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[PMID]:29380037
[Au] Autor:Miyashita N; Onozawa M; Hayasaka K; Yamada T; Migita O; Hata K; Okada K; Goto H; Nakagawa M; Hashimoto D; Kahata K; Kondo T; Kunishima S; Teshima T
[Ad] Endereço:Department of Hematology, Hokkaido University Faculty of Medicine, Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo, 0608638, Japan.
[Ti] Título:A novel heterozygous ITGB3 p.T720del inducing spontaneous activation of integrin αIIbß3 in autosomal dominant macrothrombocytopenia with aggregation dysfunction.
[So] Source:Ann Hematol;97(4):629-640, 2018 Apr.
[Is] ISSN:1432-0584
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:We identified a novel heterozygous ITGB3 p.T720del mutation in a pedigree with macrothrombocytopenia exhibiting aggregation dysfunction. Platelet aggregation induced by ADP and collagen was significantly reduced, while ristocetin aggregation was normal. Integrin αIIbß3 was partially activated in a resting status, but platelet expression of αIIbß3 was downregulated. Functional analysis using a cell line showed spontaneous phosphorylation of FAK in αIIb/ß3 (p.T720del)-transfected 293T cells in suspension conditions. Abnormal cytoplasmic protrusions, membrane ruffling, and cytoplasmic localization of αIIbß3 were observed in αIIb/ß3 (p.T720del)-transfected CHO cells. Such morphological changes were reversed by treatment with an FAK inhibitor. These findings imply spontaneous, but partial, activation of αIIbß3 followed by phosphorylation of FAK as the initial mechanism of abnormal thrombopoiesis. Internalization and decreased surface expression of αIIbß3 would contribute to aggregation dysfunction. We reviewed the literature of congenital macrothrombocytopenia associated with heterozygous ITGA2B or ITGB3 mutations. Reported mutations were highly clustered at the membrane proximal region of αIIbß3, which affected the critical interaction between αIIb R995 and ß3 D723, resulting in a constitutionally active form of the αIIbß3 complex. Macrothrombocytopenia caused by a heterozygous activating mutation of ITGA2B or ITGB3 at the membrane proximal region forms a distinct entity of rare congenital thrombocytopenia.
[Mh] Termos MeSH primário: Deleção de Genes
Genes Dominantes
Heterozigoto
Integrina beta3/genética
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/agonistas
Trombocitopenia/genética
[Mh] Termos MeSH secundário: Adulto
Animais
Células CHO
Cricetulus
Saúde da Família
Feminino
Células HEK293
Seres Humanos
Integrina beta3/metabolismo
Japão
Masculino
Meia-Idade
Mutagênese Sítio-Dirigida
Linhagem
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo
Proteínas Recombinantes/metabolismo
Trombocitopenia/sangue
Trombocitopenia/metabolismo
Trombocitopenia/fisiopatologia
Adulto Jovem
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ITGB3 protein, human); 0 (Integrin beta3); 0 (Platelet Glycoprotein GPIIb-IIIa Complex); 0 (Recombinant Proteins)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180131
[St] Status:MEDLINE
[do] DOI:10.1007/s00277-017-3214-4


  2 / 1790 MEDLINE  
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[PMID]:28467294
[Au] Autor:van der Pol E; Harrison P
[Ad] Endereço:a Biomedical Engineering & Physics , Academic Medical Centre, University of Amsterdam , Amsterdam , The Netherlands.
[Ti] Título:From platelet dust to gold dust: physiological importance and detection of platelet microvesicles.
[So] Source:Platelets;28(3):211-213, 2017 05.
[Is] ISSN:1369-1635
[Cp] País de publicação:England
[La] Idioma:eng
[Mh] Termos MeSH primário: Plaquetas/química
Micropartículas Derivadas de Células/metabolismo
Integrina beta3/genética
Trombose/fisiopatologia
[Mh] Termos MeSH secundário: Transporte Biológico/fisiologia
Biomarcadores/metabolismo
Plaquetas/ultraestrutura
Comunicação Celular/fisiologia
Micropartículas Derivadas de Células/genética
Micropartículas Derivadas de Células/ultraestrutura
Expressão Gênica
Ouro/química
Seres Humanos
Imuno-Histoquímica
Integrina beta3/metabolismo
Nanopartículas Metálicas/química
Tamanho da Partícula
Ativação Plaquetária/fisiologia
Trombose/genética
Trombose/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Biomarkers); 0 (ITGB3 protein, human); 0 (Integrin beta3); 7440-57-5 (Gold)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180301
[Lr] Data última revisão:
180301
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1080/09537104.2017.1282781


  3 / 1790 MEDLINE  
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[PMID]:29212004
[Au] Autor:Deschout H; Platzman I; Sage D; Feletti L; Spatz JP; Radenovic A
[Ad] Endereço:Laboratory of Nanoscale Biology, Institute of Bioengineering, School of Engineering, EPFL, Lausanne, Switzerland.
[Ti] Título:Investigating Focal Adhesion Substructures by Localization Microscopy.
[So] Source:Biophys J;113(11):2508-2518, 2017 Dec 05.
[Is] ISSN:1542-0086
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cells rely on focal adhesions (FAs) to carry out a variety of important tasks, including motion, environmental sensing, and adhesion to the extracellular matrix. Although attaining a fundamental characterization of FAs is a compelling goal, their extensive complexity and small size, which can be below the diffraction limit, have hindered a full understanding. In this study we have used single-molecule localization microscopy (SMLM) to investigate integrin ß3 and paxillin in rat embryonic fibroblasts growing on two different extracellular matrix-representing substrates (i.e., fibronectin-coated substrates and specifically biofunctionalized nanopatterned substrates). To quantify the substructure of FAs, we developed a clustering method based on expectation maximization of a Gaussian mixture that accounts for localization uncertainty and background. Analysis of our SMLM data indicates that the structures within FAs, characterized as a Gaussian mixture, typically have areas between 0.01 and 1 µm , contain 10-100 localizations, and can exhibit substantial eccentricity. Our approach based on SMLM opens new avenues for studying structural and functional biology of molecular assemblies that display substantial varieties in size, shape, and density.
[Mh] Termos MeSH primário: Adesões Focais/metabolismo
Microscopia
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Fibroblastos/citologia
Fibroblastos/metabolismo
Integrina beta3/metabolismo
Modelos Biológicos
Paxilina/metabolismo
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Integrin beta3); 0 (Paxillin)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180119
[Lr] Data última revisão:
180119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171207
[St] Status:MEDLINE


  4 / 1790 MEDLINE  
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[PMID]:28846069
[Au] Autor:Mitroulis I; Chen LS; Singh RP; Kourtzelis I; Economopoulou M; Kajikawa T; Troullinaki M; Ziogas A; Ruppova K; Hosur K; Maekawa T; Wang B; Subramanian P; Tonn T; Verginis P; von Bonin M; Wobus M; Bornhäuser M; Grinenko T; Di Scala M; Hidalgo A; Wielockx B; Hajishengallis G; Chavakis T
[Ad] Endereço:Department of Clinical Pathobiochemistry, Institute for Clinical Chemistry and Laboratory Medicine, and.
[Ti] Título:Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche.
[So] Source:J Clin Invest;127(10):3624-3639, 2017 Oct 02.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Hematopoietic stem cells (HSCs) remain mostly quiescent under steady-state conditions but switch to a proliferative state following hematopoietic stress, e.g., bone marrow (BM) injury, transplantation, or systemic infection and inflammation. The homeostatic balance between quiescence, self-renewal, and differentiation of HSCs is strongly dependent on their interactions with cells that constitute a specialized microanatomical environment in the BM known as the HSC niche. Here, we identified the secreted extracellular matrix protein Del-1 as a component and regulator of the HSC niche. Specifically, we found that Del-1 was expressed by several cellular components of the HSC niche, including arteriolar endothelial cells, CXCL12-abundant reticular (CAR) cells, and cells of the osteoblastic lineage. Del-1 promoted critical functions of the HSC niche, as it regulated long-term HSC (LT-HSC) proliferation and differentiation toward the myeloid lineage. Del-1 deficiency in mice resulted in reduced LT-HSC proliferation and infringed preferentially upon myelopoiesis under both steady-state and stressful conditions, such as hematopoietic cell transplantation and G-CSF- or inflammation-induced stress myelopoiesis. Del-1-induced HSC proliferation and myeloid lineage commitment were mediated by ß3 integrin on hematopoietic progenitors. This hitherto unknown Del-1 function in the HSC niche represents a juxtacrine homeostatic adaptation of the hematopoietic system in stress myelopoiesis.
[Mh] Termos MeSH primário: Proteínas de Transporte/secreção
Células-Tronco Hematopoéticas/metabolismo
Mielopoese
Nicho de Células-Tronco
Estresse Fisiológico
[Mh] Termos MeSH secundário: Animais
Proteínas de Transporte/genética
Quimiocina CXCL12/genética
Quimiocina CXCL12/metabolismo
Células Endoteliais/metabolismo
Seres Humanos
Integrina beta3/genética
Integrina beta3/metabolismo
Camundongos
Camundongos Knockout
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CXCL12 protein, human); 0 (Carrier Proteins); 0 (Chemokine CXCL12); 0 (Cxcl12 protein, mouse); 0 (EDIL3 protein, human); 0 (Edil3 protein, mouse); 0 (ITGB3 protein, human); 0 (Integrin beta3)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170829
[St] Status:MEDLINE


  5 / 1790 MEDLINE  
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[PMID]:28834730
[Au] Autor:Shams H; Mofrad MRK
[Ad] Endereço:Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering, University of California, Berkeley, Berkeley, California.
[Ti] Título:α-Actinin Induces a Kink in the Transmembrane Domain of ß -Integrin and Impairs Activation via Talin.
[So] Source:Biophys J;113(4):948-956, 2017 Aug 22.
[Is] ISSN:1542-0086
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Integrin-mediated signaling is crucial for cell-substrate adhesion and can be triggered from both intra- and extracellular interactions. Although talin binding is sufficient for inside-out activation of integrin, other cytoplasmic proteins such as α-actinin and filamin can directly interfere with talin-mediated integrin activation. Specifically, α-actinin plays distinct roles in regulating α ß versus α ß integrin. It has been shown that α-actinin competes with talin for binding to the cytoplasmic tail of ß -integrin, whereas it cooperates with talin for activating integrin α ß . In this study, molecular dynamics simulations were employed to compare and contrast molecular mechanisms of α ß and α ß activation in the presence and absence of α-actinin. Our results suggest that α-actinin impairs integrin signaling by both undermining talin binding to the ß -integrin cytoplasmic tail and inducing a kink in the transmembrane domain of ß -integrin. Furthermore, we showed that α-actinin promote talin association with ß -integrin by restricting the motion of the cytoplasmic tail and reducing the entropic barrier for talin binding. Taken together, our results showed that the interplay between talin and α-actinin regulates signal transmission via controlling the conformation of the transmembrane domain and altering natural response modes of integrins in a type-specific manner.
[Mh] Termos MeSH primário: Actinina/metabolismo
Membrana Celular/metabolismo
Integrina beta3/química
Integrina beta3/metabolismo
Simulação de Dinâmica Molecular
Talina/metabolismo
[Mh] Termos MeSH secundário: Citoplasma/metabolismo
Integrina alfa5beta1/metabolismo
Cinética
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo
Ligação Proteica
Domínios Proteicos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Integrin alpha5beta1); 0 (Integrin beta3); 0 (Platelet Glycoprotein GPIIb-IIIa Complex); 0 (Talin); 11003-00-2 (Actinin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170824
[St] Status:MEDLINE


  6 / 1790 MEDLINE  
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[PMID]:28767724
[Au] Autor:Peláez R; Morales X; Salvo E; Garasa S; Ortiz de Solórzano C; Martínez A; Larrayoz IM; Rouzaut A
[Ad] Endereço:Department of Oncology, Center for Applied Medical Research CIMA, Pamplona, Spain.
[Ti] Título:ß3 integrin expression is required for invadopodia-mediated ECM degradation in lung carcinoma cells.
[So] Source:PLoS One;12(8):e0181579, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cancer related deaths are primarily due to tumor metastasis. To facilitate their dissemination to distant sites, cancer cells develop invadopodia, actin-rich protrusions capable of degrading the surrounding extracellular matrix (ECM). We aimed to determine whether ß3 integrin participates in invadopodia formed by lung carcinoma cells, based on our previous findings of specific TGF-ß induction of ß3 integrin dependent metastasis in animal models of lung carcinoma. In this study, we demonstrate that lung carcinoma cells form invadopodia in response to TGF-ß exposure. Invadopodia formation and degradation activity is dependent on ß3 integrin expression since ß3 integrin deficient cells are not able to degrade gelatin-coated surfaces. Even more, transient over-expression of SRC did not restore invadopodia formation in ß3 integrin deficient cells. Finally, we observed that blockade of PLC-dependent signaling leads to more intense labeling for ß3 integrin in invadopodia. Our results suggest that ß3 integrin function, and location, in lung cancer cells are essential for invadopodia formation, and this integrin regulates the activation of different signal pathways necessary for the invasive structure. ß3 integrin has been associated with poor prognosis and increased metastasis in several carcinoma types, including lung cancer. Our findings provide new evidence to support the use of targeted therapies against this integrin to combat the onset of metastases.
[Mh] Termos MeSH primário: Carcinoma Pulmonar de Células não Pequenas/metabolismo
Matriz Extracelular/metabolismo
Integrina beta3/metabolismo
Neoplasias Pulmonares/metabolismo
Podossomos/metabolismo
Fator de Crescimento Transformador beta/farmacologia
[Mh] Termos MeSH secundário: Células A549
Adesão Celular
Linhagem Celular Tumoral
Seres Humanos
Metástase Neoplásica
Podossomos/efeitos dos fármacos
Transdução de Sinais
Quinases da Família src/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Integrin beta3); 0 (Transforming Growth Factor beta); EC 2.7.10.2 (src-Family Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170803
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0181579


  7 / 1790 MEDLINE  
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[PMID]:28726667
[Au] Autor:Vasylyev D; Chernobay L; Vasylieva O; Oliinyk M; Vashuk M
[Ad] Endereço:1Kharkiv Medical Academy of Postgraduate Study; 2Kharkiv National Medical University, Ukraine.
[Ti] Título:CLINICAL AND GENETIC PECULIARITIES OF VASCULAR MANIFESTATIONS OF ANTIPHOSPHOLIPID SYNDROME (CASE REPORT).
[So] Source:Georgian Med News;(267):114-119, 2017 Jun.
[Is] ISSN:1512-0112
[Cp] País de publicação:Georgia (Republic)
[La] Idioma:eng
[Ab] Resumo:Pathogenetic mechanisms of the development of antiphospholipid syndrome (APS) are considered in the article, which is the basis for the development of clinical manifestations and laboratory markers of APS. The modern literature data are analyzed, according to which the presence of antiphospholipid antibodies is a hypercoagulable background, and the formation of thrombi occurs under the influence of other allowing procoagulation factors. The classification of the main types of hereditary thrombophilia is given, which is the primary disorder, against the background of which an autoimmune thrombosis APS develops. A clinical observation of a young age patient is given, whose heterozygous carriage of mutations in the genes responsible for blood coagulation (F7, PAI-1 and ITGB3-ß-integrin), as well as homozygous carriage of a mutation in the MTRR gene associated with a violation of homocysteine methylation, APS was developed, which led to the processes of thrombosis. Timely diagnosis and individually developed pathogenetic therapy allow avoiding life-threatening complications of APS and improving the patients' quality of life. A conclusion about the need for APS and hereditary thrombophilias' examination to all patients of young age with unprovoked thrombosis of deep veins of lower extremities and PE was made.
[Mh] Termos MeSH primário: Síndrome Antifosfolipídica/genética
Fator VII/genética
Ferredoxina-NADP Redutase/genética
Integrina beta3/genética
Inibidor 1 de Ativador de Plasminogênio/genética
[Mh] Termos MeSH secundário: Adulto
Síndrome Antifosfolipídica/fisiopatologia
Heterozigoto
Homozigoto
Seres Humanos
Masculino
Mutação
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ITGB3 protein, human); 0 (Integrin beta3); 0 (Plasminogen Activator Inhibitor 1); 0 (SERPINE1 protein, human); 9001-25-6 (Factor VII); EC 1.18.1.- (methionine synthase reductase); EC 1.18.1.2 (Ferredoxin-NADP Reductase)
[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:170721
[St] Status:MEDLINE


  8 / 1790 MEDLINE  
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[PMID]:28698173
[Au] Autor:Seneviratne AN; Edsfeldt A; Cole JE; Kassiteridi C; Swart M; Park I; Green P; Khoyratty T; Saliba D; Goddard ME; Sansom SN; Goncalves I; Krams R; Udalova IA; Monaco C
[Ad] Endereço:From Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, United Kingdom (A.N.S., A.E., J.E.C., C.K., M.S., I.P., P.G., T.K., D.S., M.E.G., S.N.S., I.A.U., C.M.); Department of Bioengineering, Imperial College London
[Ti] Título:Interferon Regulatory Factor 5 Controls Necrotic Core Formation in Atherosclerotic Lesions by Impairing Efferocytosis.
[So] Source:Circulation;136(12):1140-1154, 2017 Sep 19.
[Is] ISSN:1524-4539
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Myeloid cells are central to atherosclerotic lesion development and vulnerable plaque formation. Impaired ability of arterial phagocytes to uptake apoptotic cells (efferocytosis) promotes lesion growth and establishment of a necrotic core. The transcription factor interferon regulatory factor (IRF)-5 is an important modulator of myeloid function and programming. We sought to investigate whether IRF5 affects the formation and phenotype of atherosclerotic lesions. METHODS: We investigated the role of IRF5 in atherosclerosis in 2 complementary models. First, atherosclerotic lesion development in hyperlipidemic apolipoprotein E-deficient (ApoE ) mice and ApoE mice with a genetic deletion of IRF5 (ApoE Irf5 ) was compared and then lesion development was assessed in a model of shear stress-modulated vulnerable plaque formation. RESULTS: Both lesion and necrotic core size were significantly reduced in ApoE Irf5 mice compared with IRF5-competent ApoE mice. Necrotic core size was also reduced in the model of shear stress-modulated vulnerable plaque formation. A significant loss of CD11c macrophages was evident in ApoE Irf5 mice in the aorta, draining lymph nodes, and bone marrow cell cultures, indicating that IRF5 maintains CD11c macrophages in atherosclerosis. Moreover, we revealed that the CD11c gene is a direct target of IRF5 in macrophages. In the absence of IRF5, CD11c macrophages displayed a significant increase in expression of the efferocytosis-regulating integrin-ß3 and its ligand milk fat globule-epidermal growth factor 8 protein and enhanced efferocytosis in vitro and in situ. CONCLUSIONS: IRF5 is detrimental in atherosclerosis by promoting the maintenance of proinflammatory CD11c macrophages within lesions and controlling the expansion of the necrotic core by impairing efferocytosis.
[Mh] Termos MeSH primário: Aterosclerose/patologia
Fatores Reguladores de Interferon/metabolismo
[Mh] Termos MeSH secundário: Animais
Aorta/metabolismo
Aorta/patologia
Apolipoproteínas E/deficiência
Apolipoproteínas E/genética
Aterosclerose/metabolismo
Células da Medula Óssea/citologia
Células da Medula Óssea/metabolismo
Antígeno CD11c/genética
Antígeno CD11c/metabolismo
Células Cultivadas
Imuno-Histoquímica
Integrina beta3/metabolismo
Fatores Reguladores de Interferon/deficiência
Fatores Reguladores de Interferon/genética
Linfonodos/citologia
Macrófagos/citologia
Macrófagos/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Necrose
Fagocitose
Resistência ao Cisalhamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apolipoproteins E); 0 (CD11c Antigen); 0 (Integrin beta3); 0 (Interferon Regulatory Factors); 0 (Irf5 protein, mouse)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170713
[St] Status:MEDLINE
[do] DOI:10.1161/CIRCULATIONAHA.117.027844


  9 / 1790 MEDLINE  
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[PMID]:28652408
[Au] Autor:Hirbawi J; Bialkowska K; Bledzka KM; Liu J; Fukuda K; Qin J; Plow EF
[Ad] Endereço:From the Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.
[Ti] Título:The extreme C-terminal region of kindlin-2 is critical to its regulation of integrin activation.
[So] Source:J Biol Chem;292(34):14258-14269, 2017 Aug 25.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Kindlin-2 (K2), a 4.1R-ezrin-radixin-moesin (FERM) domain adaptor protein, mediates numerous cellular responses, including integrin activation. The C-terminal 15-amino acid sequence of K2 is remarkably conserved across species but is absent in canonical FERM proteins, including talin. In CHO cells expressing integrin αIIbß3, co-expression of K2 with talin head domain resulted in robust integrin activation, but this co-activation was lost after deletion of as few as seven amino acids from the K2 C terminus. This dependence on the C terminus was also observed in activation of endogenous αIIbß3 in human erythroleukemia (HEL) cells and ß1 integrin activation in macrophage-like RAW264.1 cells. Kindlin-1 (K1) exhibited a similar dependence on its C terminus for integrin activation. Expression of the K2 C terminus as an extension of membrane-anchored P-selectin glycoprotein ligand-1 (PSGL-1) inhibited integrin-dependent cell spreading. Deletion of the K2 C terminus did not affect its binding to the integrin ß3 cytoplasmic tail, but combined biochemical and NMR analyses indicated that it can insert into the F2 subdomain. We suggest that this insertion determines the topology of the K2 FERM domain, and its deletion may affect the positioning of the membrane-binding functions of the F2 subdomain and the integrin-binding properties of its F3 subdomain. Free C-terminal peptide can still bind to K2 and displace the endogenous K2 C terminus but may not restore the conformation needed for integrin co-activation. Our findings indicate that the extreme C terminus of K2 is essential for integrin co-activation and highlight the importance of an atypical architecture of the K2 FERM domain in regulating integrin activation.
[Mh] Termos MeSH primário: Integrina alfa2/metabolismo
Integrina beta3/metabolismo
Leucemia Eritroblástica Aguda/metabolismo
Macrófagos/metabolismo
Proteínas de Membrana/metabolismo
Proteínas de Neoplasias/metabolismo
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Células CHO
Linhagem Celular Tumoral
Cricetulus
Deleção de Genes
Seres Humanos
Integrina alfa2/química
Integrina alfa2/genética
Integrina beta3/química
Integrina beta3/genética
Leucemia Eritroblástica Aguda/patologia
Proteínas Luminescentes/genética
Proteínas Luminescentes/metabolismo
Macrófagos/citologia
Proteínas de Membrana/química
Proteínas de Membrana/genética
Camundongos
Mutação
Proteínas de Neoplasias/agonistas
Proteínas de Neoplasias/química
Proteínas de Neoplasias/genética
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Domínios e Motivos de Interação entre Proteínas
Multimerização Proteica
Células RAW 264.7
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Talina/química
Talina/genética
Talina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ITGA2B protein, human); 0 (ITGB3 protein, human); 0 (Integrin alpha2); 0 (Integrin beta3); 0 (Luminescent Proteins); 0 (MIG2B protein, human); 0 (Membrane Proteins); 0 (Neoplasm Proteins); 0 (Peptide Fragments); 0 (Recombinant Fusion Proteins); 0 (Recombinant Proteins); 0 (Talin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170628
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.776195


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[PMID]:28631703
[Au] Autor:Muslimova EF; Afanasiev SA; Rebrova TY; Sergienko TN; Repin AN
[Ad] Endereço:Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia.
[Ti] Título:[Association of ITGB3, P2RY12, and CYP2C19 gene polymorphisms with platelet functional activity in patients with coronary heart disease during dual antiplatelet therapy].
[Ti] Título:Assotsiatsiia polimorfizmov genov ITGB3, P2RY12, CYP2C19 s funktsional'noi aktivnost'iu trombotsitov u patsientov s ishemicheskoi bolezn'iu serdtsa na fone dvukhkomponentnoi antiagregantnoi terapii..
[So] Source:Ter Arkh;89(5):74-78, 2017.
[Is] ISSN:0040-3660
[Cp] País de publicação:Russia (Federation)
[La] Idioma:rus
[Ab] Resumo:AIM: To assess the association of CYP2C19 G681A, P2RY12 H1/H2, and ITGB3 T1565C polymorphisms with the extent of platelet aggregation in patients with coronary heart disease (CHD) during antiplatelet therapy. SUBJECTS AND METHODS: 166 male patients with CHD, living in the Western Siberian Region, were examined. All the patients underwent a test for platelet aggregation induced by ADP (2.5 and 5.0 µm) and epinephrine (0.2 µm). Genotyping was performed using an allele-specific polymerase chain reaction technique. RESULTS: The polymorphic variants of the P2RY12 and ITGB3 genes were ascertained to have no impact on the extent of platelet aggregation in patients receiving clopidogrel and acetylsalicylic acid. An association was found between CYP2C19 681A allele carriage and the increased extent of platelet aggregation induced by ADP. CONCLUSION: The carriage of the cytochrome P450 CYP2C19 681A allele rather than platelet receptor gene polymorphisms determines a risk for clopidogrel resistance in patients with CHD.
[Mh] Termos MeSH primário: Aspirina
Doença da Artéria Coronariana
Citocromo P-450 CYP2C19/genética
Agregação Plaquetária/efeitos dos fármacos
Ticlopidina/análogos & derivados
[Mh] Termos MeSH secundário: Alelos
Aspirina/administração & dosagem
Aspirina/efeitos adversos
Plaquetas/efeitos dos fármacos
Doença da Artéria Coronariana/tratamento farmacológico
Doença da Artéria Coronariana/epidemiologia
Doença da Artéria Coronariana/genética
Resistência a Medicamentos/genética
Seres Humanos
Integrina beta3/genética
Masculino
Meia-Idade
Farmacogenética
Inibidores da Agregação de Plaquetas/administração & dosagem
Inibidores da Agregação de Plaquetas/efeitos adversos
Testes de Função Plaquetária/métodos
Polimorfismo Genético
Receptores Purinérgicos P2/genética
Sibéria/epidemiologia
Ticlopidina/administração & dosagem
Ticlopidina/efeitos adversos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ITGB3 protein, human); 0 (Integrin beta3); 0 (P2RY13 protein, human); 0 (Platelet Aggregation Inhibitors); 0 (Receptors, Purinergic P2); A74586SNO7 (clopidogrel); EC 1.14.14.1 (CYP2C19 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2C19); OM90ZUW7M1 (Ticlopidine); R16CO5Y76E (Aspirin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170831
[Lr] Data última revisão:
170831
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170621
[St] Status:MEDLINE
[do] DOI:10.17116/terarkh201789574-78



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