
Camundongos Endogâmicos C57BL
Meia-Idade
Neutrófilos/metabolismo
Traumatismo por Reperfusão/metabolismo
Proteínas de Ligação a Telômeros/metabolismo
Regulação para Cima/fisiologia
Adulto Jovem
Proteínas rap1 de Ligação ao GTP/deficiência
Proteínas rap1 de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytokines); 0 (Inflammasomes); 0 (NLR Family, Pyrin Domain-Containing 3 Protein); 0 (NLRP3 protein, human); 0 (Nlrp3 protein, mouse); 0 (TERF2IP protein, human); 0 (Telomere-Binding Proteins); EC 3.6.5.2 (Rap1 protein, mouse); EC 3.6.5.2 (rap1 GTP-Binding Proteins)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170828
[Lr] Data última revisão:
170828
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170406
[St] Status:MEDLINE
[do] DOI:10.1002/path.4901


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[PMID]:28334836
[Au] Autor:Nanavaty V; Sandhu R; Jehi SE; Pandya UM; Li B
[Ad] Endereço:Center for Gene Regulation in Health and Disease, Department of Biological, Geological, and Environmental Sciences, Cleveland State University, 2121 Euclid Avenue, Cleveland, OH 44115, USA.
[Ti] Título:Trypanosoma brucei RAP1 maintains telomere and subtelomere integrity by suppressing TERRA and telomeric RNA:DNA hybrids.
[So] Source:Nucleic Acids Res;45(10):5785-5796, 2017 Jun 02.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Trypanosoma brucei causes human African trypanosomiasis and regularly switches its major surface antigen, VSG, thereby evading the host's immune response. VSGs are monoallelically expressed from subtelomeric expression sites (ESs), and VSG switching exploits subtelomere plasticity. However, subtelomere integrity is essential for T. brucei viability. The telomeric transcript, TERRA, was detected in T. brucei previously. We now show that the active ES-adjacent telomere is transcribed. We find that TbRAP1, a telomere protein essential for VSG silencing, suppresses VSG gene conversion-mediated switching. Importantly, TbRAP1 depletion increases the TERRA level, which appears to result from longer read-through into the telomere downstream of the active ES. Depletion of TbRAP1 also results in more telomeric RNA:DNA hybrids and more double strand breaks (DSBs) at telomeres and subtelomeres. In TbRAP1-depleted cells, expression of excessive TbRNaseH1, which cleaves the RNA strand of the RNA:DNA hybrid, brought telomeric RNA:DNA hybrids, telomeric/subtelomeric DSBs and VSG switching frequency back to WT levels. Therefore, TbRAP1-regulated appropriate levels of TERRA and telomeric RNA:DNA hybrid are fundamental to subtelomere/telomere integrity. Our study revealed for the first time an important role of a long, non-coding RNA in antigenic variation and demonstrated a link between telomeric silencing and subtelomere/telomere integrity through TbRAP1-regulated telomere transcription.
[Mh] Termos MeSH primário: DNA de Protozoário/genética
RNA Longo não Codificante/genética
RNA de Protozoário/genética
Telômero/química
Trypanosoma brucei brucei/genética
Glicoproteínas Variantes de Superfície de Trypanosoma/genética
Proteínas rap1 de Ligação ao GTP/genética
[Mh] Termos MeSH secundário: Pareamento de Bases
Quebras de DNA de Cadeia Dupla
DNA de Protozoário/metabolismo
Hibridização de Ácido Nucleico
Proteínas de Protozoários/genética
Proteínas de Protozoários/metabolismo
RNA Longo não Codificante/metabolismo
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
RNA de Protozoário/metabolismo
Ribonuclease H/genética
Ribonuclease H/metabolismo
Telômero/metabolismo
Transcrição Genética
Trypanosoma brucei brucei/metabolismo
Glicoproteínas Variantes de Superfície de Trypanosoma/metabolismo
Proteínas rap1 de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Protozoan); 0 (Protozoan Proteins); 0 (RNA, Long Noncoding); 0 (RNA, Messenger); 0 (RNA, Protozoan); 0 (Variant Surface Glycoproteins, Trypanosoma); EC 3.1.26.4 (Ribonuclease H); EC 3.1.26.4 (ribonuclease HI); EC 3.6.5.2 (rap1 GTP-Binding Proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170324
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx184


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[PMID]:28278256
[Au] Autor:Yu X; Zhang Q; Zhao Y; Schwarz BJ; Stallone JN; Heaps CL; Han G
[Ad] Endereço:Department of Physiology and Pharmacology, Texas A&M University, College Station, TX, United States of America.
[Ti] Título:Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA.
[So] Source:PLoS One;12(3):e0173085, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Previously, we reported that cAMP/PKA signaling is involved in GPER-mediated coronary relaxation by activating MLCP via inhibition of RhoA pathway. In the current study, we tested the hypothesis that activation of GPER induces coronary artery relaxation via inhibition of RhoA/Rho kinase pathway by cAMP downstream targets, exchange proteins directly activated by cAMP (Epac) as well as PKA. Our results show that Epac inhibitors, brefeldin A (BFA, 50 µM), or ESI-09 (20 µM), or CE3F4 (100 µM), all partially inhibited porcine coronary artery relaxation response to the selective GPER agonist, G-1 (0.3-3 µM); while concurrent administration of BFA and PKI (5 µM), a PKA inhibitor, almost completely blocked the relaxation effect of G-1. The Epac specific agonist, 8-CPT-2Me-cAMP (007, 1-100 µM), induced a concentration-dependent relaxation response. Furthermore, the activity of Ras-related protein 1 (Rap1) was up regulated by G-1 (1 µM) treatment of porcine coronary artery smooth muscle cells (CASMCs). Phosphorylation of vasodilator-stimulated phosphoprotein (p-VASP) was elevated by G-1 (1 µM) treatment, but not by 007 (50 µM); and the effect of G-1 on p-VASP was blocked by PKI, but not by ESI-09, an Epac antagonist. RhoA activity was similarly down regulated by G-1 and 007, whereas ESI-09 restored most of the reduced RhoA activity by G-1 treatment. Furthermore, G-1 decreased PGF2α-induced p-MYPT1, which was partially reversed with either ESI-09 or PKI; whereas, concurrent administration of ESI-09 and PKI totally prevented the inhibitory effect of G-1. The inhibitory effects of G-1 on p- MLC levels in CASMCs were mostly restored by either ESI-09 or PKI. These results demonstrate that activation of GPER induces coronary artery relaxation via concurrent inhibition of RhoA/Rho kinase by Epac/Rap1 and PKA. GPER could be a potential drug target for preventing and treating cardiovascular diseases.
[Mh] Termos MeSH primário: Vasos Coronários/fisiologia
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
Receptores Estrogênicos/metabolismo
Proteínas rap1 de Ligação ao GTP/metabolismo
Quinases Associadas a rho/metabolismo
Proteína rhoA de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
AMP Cíclico/análogos & derivados
AMP Cíclico/farmacologia
Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores
Ciclopentanos/farmacologia
Fatores de Troca do Nucleotídeo Guanina/antagonistas & inibidores
Fatores de Troca do Nucleotídeo Guanina/metabolismo
Hidrazonas/farmacologia
Isoxazóis/farmacologia
Músculo Liso Vascular/citologia
Músculo Liso Vascular/efeitos dos fármacos
Músculo Liso Vascular/metabolismo
Fosfatase de Miosina-de-Cadeia-Leve/metabolismo
Fosforilação/efeitos dos fármacos
Quinolinas/farmacologia
Interferência de RNA
RNA Interferente Pequeno/metabolismo
Transdução de Sinais/efeitos dos fármacos
Suínos
Tionucleotídeos/farmacologia
Proteínas rap1 de Ligação ao GTP/antagonistas & inibidores
Proteínas rap1 de Ligação ao GTP/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone); 0 (3-(5-tert-butylisoxazol-3-yl)-2-((3-chlorophenyl)hydrazono)-3-oxopropionitrile); 0 (Cyclopentanes); 0 (Guanine Nucleotide Exchange Factors); 0 (Hydrazones); 0 (Isoxazoles); 0 (Quinolines); 0 (RNA, Small Interfering); 0 (Receptors, Estrogen); 0 (Thionucleotides); 41941-66-6 (8-((4-chlorophenyl)thio)cyclic-3',5'-AMP); E0399OZS9N (Cyclic AMP); EC 2.7.11.1 (rho-Associated Kinases); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); EC 3.1.3.53 (Myosin-Light-Chain Phosphatase); EC 3.6.5.2 (rap1 GTP-Binding Proteins); EC 3.6.5.2 (rhoA GTP-Binding Protein)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170830
[Lr] Data última revisão:
170830
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170310
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0173085


  7 / 882 MEDLINE  
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[PMID]:28273099
[Au] Autor:Eppler FJ; Quast T; Kolanus W
[Ad] Endereço:Division of Molecular Immunology and Cell Biology, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany.
[Ti] Título:Dynamin2 controls Rap1 activation and integrin clustering in human T lymphocyte adhesion.
[So] Source:PLoS One;12(3):e0172443, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Leukocyte trafficking is crucial to facilitate efficient immune responses. Here, we report that the large GTPase dynamin2, which is generally considered to have a key role in endocytosis and membrane remodeling, is an essential regulator of integrin-dependent human T lymphocyte adhesion and migration. Chemical inhibition or knockdown of dynamin2 expression significantly reduced integrin-dependent T cell adhesion in vitro. This phenotype was not observed when T cells were treated with various chemical inhibitors which abrogate endocytosis or actin polymerization. We furthermore detected dynamin2 in signaling complexes and propose that it controls T cell adhesion via FAK/Pyk2- and RapGEF1-mediated Rap1 activation. In addition, the dynamin2 inhibitor-induced reduction of lymphocyte adhesion can be rescued by Rap1a overexpression. We demonstrate that the dynamin2 effect on T cell adhesion does not involve integrin affinity regulation but instead relies on its ability to modulate integrin valency. Taken together, we suggest a previously unidentified role of dynamin2 in the regulation of integrin-mediated lymphocyte adhesion via a Rap1 signaling pathway.
[Mh] Termos MeSH primário: Adesão Celular
Dinamina II/metabolismo
Integrinas/metabolismo
Linfócitos T/imunologia
Linfócitos T/metabolismo
Proteínas rap1 de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Transporte Biológico
Movimento Celular
Vesículas Citoplasmáticas/metabolismo
Quinase 2 de Adesão Focal/metabolismo
Proteína-Tirosina Quinases de Adesão Focal/metabolismo
Expressão Gênica
Genes Reporter
Seres Humanos
Ligação Proteica
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Integrins); EC 2.7.10.2 (Focal Adhesion Kinase 2); EC 2.7.10.2 (Focal Adhesion Protein-Tyrosine Kinases); EC 3.6.5.2 (rap1 GTP-Binding Proteins); EC 3.6.5.5 (Dynamin II)
[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:170309
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0172443


  8 / 882 MEDLINE  
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[PMID]:28263956
[Au] Autor:Lilja J; Zacharchenko T; Georgiadou M; Jacquemet G; De Franceschi N; Peuhu E; Hamidi H; Pouwels J; Martens V; Nia FH; Beifuss M; Boeckers T; Kreienkamp HJ; Barsukov IL; Ivaska J
[Ad] Endereço:Turku Centre for Biotechnology, University of Turku, FIN-20520 Turku, Finland.
[Ti] Título:SHANK proteins limit integrin activation by directly interacting with Rap1 and R-Ras.
[So] Source:Nat Cell Biol;19(4):292-305, 2017 Apr.
[Is] ISSN:1476-4679
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:SHANK3, a synaptic scaffold protein and actin regulator, is widely expressed outside of the central nervous system with predominantly unknown function. Solving the structure of the SHANK3 N-terminal region revealed that the SPN domain is an unexpected Ras-association domain with high affinity for GTP-bound Ras and Rap G-proteins. The role of Rap1 in integrin activation is well established but the mechanisms to antagonize it remain largely unknown. Here, we show that SHANK1 and SHANK3 act as integrin activation inhibitors by sequestering active Rap1 and R-Ras via the SPN domain and thus limiting their bioavailability at the plasma membrane. Consistently, SHANK3 silencing triggers increased plasma membrane Rap1 activity, cell spreading, migration and invasion. Autism-related mutations within the SHANK3 SPN domain (R12C and L68P) disrupt G-protein interaction and fail to counteract integrin activation along the Rap1-RIAM-talin axis in cancer cells and neurons. Altogether, we establish SHANKs as critical regulators of G-protein signalling and integrin-dependent processes.
[Mh] Termos MeSH primário: Integrina beta1/metabolismo
Proteínas do Tecido Nervoso/metabolismo
Proteínas rap1 de Ligação ao GTP/metabolismo
Proteínas ras/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Adesão Celular
Linhagem Celular
Movimento Celular
Extensões da Superfície Celular/metabolismo
Feminino
Citometria de Fluxo
Camundongos Endogâmicos C57BL
Modelos Biológicos
Mutação/genética
Proteínas do Tecido Nervoso/química
Proteínas do Tecido Nervoso/genética
Reação em Cadeia da Polimerase
Ligação Proteica
Domínios Proteicos
Ratos Wistar
Alinhamento de Sequência
Talina/metabolismo
Ubiquitinas/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Integrin beta1); 0 (Nerve Tissue Proteins); 0 (SHARPIN protein, human); 0 (Talin); 0 (Ubiquitins); EC 3.6.1.- (RRAS protein, human); EC 3.6.5.2 (rap1 GTP-Binding Proteins); EC 3.6.5.2 (ras 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:170307
[St] Status:MEDLINE
[do] DOI:10.1038/ncb3487


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[PMID]:28183814
[Au] Autor:Schmölders J; Manske C; Otto A; Hoffmann C; Steiner B; Welin A; Becher D; Hilbi H
[Ad] Endereço:From the ‡Max von Pettenkofer Institute, Ludwig-Maximilians University, Munich, Germany.
[Ti] Título:Comparative Proteomics of Purified Pathogen Vacuoles Correlates Intracellular Replication of with the Small GTPase Ras-related protein 1 (Rap1).
[So] Source:Mol Cell Proteomics;16(4):622-641, 2017 Apr.
[Is] ISSN:1535-9484
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:is an opportunistic bacterial pathogen that causes a severe lung infection termed "Legionnaires' disease." The pathogen replicates in environmental protozoa as well as in macrophages within a unique membrane-bound compartment, the -containing-vacuole (LCV). LCV formation requires the bacterial Icm/Dot type IV secretion system, which translocates ca. 300 "effector proteins" into host cells, where they target distinct host factors. The "pentuple" mutant (Δpentuple) lacks 5 gene clusters (31% of the effector proteins) and replicates in macrophages but not in amoeba. To elucidate the host factors defining a replication-permissive compartment, we compare here the proteomes of intact LCVs isolated from or macrophages infected with Δpentuple or the parental strain Lp02. This analysis revealed that the majority of host proteins are shared in or macrophage LCVs containing the mutant or the parental strain, respectively, whereas some proteins preferentially localize to distinct LCVs. The small GTPase Rap1 was identified on LCVs containing strain Lp02 but not the Δpentuple mutant and on macrophage LCVs containing either strain. The localization pattern of active Rap1 on or macrophage LCVs was confirmed by fluorescence microscopy and imaging flow cytometry, and the depletion of Rap1 by RNA interference significantly reduced the intracellular growth of Thus, comparative proteomics identified Rap1 as a novel LCV host component implicated in intracellular replication of .
[Mh] Termos MeSH primário: Proteínas de Bactérias/genética
Dictyostelium/metabolismo
Legionella pneumophila/fisiologia
Macrófagos/metabolismo
Proteínas Monoméricas de Ligação ao GTP/metabolismo
Proteômica/métodos
Vacúolos/microbiologia
Proteínas rap1 de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteínas de Bactérias/metabolismo
Cromatografia Líquida
Replicação do DNA
Dictyostelium/microbiologia
Deleção de Genes
Legionella pneumophila/genética
Doença dos Legionários/microbiologia
Macrófagos/microbiologia
Camundongos
Proteínas de Protozoários/metabolismo
Células RAW 264.7
Espectrometria de Massas em Tandem
Vacúolos/metabolismo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Protozoan Proteins); EC 3.6.5.2 (Monomeric GTP-Binding Proteins); EC 3.6.5.2 (Rap1 protein, mouse); EC 3.6.5.2 (rap1 GTP-Binding Proteins)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170627
[Lr] Data última revisão:
170627
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170211
[St] Status:MEDLINE
[do] DOI:10.1074/mcp.M116.063453


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[PMID]:28178039
[Au] Autor:Chrzanowska-Wodnicka M
[Ad] Endereço:Blood Research Institute, BloodCenter of Wisconsin, Part of Versiti, Milwaukee, Wisconsin.
[Ti] Título:Rap1 in endothelial biology.
[So] Source:Curr Opin Hematol;24(3):248-255, 2017 May.
[Is] ISSN:1531-7048
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE OF REVIEW: Ubiquitously-expressed small GTPase Rap1 is a key modulator of integrin- and cadherin-regulated processes. In endothelium, Rap1 promotes angiogenesis and endothelial barrier function, acting downstream from cAMP-activated Rap1GEF, Epac. Recent in-vivo studies in mouse models have provided more information about the physiological role of Rap1 in vessel development and after birth under normal and pathologic conditions. Important molecular details of dynamic regulation of endothelial barrier are uncovered. RECENT FINDINGS: Rap1 is not essential for initial vessel formation but is critical for vessel stabilization, as double knockout of the two Rap1 isoforms leads to hemorrhage and embryonic lethality. After development, Rap1 is not required for endothelial barrier maintenance but is critical for nitric oxide production and endothelial function. Radil and Afadin mediate Rap1 effects on endothelial barrier function by regulating connection with Rho GTPases, actomyosin cytoskeleton, and cell-cell adhesion receptors. SUMMARY: Rap1 is critically required for nitric oxide release and normal endothelial function in vivo. Mechanistic studies lead to a novel paradigm of Rap1 as a critical regulator of endothelial cell shear stress responses and endothelial homeostasis. Increased understanding of molecular mechanisms underlying endothelial barrier regulation may identify novel pharmacological targets for retinopathies and conditions with altered endothelial barrier function or when increased endothelial barrier is desired.
[Mh] Termos MeSH primário: Células Endoteliais/metabolismo
Proteínas rap1 de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Junções Aderentes/metabolismo
Animais
Biomarcadores
Proteínas de Transporte/metabolismo
Seres Humanos
Inflamação/metabolismo
Inflamação/patologia
Proteínas dos Microfilamentos/metabolismo
Neovascularização Patológica/genética
Neovascularização Patológica/metabolismo
Neovascularização Patológica/patologia
Neovascularização Fisiológica
Óxido Nítrico/metabolismo
Ligação Proteica
Resistência ao Cisalhamento
Transdução de Sinais
Estresse Fisiológico/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Biomarkers); 0 (Carrier Proteins); 0 (Microfilament Proteins); 0 (afadin); 31C4KY9ESH (Nitric Oxide); EC 3.6.5.2 (rap1 GTP-Binding Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170209
[St] Status:MEDLINE
[do] DOI:10.1097/MOH.0000000000000332



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