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Pesquisa : G02.111.570.820.709.275.500.480 [Categoria DeCS]
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  1 / 12 MEDLINE  
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[PMID]:28465343
[Au] Autor:Coxon CH; Geer MJ; Senis YA
[Ad] Endereço:Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Headington, United Kingdom; and.
[Ti] Título:ITIM receptors: more than just inhibitors of platelet activation.
[So] Source:Blood;129(26):3407-3418, 2017 06 29.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Since their discovery, immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptors have been shown to inhibit signaling from immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors in almost all hematopoietic cells, including platelets. However, a growing body of evidence has emerged demonstrating that this is an oversimplification, and that ITIM-containing receptors are versatile regulators of platelet signal transduction, with functions beyond inhibiting ITAM-mediated platelet activation. PECAM-1 was the first ITIM-containing receptor identified in platelets and appeared to conform to the established model of ITIM-mediated attenuation of ITAM-driven activation. PECAM-1 was therefore widely accepted as a major negative regulator of platelet activation and thrombosis for many years, but more recent findings suggest a more complex role for this receptor, including the facilitation of α ß -mediated platelet functions. Since the identification of PECAM-1, several other ITIM-containing platelet receptors have been discovered. These include G6b-B, a critical regulator of platelet reactivity and production, and the noncanonical ITIM-containing receptor TREM-like transcript-1, which is localized to α-granules in resting platelets, binds fibrinogen, and acts as a positive regulator of platelet activation. Despite structural similarities and shared binding partners, including the Src homology 2 domain-containing protein-tyrosine phosphatases Shp1 and Shp2, knockout and transgenic mouse models have revealed distinct phenotypes and nonredundant functions for each ITIM-containing receptor in the context of platelet homeostasis. These roles are likely influenced by receptor density, compartmentalization, and as-yet unknown binding partners. In this review, we discuss the diverse repertoire of ITIM-containing receptors in platelets, highlighting intriguing new functions, controversies, and future areas of investigation.
[Mh] Termos MeSH primário: Motivo de Inibição do Imunorreceptor Baseado em Tirosina/fisiologia
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Motivo de Ativação do Imunorreceptor Baseado em Tirosina
Ativação Plaquetária
Inibidores da Agregação de Plaquetas
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Platelet Aggregation Inhibitors)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180113
[Lr] Data última revisão:
180113
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2016-12-720185


  2 / 12 MEDLINE  
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[PMID]:27558333
[Au] Autor:Favier B
[Ad] Endereço:CEA, DRF, IMETI, IMVA, UMR 1184, INSERM, Université Paris-Sud, IDMIT Infrastructure, Fontenay-aux-Roses, France.
[Ti] Título:Regulation of neutrophil functions through inhibitory receptors: an emerging paradigm in health and disease.
[So] Source:Immunol Rev;273(1):140-55, 2016 09.
[Is] ISSN:1600-065X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Neutrophils are the most abundant subset of leukocytes and play a crucial role in the immune responses against the daily pathogen attacks faced by the host. Neutrophils exhibit several functions for fighting microbes, including the release of granules containing highly toxic molecules, the production of reactive oxygen species and inflammatory cytokines as well as NETosis. Therefore, immune responses mediated by neutrophils must be tightly regulated to protect the host from pathogen assaults without inducing detrimental inflammation and tissue damage. There is now compelling evidence showing that neutrophils express various inhibitory receptors that specifically control their functions. Some of these inhibitory receptors are contained in the membrane of granules and rapidly move to the cell surface upon neutrophil stimulation. This fast upregulation of inhibitory receptors is an efficient way to rapidly enhance inhibitory signals and increase the neutrophil activation threshold. However, because of their ability to attenuate the immune responses of neutrophils, the inhibitory receptors are attractive target for pathogens. This review discusses these various aspects with a particular emphasis on the regulation of neutrophil behavior through immunoreceptor tyrosine-based inhibition motif (ITIM)-bearing inhibitory receptors belonging to LILR and SIGLEC multi-gene families in humans and animal models.
[Mh] Termos MeSH primário: Motivo de Inibição do Imunorreceptor Baseado em Tirosina/genética
Neutrófilos/imunologia
Receptores Imunológicos/metabolismo
Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo
[Mh] Termos MeSH secundário: Animais
Citocinas/metabolismo
Armadilhas Extracelulares/metabolismo
Seres Humanos
Imunidade Inata
Receptores Imunológicos/genética
Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/genética
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cytokines); 0 (Receptors, Immunologic); 0 (Sialic Acid Binding Immunoglobulin-like Lectins); 0 (leukocyte-immunoglobulin--like receptor 6)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160826
[St] Status:MEDLINE
[do] DOI:10.1111/imr.12457


  3 / 12 MEDLINE  
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[PMID]:25980030
[Au] Autor:Zenarruzabeitia O; Vitallé J; Eguizabal C; Simhadri VR; Borrego F
[Ad] Endereço:Immunopathology Group, BioCruces Health Research Institute, Barakaldo 48903, Spain;
[Ti] Título:The Biology and Disease Relevance of CD300a, an Inhibitory Receptor for Phosphatidylserine and Phosphatidylethanolamine.
[So] Source:J Immunol;194(11):5053-60, 2015 Jun 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The CD300a inhibitory receptor belongs to the CD300 family of cell surface molecules that regulate a diverse array of immune cell processes. The inhibitory signal of CD300a depends on the phosphorylation of tyrosine residues embedded in ITIMs of the cytoplasmic tail. CD300a is broadly expressed on myeloid and lymphoid cells, and its expression is differentially regulated depending on the cell type. The finding that CD300a recognizes phosphatidylserine and phosphatidylethanolamine, two aminophospholipids exposed on the outer leaflet of dead and activated cells, has shed new light on its role in the modulation of immune functions and in its participation in the host response to several diseases states, such as infectious diseases, cancer, allergy, and chronic inflammatory diseases. This review summarizes the literature on CD300a expression, regulation, signaling pathways, and ligand interaction, as well as its role in fine tuning immune cell functions and its clinical relevance.
[Mh] Termos MeSH primário: Antígenos CD/metabolismo
Motivo de Inibição do Imunorreceptor Baseado em Tirosina/genética
Fosfatidiletanolaminas/antagonistas & inibidores
Fosfatidilserinas/antagonistas & inibidores
Receptores Imunológicos/metabolismo
[Mh] Termos MeSH secundário: Animais
Antígenos CD/biossíntese
Antígenos CD/genética
Doenças Autoimunes/genética
Doenças Autoimunes/metabolismo
Seres Humanos
Ligantes
Camundongos
Neoplasias/genética
Neoplasias/metabolismo
Ligação Proteica
Receptores Imunológicos/biossíntese
Receptores Imunológicos/genética
Transdução de Sinais
Viroses/genética
Viroses/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Antigens, CD); 0 (CD300A protein, human); 0 (Ligands); 0 (Phosphatidylethanolamines); 0 (Phosphatidylserines); 0 (Receptors, Immunologic); 39382-08-6 (phosphatidylethanolamine)
[Em] Mês de entrada:1508
[Cu] Atualização por classe:150518
[Lr] Data última revisão:
150518
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:150517
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1500304


  4 / 12 MEDLINE  
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[PMID]:25033984
[Au] Autor:Kane BA; Bryant KJ; McNeil HP; Tedla NT
[Ad] Endereço:Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, N.S.W., Australia.
[Ti] Título:Termination of immune activation: an essential component of healthy host immune responses.
[So] Source:J Innate Immun;6(6):727-38, 2014.
[Is] ISSN:1662-8128
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:The ideal immune response is rapid, proportionate and effective. Crucially, it must also be finite. An inflammatory response which is disproportionate or lasts too long risks injury to the host; chronic un-regulated inflammation in autoimmune diseases is one example of this. Thus, mechanisms to regulate and ultimately terminate immune responses are central to a healthy immune system. Despite extensive knowledge of what drives immune responses, our understanding of mechanisms of immune termination remains relatively sparse. It is clear that such processes are more complex than a one-dimensional homeostatic balance. Recent discoveries have revealed ever more nuanced mechanisms of signal termination, such as intrinsically self-limiting signals, multiple inhibitory mechanisms acting in tandem and activating proteins behaving differently in a variety of contexts. This review will summarise some important mechanisms, including termination by immunoreceptor tyrosine-based inhibitory motifs (ITIM), inhibition by soluble antagonists, receptor endocytosis or ubiquitination, and auto-inhibition by newly synthesised intracellular inhibitory molecules. Several recent discoveries showing immunoreceptor tyrosine-based activation motifs transducing inhibitory signals, ITIM mediating activating responses and the possible roles of immunoreceptor tyrosine-based switch motifs will also be explored.
[Mh] Termos MeSH primário: Endocitose/imunologia
Sistema Imunitário/fisiologia
Motivo de Inibição do Imunorreceptor Baseado em Tirosina/imunologia
Ubiquitinação/imunologia
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Em] Mês de entrada:1506
[Cu] Atualização por classe:141017
[Lr] Data última revisão:
141017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140719
[St] Status:MEDLINE
[do] DOI:10.1159/000363449


  5 / 12 MEDLINE  
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[PMID]:24925975
[Au] Autor:Stegner D; Haining EJ; Nieswandt B
[Ad] Endereço:From the Department of Experimental Biomedicine, University Hospital Würzburg and Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
[Ti] Título:Targeting glycoprotein VI and the immunoreceptor tyrosine-based activation motif signaling pathway.
[So] Source:Arterioscler Thromb Vasc Biol;34(8):1615-20, 2014 Aug.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Coronary artery thrombosis and ischemic stroke are often initiated by the disruption of an atherosclerotic plaque and consequent intravascular platelet activation. Thus, antiplatelet drugs are central in the treatment and prevention of the initial, and subsequent, vascular events. However, novel pharmacological targets for platelet inhibition remain an important goal of cardiovascular research because of the negative effect of existing antiplatelet drugs on primary hemostasis. One promising target is the platelet collagen receptor glycoprotein VI. Blockade or antibody-mediated depletion of this receptor in circulating platelets is beneficial in experimental models of thrombosis and thrombo-inflammatory diseases, such as stroke, without impairing hemostasis. In this review, we summarize the importance of glycoprotein VI and (hem)immunoreceptor tyrosine-based activation motif signaling in hemostasis, thrombosis, and thrombo-inflammatory processes and discuss the targeting strategies currently under development for inhibiting glycoprotein VI and its signaling.
[Mh] Termos MeSH primário: Plaquetas/efeitos dos fármacos
Desenho de Drogas
Motivo de Inibição do Imunorreceptor Baseado em Tirosina
Terapia de Alvo Molecular
Inibidores da Agregação de Plaquetas/uso terapêutico
Glicoproteínas da Membrana de Plaquetas/antagonistas & inibidores
Transdução de Sinais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Plaquetas/metabolismo
Hemorragia/induzido quimicamente
Hemostasia/efeitos dos fármacos
Seres Humanos
Inibidores da Agregação de Plaquetas/efeitos adversos
Inibidores da Agregação de Plaquetas/química
Glicoproteínas da Membrana de Plaquetas/química
Glicoproteínas da Membrana de Plaquetas/metabolismo
Conformação Proteica
Trombose/sangue
Trombose/tratamento farmacológico
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Platelet Aggregation Inhibitors); 0 (Platelet Membrane Glycoproteins); 0 (platelet membrane glycoprotein VI)
[Em] Mês de entrada:1409
[Cu] Atualização por classe:150513
[Lr] Data última revisão:
150513
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140614
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.114.303408


  6 / 12 MEDLINE  
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[PMID]:24650050
[Au] Autor:Dery KJ; Kujawski M; Grunert D; Wu X; Ngyuen T; Cheung C; Yim JH; Shively JE
[Ti] Título:IRF-1 regulates alternative mRNA splicing of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in breast epithelial cells generating an immunoreceptor tyrosine-based inhibition motif (ITIM) containing isoform.
[So] Source:Mol Cancer;13:64, 2014 Mar 21.
[Is] ISSN:1476-4598
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Interferon regulatory factor-1 (IRF-1) is a master regulator of IFN-γ induced gene transcription. Previously we have shown that IRF-1 transcriptionally induces CEACAM1 via an ISRE (Interferon-Stimulated Response Element) in its promoter. CEACAM1 pre-mRNA undergoes extensive alternative splicing (AS) generating isoforms to produce either a short (S) cytoplasmic domain expressed primarily in epithelial cells or as an ITIM-containing long (L) isoform in immune cells. METHODS: The transcriptional and molecular mechanism of CEACAM1 minigenes AS containing promoter ISREs mutations in the breast epithelial, MDA-MB-468, cell line was detected using flow cytometry. In addition, transcriptome sequencing was utilized to determine whether IRF-1 could direct the AS of other genes as well. Tumor xenografts were used to evaluate CEACAM1 isoform expression on the leading edge of breast tumor cells. RESULTS: In the present study, we provide evidence that CEACAM1's promoter and variable exon 7 cross-talk allowing IRF-1 to direct AS events. Transcriptome sequencing shows that IRF-1 can also induce the global AS of genes involved in regulation of growth and differentiation as well as genes of the cytokine family. Furthermore, MDA-MB-468 cells grown as tumor xenografts exhibit an AS switch to the L-isoform of CEACAM1, demonstrating that an in vivo inflammatory milieu is also capable of generating the AS switch, similar to that found in human breast cancers Mol Cancer 7:46, 2008. CONCLUSIONS: The novel AS regulatory activities attributed to IRF-1 indicate that the IFN-γ response involves a global change in both gene transcription and AS in breast epithelial cells.
[Mh] Termos MeSH primário: Processamento Alternativo/genética
Antígenos CD/genética
Moléculas de Adesão Celular/genética
Motivo de Inibição do Imunorreceptor Baseado em Tirosina/genética
Fator Regulador 1 de Interferon/metabolismo
[Mh] Termos MeSH secundário: Animais
Antígenos CD/biossíntese
Mama/metabolismo
Mama/patologia
Moléculas de Adesão Celular/biossíntese
Linhagem Celular Tumoral
Células Epiteliais/metabolismo
Feminino
Regulação Neoplásica da Expressão Gênica
Seres Humanos
Fator Regulador 1 de Interferon/genética
Interferon gama/metabolismo
Camundongos
Isoformas de Proteínas/biossíntese
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD); 0 (CD66 antigens); 0 (Cell Adhesion Molecules); 0 (Interferon Regulatory Factor-1); 0 (Protein Isoforms); 82115-62-6 (Interferon-gamma)
[Em] Mês de entrada:1412
[Cu] Atualização por classe:161025
[Lr] Data última revisão:
161025
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140322
[St] Status:MEDLINE
[do] DOI:10.1186/1476-4598-13-64


  7 / 12 MEDLINE  
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[PMID]:24642916
[Au] Autor:Wilson TJ; Garner LI; Metcalfe C; King E; Margraf S; Brown MH
[Ad] Endereço:Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
[Ti] Título:Fine specificity and molecular competition in SLAM family receptor signalling.
[So] Source:PLoS One;9(3):e92184, 2014.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:SLAM family receptors regulate activation and inhibition in immunity through recruitment of activating and inhibitory SH2 domain containing proteins to immunoreceptor tyrosine based switch motifs (ITSMs). Binding of the adaptors, SAP and EAT-2 to ITSMs in the cytoplasmic regions of SLAM family receptors is important for activation. We analysed the fine specificity of SLAM family receptor phosphorylated ITSMs and the conserved tyrosine motif in EAT-2 for SH2 domain containing signalling proteins. Consistent with the literature describing dependence of CRACC (SLAMF7) on EAT-2, CRACC bound EAT-2 (KD = 0.003 µM) with approximately 2 orders of magnitude greater affinity than SAP (KD = 0.44 µM). RNA interference in cytotoxicity assays in NK92 cells showed dependence of CRACC on SAP in addition to EAT-2, indicating selectivity of SAP and EAT-2 may depend on the relative concentrations of the two adaptors. The concentration of SAP was four fold higher than EAT-2 in NK92 cells. Compared with SAP, the significance of EAT-2 recruitment and its downstream effectors are not well characterised. We identified PLCγ1 and PLCγ2 as principal binding partners for the EAT-2 tail. Both PLCγ1 and PLCγ2 are functionally important for cytotoxicity in NK92 cells through CD244 (SLAMF4), NTB-A (SLAMF6) and CRACC. Comparison of the specificity of SH2 domains from activating and inhibitory signalling mediators revealed a hierarchy of affinities for CD244 (SLAMF4) ITSMs. While binding of phosphatase SH2 domains to individual ITSMs of CD244 was weak compared with SAP or EAT-2, binding of tandem SH2 domains of SHP-2 to longer peptides containing tandem phosphorylated ITSMs in human CD244 increased the affinity ten fold. The concentration of the tyrosine phosphatase, SHP-2 was in the order of a magnitude higher than the adaptors, SAP and EAT-2. These data demonstrate a mechanism for direct recruitment of phosphatases in inhibitory signalling by ITSMs, while explaining competitive dominance of SAP and EAT-2.
[Mh] Termos MeSH primário: Antígenos CD/metabolismo
Células Matadoras Naturais/metabolismo
Receptores de Superfície Celular/metabolismo
Receptores Imunológicos/metabolismo
Transdução de Sinais/genética
[Mh] Termos MeSH secundário: Antígenos CD/genética
Sítios de Ligação
Ligação Competitiva
Linhagem Celular
Regulação da Expressão Gênica
Seres Humanos
Imunidade Inata
Motivo de Ativação do Imunorreceptor Baseado em Tirosina
Motivo de Inibição do Imunorreceptor Baseado em Tirosina
Células Matadoras Naturais/citologia
Células Matadoras Naturais/imunologia
Dados de Sequência Molecular
Fosfolipase C gama/genética
Fosfolipase C gama/metabolismo
Ligação Proteica
Estrutura Terciária de Proteína
Proteína Tirosina Fosfatase não Receptora Tipo 11/genética
Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/metabolismo
Receptores de Superfície Celular/genética
Receptores Imunológicos/genética
Família de Moléculas de Sinalização da Ativação Linfocitária
Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária
Fatores de Transcrição/genética
Fatores de Transcrição/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antigens, CD); 0 (CD244 protein, human); 0 (Receptors, Cell Surface); 0 (Receptors, Immunologic); 0 (SH2D1B protein, human); 0 (SLAMF6 protein, human); 0 (SLAMF7 protein, human); 0 (Signaling Lymphocytic Activation Molecule Family); 0 (Transcription Factors); 169535-43-7 (Signaling Lymphocytic Activation Molecule Family Member 1); EC 3.1.3.48 (PTPN11 protein, human); EC 3.1.3.48 (PTPRH protein, human); EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11); EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 3); EC 3.1.4.3 (Phospholipase C gamma)
[Em] Mês de entrada:1412
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140320
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0092184


  8 / 12 MEDLINE  
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[PMID]:24265393
[Au] Autor:Dütting S; Vögtle T; Morowski M; Schiessl S; Schäfer CM; Watson SK; Hughes CE; Ackermann JA; Radtke D; Hermanns HM; Watson SP; Nitschke L; Nieswandt B
[Ad] Endereço:Department of Experimental Biomedicine, University Hospital Würzburg (S.D., T.V., M.M., S.S., B.N.) and Rudolf Virchow Center for Experimental Biomedicine (S.D., T.V., C.M.S., H.M.H., B.N.), University of Würzburg, Würzburg, Germany; Centre for Cardiovascular Sciences, Institute for Biomedical Resea
[Ti] Título:Growth factor receptor-bound protein 2 contributes to (hem)immunoreceptor tyrosine-based activation motif-mediated signaling in platelets.
[So] Source:Circ Res;114(3):444-453, 2014 Jan 31.
[Is] ISSN:1524-4571
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: Platelets are anuclear cell fragments derived from bone marrow megakaryocytes (MKs) that safeguard vascular integrity but may also cause pathological vessel occlusion. One major pathway of platelet activation is triggered by 2 receptors that signal through an (hem)immunoreceptor tyrosine-based activation motif (ITAM), the activating collagen receptor glycoprotein (GP) VI and the C-type lectin-like receptor 2 (CLEC-2). Growth factor receptor-bound protein 2 (Grb2) is a ubiquitously expressed adapter molecule involved in signaling processes of numerous receptors in different cell types, but its function in platelets and MKs is unknown. OBJECTIVE: We tested the hypothesis that Grb2 is a crucial adapter protein in (hem)immunoreceptor tyrosine-based activation motif signaling in platelets. METHODS AND RESULTS: Here, we show that genetic ablation of Grb2 in MKs and platelets did not interfere with MK differentiation or platelet production. However, Grb2-deficiency severely impaired glycoprotein VI-mediated platelet activation because of defective stabilization of the linker of activated T-cell (LAT) signalosome and activation of downstream signaling proteins that resulted in reduced adhesion, aggregation, and coagulant activity on collagen in vitro. Similarly, CLEC-2-mediated signaling was impaired in Grb2-deficient platelets, whereas the cells responded normally to stimulation of G protein-coupled receptors. In vivo, this selective (hem)immunoreceptor tyrosine-based activation motif signaling defect resulted in prolonged bleeding times but affected arterial thrombus formation only after concomitant treatment with acetylsalicylic acid, indicating that defective glycoprotein VI signaling in the absence of Grb2 can be compensated through thromboxane A2-induced G protein-coupled receptor signaling pathways. CONCLUSIONS: These results reveal an important contribution of Grb2 in (hem)immunoreceptor tyrosine-based activation motif signaling in platelets in hemostasis and thrombosis by stabilizing the LAT signalosome.
[Mh] Termos MeSH primário: Plaquetas/metabolismo
Proteína Adaptadora GRB2/fisiologia
Motivo de Ativação do Imunorreceptor Baseado em Tirosina/genética
Transdução de Sinais/genética
[Mh] Termos MeSH secundário: Motivos de Aminoácidos/genética
Animais
Células Cultivadas
Proteína Adaptadora GRB2/genética
Hemostasia/genética
Motivo de Inibição do Imunorreceptor Baseado em Tirosina/genética
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Ativação Plaquetária/genética
Trombose/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (GRB2 Adaptor Protein); 0 (Grb2 protein, mouse)
[Em] Mês de entrada:1403
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:131123
[St] Status:MEDLINE
[do] DOI:10.1161/CIRCRESAHA.114.302670


  9 / 12 MEDLINE  
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[PMID]:23322733
[Au] Autor:Oliver SL; Brady JJ; Sommer MH; Reichelt M; Sung P; Blau HM; Arvin AM
[Ad] Endereço:Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA. sloliver@stanford.edu
[Ti] Título:An immunoreceptor tyrosine-based inhibition motif in varicella-zoster virus glycoprotein B regulates cell fusion and skin pathogenesis.
[So] Source:Proc Natl Acad Sci U S A;110(5):1911-6, 2013 Jan 29.
[Is] ISSN:1091-6490
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Herpesvirus entry functions of the conserved glycoproteins gB and gH-gL have been delineated, but their role in regulating cell-cell fusion is poorly understood. Varicella-zoster virus (VZV) infection provides a valuable model for investigating cell-cell fusion because of the importance of this process for pathogenesis in human skin and sensory ganglia. The present study identifies a canonical immunoreceptor tyrosine-based inhibition motif (ITIM) in the gB cytoplasmic domain (gBcyt) and demonstrates that the gBcyt is a tyrosine kinase substrate. Orbitrap mass spectrometry confirmed that Y881, central to the ITIM, is phosphorylated. To determine whether the gBcyt ITIM regulates gB/gH-gL-induced cell-cell fusion in vitro, tyrosine residues Y881 and Y920 in the gBcyt were substituted with phenylalanine separately or together. Recombinant viruses with these substitutions were generated to establish their effects on syncytia formation in replication in vitro and in the human skin xenograft model of VZV pathogenesis. The Y881F substitution caused significantly increased cell-cell fusion despite reduced cell-surface gB. Importantly, the Y881F or Y881/920F substitutions in VZV caused aggressive syncytia formation, reducing cell-cell spread. These in vitro effects of aggressive syncytia formation translated to severely impaired skin infection in vivo. In contrast, the Y920F substitution did not affect virus replication in vitro or in vivo. These observations suggest that gB modulates cell-cell fusion via an ITIM-mediated Y881 phosphorylation-dependent mechanism, supporting a unique concept that intracellular signaling through this gBcyt motif regulates VZV syncytia formation and is essential for skin pathogenesis.
[Mh] Termos MeSH primário: Herpesvirus Humano 3/metabolismo
Motivo de Inibição do Imunorreceptor Baseado em Tirosina
Pele/patologia
Proteínas do Envelope Viral/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Western Blotting
Células CHO
Fusão Celular
Linhagem Celular Tumoral
Células Cultivadas
Cricetinae
Cricetulus
Células Gigantes/ultraestrutura
Células Gigantes/virologia
Células HEK293
Herpesvirus Humano 3/genética
Herpesvirus Humano 3/fisiologia
Seres Humanos
Melanoma/patologia
Melanoma/ultraestrutura
Melanoma/virologia
Microscopia Confocal
Microscopia Eletrônica de Transmissão
Modelos Moleculares
Mutação
Fosforilação
Estrutura Terciária de Proteína
Pele/virologia
Transplante Heterólogo
Tirosina/genética
Tirosina/metabolismo
Proteínas do Envelope Viral/química
Proteínas do Envelope Viral/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Viral Envelope Proteins); 0 (glycoprotein B, varicella-zoster virus); 42HK56048U (Tyrosine)
[Em] Mês de entrada:1305
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130117
[St] Status:MEDLINE
[do] DOI:10.1073/pnas.1216985110


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[PMID]:23314616
[Au] Autor:Kim EJ; Suk K; Lee WH
[Ad] Endereço:School of Life Sciences and Biotechnology, Kyungpook National University, Daegu 702-701, Korea.
[Ti] Título:SHPS-1 and a synthetic peptide representing its ITIM inhibit the MyD88, but not TRIF, pathway of TLR signaling through activation of SHP and PI3K in THP-1 cells.
[So] Source:Inflamm Res;62(4):377-86, 2013 Apr.
[Is] ISSN:1420-908X
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Src homology 2 domain-containing protein tyrosine phosphatase substrate (SHPS)-1 is known to have regulatory effects on myeloid cells. However, its role in macrophage activation is not clearly understood. METHODS AND RESULTS: In order to investigate the role of SHPS-1 in Toll-like receptor (TLR)-mediated activation, human monocytic cell lines were treated with anti-SHPS-1 monoclonal antibody. The triggering of SHPS-1 blocked the expression of IL-8 and TNF-α in cells treated with a TLR4 ligand that induces a signaling pathway involving myeloid differentiation factor 88 (MyD88) and Toll-interleukin-1 receptor (TIR)-domain-containing adapter-inducing interferon-ß (TRIF). Interestingly, SHPS-1 inhibited TLR9/MyD88-mediated, but not TLR3/TRIF-mediated, expression of IL-8. Accordingly, a synthetic peptide representing the immunoreceptor tyrosine-based inhibition motif (ITIM) of SHPS-1 suppressed only the MyD88 pathway. Utilization of specific inhibitors and Western blot analysis indicated that the inhibitory effects were mediated by Src homology 2 domain-containing phosphatases (SHPs) and phosphoinositide 3-kinase (PI3K). CONCLUSION: SHPS-1 negatively regulates the MyD88-dependent TLR signaling pathway through the inhibition of NF-κB activation.
[Mh] Termos MeSH primário: Antígenos de Diferenciação/metabolismo
Fator 88 de Diferenciação Mieloide/metabolismo
NF-kappa B/metabolismo
Receptores Imunológicos/metabolismo
Receptores Toll-Like/metabolismo
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transporte Vesicular/metabolismo
Linhagem Celular
DNA/metabolismo
Seres Humanos
Motivo de Inibição do Imunorreceptor Baseado em Tirosina
Interleucina-8/metabolismo
Peptídeos/farmacologia
Fosfatidilinositol 3-Quinases/metabolismo
Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo
Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo
Fator de Necrose Tumoral alfa/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Adaptor Proteins, Vesicular Transport); 0 (Antigens, Differentiation); 0 (Interleukin-8); 0 (MYD88 protein, human); 0 (Myeloid Differentiation Factor 88); 0 (NF-kappa B); 0 (Peptides); 0 (Receptors, Immunologic); 0 (SIRPA protein, human); 0 (TICAM1 protein, human); 0 (Toll-Like Receptors); 0 (Tumor Necrosis Factor-alpha); 9007-49-2 (DNA); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 3.1.3.48 (PTPN11 protein, human); EC 3.1.3.48 (PTPN6 protein, human); EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11); EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 6)
[Em] Mês de entrada:1308
[Cu] Atualização por classe:170718
[Lr] Data última revisão:
170718
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130115
[St] Status:MEDLINE
[do] DOI:10.1007/s00011-013-0589-0



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