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[PMID]:29196264
[Au] Autor:de Oliveira AS; de Almeida VH; Gomes FG; Rezaie AR; Monteiro RQ
[Ad] Endereço:Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
[Ti] Título:TR47, a PAR1-based peptide, inhibits melanoma cell migration in vitro and metastasis in vivo.
[So] Source:Biochem Biophys Res Commun;495(1):1300-1304, 2018 01 01.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Activated Protein C (APC) is a serine-protease that displays antithrombotic and anti-inflammatory properties. In addition, cleavage of protease-activated receptor 1 (PAR1) by APC exerts endothelial cytoprotective actions. The effects of APC on endothelial cells may be reproduced by TR47, a PAR1-based peptide that mimics the novel N-terminus of PAR1 generated upon cleavage at Arg-46 by APC. In this study we demonstrate that wild-type APC and its signaling-proficient mutant, APC-2Cys (which has dramatically reduced anticoagulant activity), display similar inhibitory effects towards the transendothelial migration of A375 human melanoma cells. Consistent with this observation, APC and APC-2Cys significantly reduced the in vivo metastatic potential of the B16F10 murine melanoma cells. TR47 recapitulated the in vitro and in vivo protective profiles of APC and APC-2Cys. Treatment of EA.hy926 endothelial cells with TR47 (20 µM) significantly decreased the A375 cell migration. In addition, treatment of C57/BL6 mice with a single TR47 dose (125 µg/animal) strongly reduced the metastatic burden of B16F10 cells. Together, our results suggest that protection of the endothelial barrier by APC/TR47-mediated signaling pathways might be a valuable therapeutic approach to prevent metastasis.
[Mh] Termos MeSH primário: Movimento Celular/efeitos dos fármacos
Transformação Celular Neoplásica/efeitos dos fármacos
Melanoma/metabolismo
Melanoma/secundário
Peptídeos/administração & dosagem
Receptor PAR-1/química
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Transformação Celular Neoplásica/metabolismo
Transformação Celular Neoplásica/patologia
Seres Humanos
Melanoma/patologia
Camundongos
Camundongos Endogâmicos C57BL
Invasividade Neoplásica/patologia
Peptídeos/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 (Peptides); 0 (Receptor, PAR-1)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180210
[Lr] Data última revisão:
180210
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171203
[St] Status:MEDLINE


  2 / 1731 MEDLINE  
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[PMID]:27770804
[Au] Autor:Natarajan K; Gottipati KR; Berhane K; Samten B; Pendurthi U; Boggaram V
[Ad] Endereço:Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, 11937 US Highway 271, Tyler, TX, 75708-3154, USA.
[Ti] Título:Proteases and oxidant stress control organic dust induction of inflammatory gene expression in lung epithelial cells.
[So] Source:Respir Res;17(1):137, 2016 10 22.
[Is] ISSN:1465-993X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Persistant inflammatory responses to infectious agents and other components in organic dust underlie lung injury and development of respiratory diseases. Organic dust components responsible for eliciting inflammation and the mechanisms by which they cause lung inflammation are not fully understood. We studied the mechanisms by which protease activities in poultry dust extracts and intracellular oxidant stress induce inflammatory gene expression in A549 and Beas2B lung epithelial cells. METHODS: The effects of dust extracts on inflammatory gene expression were analyzed by quantitative polymerase chain reaction (qPCR), enzyme linked immunosorbent (ELISA) and western blot assays. Oxidant stress was probed by dihydroethidium (DHE) labeling, and immunostaining for 4-hydroxynonenal (4-HNE). Effects on interleukin-8 (IL-8) promoter regulation were determined by transient transfection assay. RESULTS: Dust extracts contained trypsin and elastase activities, and activated protease activated receptor (PAR)-1 and -2. Serine protease inhibitors and PAR-1 or PAR-2 knockdown suppressed inflammatory gene induction. Dust extract induction of IL-8 gene expression was associated with increased DHE-fluorescence and 4-HNE staining, and antioxidants suppressed inflammatory gene induction. Protease inhibitors and antioxidants suppressed protein kinase C and NF-κB activation and induction of IL-8 promoter activity in cells exposed to dust extract. CONCLUSIONS: Our studies demonstrate that proteases and intracellular oxidants control organic dust induction of inflammatory gene expression in lung epithelial cells. Targeting proteases and oxidant stress may serve as novel approaches for the treatment of organic dust induced lung diseases. This is the first report on the involvement of oxidant stress in the induction of inflammatory gene expression by organic dust.
[Mh] Termos MeSH primário: Poeira
Células Epiteliais/efeitos dos fármacos
Mediadores da Inflamação/metabolismo
Pulmão/efeitos dos fármacos
Compostos Orgânicos/toxicidade
Estresse Oxidativo/efeitos dos fármacos
Peptídeo Hidrolases/metabolismo
Pneumonia/induzido quimicamente
[Mh] Termos MeSH secundário: Células A549
Animais
Anti-Inflamatórios/farmacologia
Antioxidantes/farmacologia
Células Epiteliais/enzimologia
Regulação da Expressão Gênica
Abrigo para Animais
Seres Humanos
Exposição por Inalação/efeitos adversos
Interleucina-8/genética
Interleucina-8/metabolismo
Pulmão/enzimologia
Metaloproteinases da Matriz/genética
Metaloproteinases da Matriz/metabolismo
Pneumonia/enzimologia
Pneumonia/genética
Pneumonia/prevenção & controle
Aves Domésticas
Receptor PAR-1/genética
Receptor PAR-1/metabolismo
Receptor PAR-2/genética
Receptor PAR-2/metabolismo
Inibidores de Serino Proteinase/farmacologia
Transdução de Sinais/efeitos dos fármacos
Fatores de Tempo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, U.S. GOV'T, P.H.S.
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents); 0 (Antioxidants); 0 (Dust); 0 (IL8 protein, human); 0 (Inflammation Mediators); 0 (Interleukin-8); 0 (Organic Chemicals); 0 (Receptor, PAR-1); 0 (Receptor, PAR-2); 0 (Serine Proteinase Inhibitors); EC 3.4.- (Peptide Hydrolases); EC 3.4.24.- (Matrix Metalloproteinases)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180208
[Lr] Data última revisão:
180208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE


  3 / 1731 MEDLINE  
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[PMID]:29242206
[Au] Autor:Lentz SR
[Ad] Endereço:UNIVERSITY OF IOWA.
[Ti] Título:On PAR with aPC to target inflammasomes.
[So] Source:Blood;130(24):2579-2581, 2017 12 14.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Inflamassomos
Receptor PAR-1
[Mh] Termos MeSH secundário: Proteína C
[Pt] Tipo de publicação:JOURNAL ARTICLE; COMMENT
[Nm] Nome de substância:
0 (Inflammasomes); 0 (Protein C); 0 (Receptor, PAR-1)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180118
[Lr] Data última revisão:
180118
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171216
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2017-09-806307


  4 / 1731 MEDLINE  
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[PMID]:28918742
[Au] Autor:Gorbacheva LR; Kiseleva EV; Savinkova IG; Strukova SM
[Ad] Endereço:Lomonosov Moscow State University, Faculty of Biology, Moscow, 119991, Russia. sstrukova@yahoo.com.
[Ti] Título:A New Concept of Action of Hemostatic Proteases on Inflammation, Neurotoxicity, and Tissue Regeneration.
[So] Source:Biochemistry (Mosc);82(7):778-790, 2017 Jul.
[Is] ISSN:1608-3040
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Key hemostatic serine proteases such as thrombin and activated protein C (APC) are signaling molecules controlling blood coagulation and inflammation, tissue regeneration, neurodegeneration, and some other processes. By interacting with protease-activated receptors (PARs), these enzymes cleave a receptor exodomain and liberate new amino acid sequence known as a tethered ligand, which then activates the initial receptor and induces multiple signaling pathways and cell responses. Among four PAR family members, APC and thrombin mainly act via PAR1, and they trigger divergent effects. APC is an anticoagulant with antiinflammatory and cytoprotective activity, whereas thrombin is a protease with procoagulant and proinflammatory effects. Hallmark features of APC-induced effects result from acting via different pathways: limited proteolysis of PAR1 localized in membrane caveolae with coreceptor (endothelial protein C receptor) as well as its targeted proteolytic action at a receptor exodomain site differing from the canonical thrombin cleavage site. Hence, a new noncanonical tethered PAR1 agonist peptide (PAR1-AP) is formed, whose effects are poorly investigated in inflammation, tissue regeneration, and neurotoxicity. In this review, a concept about a role of biased agonism in effects exerted by APC and PAR1-AP via PAR1 on cells involved in inflammation and related processes is developed. New evidence showing a role for a biased agonism in activating PAR1 both by APC and PAR1-AP as well as induction of antiinflammatory and cytoprotective cellular responses in experimental inflammation, wound healing, and excitotoxicity is presented. It seems that synthetic PAR1 peptide-agonists may compete with APC in controlling some inflammatory and neurodegenerative diseases.
[Mh] Termos MeSH primário: Inflamação
Proteína C/metabolismo
Regeneração/fisiologia
Trombina/metabolismo
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Fatores de Coagulação Sanguínea/agonistas
Fatores de Coagulação Sanguínea/metabolismo
Ácido Glutâmico/toxicidade
Seres Humanos
Mastócitos/citologia
Mastócitos/efeitos dos fármacos
Mastócitos/metabolismo
Fármacos Neuroprotetores/farmacologia
Receptor PAR-1/agonistas
Receptor PAR-1/metabolismo
Receptores de Superfície Celular/agonistas
Receptores de Superfície Celular/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Blood Coagulation Factors); 0 (Neuroprotective Agents); 0 (Protein C); 0 (Receptor, PAR-1); 0 (Receptors, Cell Surface); 0 (activated protein C receptor); 3KX376GY7L (Glutamic Acid); EC 3.4.21.5 (Thrombin)
[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:170919
[St] Status:MEDLINE
[do] DOI:10.1134/S0006297917070033


  5 / 1731 MEDLINE  
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[PMID]:28818855
[Au] Autor:van den Eshof BL; Hoogendijk AJ; Simpson PJ; van Alphen FPJ; Zanivan S; Mertens K; Meijer AB; van den Biggelaar M
[Ad] Endereço:From the Department Plasma Proteins (B.L.v.d.E., A.J.H., P.J.S., K.M., A.B.M., M.v.d.B.), Department of Research Facilities (F.P.J.v.A., A.B.M.), Sanquin Research, Amsterdam, The Netherlands; Tumour Microenvironment and Proteomics Laboratory, Cancer Research UK Beatson Institute, Glasgow, United Kin
[Ti] Título:Paradigm of Biased PAR1 (Protease-Activated Receptor-1) Activation and Inhibition in Endothelial Cells Dissected by Phosphoproteomics.
[So] Source:Arterioscler Thromb Vasc Biol;37(10):1891-1902, 2017 Oct.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Thrombin is the key serine protease of the coagulation cascade and mediates cellular responses by activation of PARs (protease-activated receptors). The predominant thrombin receptor is PAR1, and in endothelial cells (ECs), thrombin dynamically regulates a plethora of phosphorylation events. However, it has remained unclear whether thrombin signaling is exclusively mediated through PAR1. Furthermore, mechanistic insight into activation and inhibition of PAR1-mediated EC signaling is lacking. In addition, signaling networks of biased PAR1 activation after differential cleavage of the PAR1 N terminus have remained an unresolved issue. APPROACH AND RESULTS: Here, we used a quantitative phosphoproteomics approach to show that classical and peptide activation of PAR1 induce highly similar signaling, that low thrombin concentrations initiate only limited phosphoregulation, and that the PAR1 inhibitors vorapaxar and parmodulin-2 demonstrate distinct antagonistic properties. Subsequent analysis of the thrombin-regulated phosphosites in the presence of PAR1 inhibitors revealed that biased activation of PAR1 is not solely linked to a specific G-protein downstream of PAR1. In addition, we showed that only the canonical thrombin PAR1 tethered ligand induces extensive early phosphoregulation in ECs. CONCLUSIONS: Our study provides detailed insight in the signaling mechanisms downstream of PAR1. Our data demonstrate that thrombin-induced EC phosphoregulation is mediated exclusively through PAR1, that thrombin and thrombin-tethered ligand peptide induce similar phosphoregulation, and that only canonical PAR1 cleavage by thrombin generates a tethered ligand that potently induces early signaling. Furthermore, platelet PAR1 inhibitors directly affect EC signaling, indicating that it will be a challenge to design a PAR1 antagonist that will target only those pathways responsible for tissue pathology.
[Mh] Termos MeSH primário: Células Endoteliais/fisiologia
Receptor PAR-1/antagonistas & inibidores
Receptor PAR-1/fisiologia
[Mh] Termos MeSH secundário: Seres Humanos
Lactonas/farmacologia
Fosforilação
Proteômica
Piridinas/farmacologia
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lactones); 0 (Pyridines); 0 (Receptor, PAR-1); ZCE93644N2 (vorapaxar)
[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:170819
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.117.309926


  6 / 1731 MEDLINE  
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[PMID]:28697175
[Au] Autor:Jiang L; Luan Y; Miao X; Sun C; Li K; Huang Z; Xu D; Zhang M; Kong F; Li N
[Ad] Endereço:Department of Medicine-Solna, Clinical Pharmacology Group, Karolinska University Hospital-Solna, Karolinska Institutet, Stockholm 171 76, Sweden.
[Ti] Título:Platelet releasate promotes breast cancer growth and angiogenesis via VEGF-integrin cooperative signalling.
[So] Source:Br J Cancer;117(5):695-703, 2017 Aug 22.
[Is] ISSN:1532-1827
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Selective platelet release of pro- or anti-angiogenic factors distinctly regulated angiogenesis. We hypothesised that selective release of platelet angiogenic factors could differently regulate tumour growth. METHODS: Breast cancer cell proliferation, cancer cell-induced endothelial tube formation in vitro, and tumour growth in vivo were studied in the presence of protease-activated receptor 1-stimulated platelet releasate (PAR1-PR; rich in pro-angiogenic factors) or PAR4-PR (rich in anti-angiogenic factors). RESULTS: The PAR1-PR and PAR4-PR supplementation (10%) similarly enhanced cell proliferation of MCF-7 and MDA-MB-231 breast cancer cells. The cancer cells triggered capillary-like tube formation of endothelial cells that was further enhanced by pro-angiogenic factor-rich PAR1-PR. The VEGF, but not SDF-1α, receptor blockade abolished PAR1-PR/PAR4-PR-enhanced cancer cell proliferation. Integrin blockade by RGDS had identical effects as VEGF inhibition. The Src and ERK inhibition diminished, whereas PI3K and PKC blockade abolished platelet releasate-enhanced cancer cell proliferation. Using a model of subcutaneous implantation of MDA-MB-231 cells in nude mice, PAR1-PR enhanced tumour growth more markedly than PAR4-PR, and seemed to achieve the exaggeration by promoting more profound tumour angiogenesis. CONCLUSIONS: Platelet releasate increases breast cancer cell proliferation through VEGF-integrin cooperative signalling. Pro-angiogenic factor-rich platelet releasate enhances cancer cell-induced angiogenesis more markedly, and thus exaggerates tumour growth in vivo.
[Mh] Termos MeSH primário: Plaquetas/metabolismo
Neoplasias da Mama/metabolismo
Integrinas/metabolismo
Neovascularização Patológica/metabolismo
Receptor PAR-1/metabolismo
Receptores de Trombina/metabolismo
Fator A de Crescimento do Endotélio Vascular/metabolismo
[Mh] Termos MeSH secundário: Adulto
Animais
Plaquetas/efeitos dos fármacos
Neoplasias da Mama/irrigação sanguínea
Neoplasias da Mama/patologia
Proliferação Celular
Células Endoteliais/efeitos dos fármacos
Células Endoteliais/fisiologia
Feminino
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Integrinas/antagonistas & inibidores
Células MCF-7
Masculino
Camundongos
Camundongos Nus
Meia-Idade
Oligopeptídeos/farmacologia
Compostos de Fenilureia/farmacologia
Fosfatidilinositol 3-Quinases/metabolismo
Proteína Quinase C/metabolismo
Quinolinas/farmacologia
Receptores CXCR4/antagonistas & inibidores
Transdução de Sinais
Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CXCR4 protein, human); 0 (Integrins); 0 (N-(2,4-difluorophenyl)-N'-(4-((6,7-dimethoxy-4-quinolyl)oxy)-2-fluorophenyl)urea); 0 (Oligopeptides); 0 (Phenylurea Compounds); 0 (Quinolines); 0 (Receptor, PAR-1); 0 (Receptors, CXCR4); 0 (Receptors, Thrombin); 0 (Vascular Endothelial Growth Factor A); 0 (protease-activated receptor 4); AC6UDA2MFC (arginyl-glycyl-aspartyl-serine); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2); EC 2.7.11.13 (Protein Kinase C)
[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:170712
[St] Status:MEDLINE
[do] DOI:10.1038/bjc.2017.214


  7 / 1731 MEDLINE  
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[PMID]:28670703
[Au] Autor:Wang T; Jiao J; Zhang H; Zhou W; Li Z; Han S; Wang J; Yang X; Huang Q; Wu Z; Yan W; Xiao J
[Ad] Endereço:Department of Bone Tumor Surgery, Changzheng Hospital, Second MilitaryMedical University, Shanghai, China.
[Ti] Título:TGF-ß induced PAR-1 expression promotes tumor progression and osteoclast differentiation in giant cell tumor of bone.
[So] Source:Int J Cancer;141(8):1630-1642, 2017 Oct 15.
[Is] ISSN:1097-0215
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Although protease activated receptor-1 (PAR-1) has been confirmed as an oncogene in many cancers, the role of PAR-1 in giant cell tumor (GCT) of bone has been rarely reported. The mechanism of PAR-1 in tumor-induced osteoclastogenesis still remains unclear. In the present study, we detected that PAR-1 was significantly upregulated in GCT of bone compared to normal tissues, while TGF-ß was also overexpressed in GCT tissues and could promote the expression of PAR-1 in a dose and time dependent manner. Using the luciferase reporter assay, we found that two downstreams of TGF-ß, Smad3 and Smad4, could activate the promoter of PAR-1, which might explain the mechanism of TGF-ß induced PAR-1 expression. Meanwhile, PAR-1 was also overexpressed in microvesicles from stromal cells of GCT (GCTSCs), and might be transported from GCTSCs to monocytes through microvesicles. In addition, knockout of PAR-1 by TALENs in GCTSCs inhibited tumor growth, angiogenesis and osteoclastogenesis in GCT in vitro. Using the chick CAM models, we further showed that inhibition of PAR-1 suppressed tumor growth and giant cell formation in vivo. Using microarray assay, we detected a number of genes involved in osteoclastogenesis as the possible downstreams of PAR-1, which may partly explain the mechanism of PAR-1 in GCT. In brief, for the first time, these results reveal an upstream regulatory role of TGF-ß in PAR-1 expression, and PAR-1 expression promotes tumor growth, angiogenesis and osteoclast differentiation in GCT of bone. Hence, PAR-1 represents a novel potential therapeutic target for GCT of bone.
[Mh] Termos MeSH primário: Neoplasias Ósseas/patologia
Tumor de Células Gigantes do Osso/patologia
Osteoclastos/patologia
Receptor PAR-1/biossíntese
Fator de Crescimento Transformador beta/metabolismo
[Mh] Termos MeSH secundário: Adulto
Animais
Neoplasias Ósseas/genética
Neoplasias Ósseas/metabolismo
Diferenciação Celular/fisiologia
Embrião de Galinha
Progressão da Doença
Técnicas de Silenciamento de Genes
Tumor de Células Gigantes do Osso/genética
Tumor de Células Gigantes do Osso/metabolismo
Células HEK293
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Meia-Idade
Osteoclastos/metabolismo
Fator de Crescimento Transformador beta/biossíntese
Fator de Crescimento Transformador beta/genética
Células Tumorais Cultivadas
Regulação para Cima
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptor, PAR-1); 0 (Transforming Growth Factor beta)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170704
[St] Status:MEDLINE
[do] DOI:10.1002/ijc.30862


  8 / 1731 MEDLINE  
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[PMID]:28652403
[Au] Autor:Smith TH; Li JG; Dores MR; Trejo J
[Ad] Endereço:From the Biomedical Sciences Graduate Program and.
[Ti] Título:Protease-activated receptor-4 and purinergic receptor P2Y12 dimerize, co-internalize, and activate Akt signaling via endosomal recruitment of ß-arrestin.
[So] Source:J Biol Chem;292(33):13867-13878, 2017 Aug 18.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Vascular inflammation and thrombosis require the concerted actions of several different agonists, many of which act on G protein-coupled receptors (GPCRs). GPCR dimerization is a well-established phenomenon that can alter protomer function. In platelets and other cell types, protease-activated receptor-4 (PAR4) has been shown to dimerize with the purinergic receptor P2Y12 to coordinate ß-arrestin-mediated Akt signaling, an important mediator of integrin activation. However, the mechanism by which the PAR4-P2Y12 dimer controls ß-arrestin-dependent Akt signaling is not known. We now report that PAR4 and P2Y12 heterodimer internalization is required for ß-arrestin recruitment to endosomes and Akt signaling. Using bioluminescence resonance energy transfer, immunofluorescence microscopy, and co-immunoprecipitation in cells expressing receptors exogenously and endogenously, we demonstrate that PAR4 and P2Y12 specifically interact and form dimers expressed at the cell surface. We also found that activation of PAR4 but not of P2Y12 drives internalization of the PAR4-P2Y12 heterodimer. Remarkably, activated PAR4 internalization was required for recruitment of ß-arrestin to endocytic vesicles, which was dependent on co-expression of P2Y12. Interestingly, stimulation of the PAR4-P2Y12 heterodimer promotes ß-arrestin and Akt co-localization to intracellular vesicles. Moreover, activated PAR4-P2Y12 internalization is required for sustained Akt activation. Thus, internalization of the PAR4-P2Y12 heterodimer is necessary for ß-arrestin recruitment to endosomes and Akt signaling and lays the foundation for examining whether blockade of PAR4 internalization reduces integrin and platelet activation.
[Mh] Termos MeSH primário: Endocitose
Proteínas Proto-Oncogênicas c-akt/agonistas
Receptores Purinérgicos P2Y12/metabolismo
Receptores de Trombina/agonistas
Transdução de Sinais
beta-Arrestina 2/metabolismo
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Técnicas de Transferência de Energia por Ressonância de Bioluminescência
Células COS
Linhagem Celular Tumoral
Cercopithecus aethiops
Endossomos/metabolismo
Seres Humanos
Imunoprecipitação
Microscopia de Fluorescência
Multimerização Proteica
Transporte Proteico
Proteínas Proto-Oncogênicas c-akt/metabolismo
Receptor PAR-1/agonistas
Receptor PAR-1/química
Receptor PAR-1/genética
Receptor PAR-1/metabolismo
Receptores Purinérgicos P2Y12/química
Receptores Purinérgicos P2Y12/genética
Receptores de Trombina/química
Receptores de Trombina/genética
Receptores de Trombina/metabolismo
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
beta-Arrestina 2/química
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ARRB2 protein, human); 0 (P2RY12 protein, human); 0 (Receptor, PAR-1); 0 (Receptors, Purinergic P2Y12); 0 (Receptors, Thrombin); 0 (Recombinant Fusion Proteins); 0 (beta-Arrestin 2); 0 (protease-activated receptor 4); EC 2.7.11.1 (AKT1 protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170628
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.782359


  9 / 1731 MEDLINE  
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[PMID]:28558960
[Au] Autor:Flaumenhaft R; De Ceunynck K
[Ad] Endereço:Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. Electronic address: rflaumen@bidmc.harvard.edu.
[Ti] Título:Targeting PAR1: Now What?
[So] Source:Trends Pharmacol Sci;38(8):701-716, 2017 Aug.
[Is] ISSN:1873-3735
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Protease-activated receptors (PARs) are a ubiquitously expressed class of G-protein-coupled receptors (GPCRs) that enable cells to respond to proteases in the extracellular environment in a nuanced and dynamic manner. PAR1 is the archetypal family member and has been the object of large-scale drug development programs since the 1990s. Vorapaxar and drotrecogin-alfa are approved PAR1-targeted therapeutics, but safety concerns have limited the clinical use of vorapaxar and questions regarding the efficacy of drotrecogin-alfa led to its withdrawal from the market. New understanding of mechanisms of PAR1 function, discovery of improved strategies for modifying PAR1 function, and identification of novel indications for PAR1 modulators have provided new opportunities for therapies targeting PAR1. In this review, we critically evaluate prospects for the next generation of PAR1-targeted therapeutics.
[Mh] Termos MeSH primário: Peptídeos/farmacologia
Receptor PAR-1/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Lactonas/farmacologia
Terapia de Alvo Molecular
Proteína C/farmacologia
Piridinas/farmacologia
Proteínas Recombinantes/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Lactones); 0 (Peptides); 0 (Protein C); 0 (Pyridines); 0 (Receptor, PAR-1); 0 (Recombinant Proteins); JGH8MYC891 (drotrecogin alfa activated); ZCE93644N2 (vorapaxar)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170601
[St] Status:MEDLINE


  10 / 1731 MEDLINE  
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[PMID]:28507169
[Au] Autor:Grechowa I; Horke S; Wallrath A; Vahl CF; Dorweiler B
[Ad] Endereço:Division of Vascular Surgery, Department of Cardiothoracic and Vascular Surgery, University Medical Center, Johannes-Gutenberg University, Mainz, Germany.
[Ti] Título:Human neutrophil elastase induces endothelial cell apoptosis by activating the PERK-CHOP branch of the unfolded protein response.
[So] Source:FASEB J;31(9):3868-3881, 2017 Sep.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human neutrophil elastase impacts on atherosclerotic plaque stability by inducing apoptosis in endothelial cells. Our aim was to investigate the proapoptotic mechanism of elastase on endothelial cells and to evaluate the presence of elastase in human plaque material. Human endothelial cells were treated with purified human neutrophil elastase. Apoptosis was assayed by capsase-3/7 activation, TUNEL, and sub-G assay. Activation of unfolded protein response (UPR) effector molecules binding Ig protein, soluble X-binding protein-1, protein kinase RNA-like ER kinase (PERK), and C/EBP-homologous protein (CHOP) was analyzed by RT-PCR, immunocytochemistry, and Western blot. Genetic silencing of CHOP was achieved by small interfering RNA. Elastase induces autophagic-apoptotic forms of endothelial cell death in a time- and dose-dependent manner, in conjunction with a significant increase in phosphorylation/expression of the canonical UPR-activation markers PERK and CHOP. By using CHOP knockdown, we identified CHOP as a key mediator of elastase-induced endothelial cell death. Immunohistochemical analysis of human rupture-prone plaque specimens confirmed the presence of elastase and colocalization with apoptosis. We have demonstrated for the first time that the PERK-CHOP branch of the UPR is causally involved in elastase-induced apoptosis of endothelial cells. analysis of human rupture-prone plaques confirmed the presence of elastase and its colocalization with markers of apoptosis. This novel role of elastase underlines the potential of combined targeting of elastase and endoplasmic reticulum stress in the prevention of plaque progression and cardiovascular events.-Grechowa, I., Horke, S., Wallrath, A., Vahl, C.-F., Dorweiler, B. Human neutrophil elastase induces endothelial cell apoptosis by activating the PERK-CHOP branch of the unfolded protein response.
[Mh] Termos MeSH primário: Apoptose/fisiologia
Células Endoteliais/enzimologia
Elastase de Leucócito/metabolismo
Fator de Transcrição CHOP/metabolismo
Resposta a Proteínas não Dobradas/fisiologia
eIF-2 Quinase/metabolismo
[Mh] Termos MeSH secundário: Aterosclerose/patologia
Artérias Carótidas/patologia
Caspase 3/genética
Caspase 3/metabolismo
Caspase 7/genética
Caspase 7/metabolismo
Linhagem Celular
Sobrevivência Celular
Células Endoteliais/fisiologia
Regulação Enzimológica da Expressão Gênica/fisiologia
Seres Humanos
Elastase de Leucócito/genética
Receptor PAR-1
Receptor PAR-2
Fator de Transcrição CHOP/genética
eIF-2 Quinase/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DDIT3 protein, human); 0 (Receptor, PAR-1); 0 (Receptor, PAR-2); 147336-12-7 (Transcription Factor CHOP); EC 2.7.11.1 (PERK kinase); EC 2.7.11.1 (eIF-2 Kinase); EC 3.4.21.37 (Leukocyte Elastase); EC 3.4.22.- (Caspase 3); EC 3.4.22.- (Caspase 7)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170517
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201700012R



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