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Pesquisa : D12.776.220.985 [Categoria DeCS]
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  1 / 1041 MEDLINE  
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[PMID]:27775586
[Au] Autor:van de Klundert MA; van den Biggelaar M; Kootstra NA; Zaaijer HL
[Ad] Endereço:Department of Blood-borne Infections, Sanquin Research, 1006 AD Amsterdam, The Netherlands.
[Ti] Título:Hepatitis B Virus Protein X Induces Degradation of Talin-1.
[So] Source:Viruses;8(10), 2016 10 19.
[Is] ISSN:1999-4915
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:In the infected human hepatocyte, expression of the hepatitis B virus (HBV) accessory protein X (HBx) is essential to maintain viral replication in vivo. HBx critically interacts with the host damaged DNA binding protein 1 (DDB1) and the associated ubiquitin ligase machinery, suggesting that HBx functions by inducing the degradation of host proteins. To identify such host proteins, we systematically analyzed the HBx interactome. One HBx interacting protein, talin-1 (TLN1), was proteasomally degraded upon HBx expression. Further analysis showed that TLN1 levels indeed modulate HBV transcriptional activity in an HBx-dependent manner. This indicates that HBx-mediated TLN1 degradation is essential and sufficient to stimulate HBV replication. Our data show that TLN1 can act as a viral restriction factor that suppresses HBV replication, and suggest that the HBx relieves this restriction by inducing TLN1 degradation.
[Mh] Termos MeSH primário: Vírus da Hepatite B/fisiologia
Interações Hospedeiro-Patógeno
Proteólise
Talina/metabolismo
Transativadores/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (TLN1 protein, human); 0 (Talin); 0 (Trans-Activators); 0 (hepatitis B virus X protein)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171212
[Lr] Data última revisão:
171212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE


  2 / 1041 MEDLINE  
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[PMID]:28945706
[Au] Autor:Ringer P; Weißl A; Cost AL; Freikamp A; Sabass B; Mehlich A; Tramier M; Rief M; Grashoff C
[Ad] Endereço:Group of Molecular Mechanotransduction, Max Planck Institute of Biochemistry, Martinsried, Germany.
[Ti] Título:Multiplexing molecular tension sensors reveals piconewton force gradient across talin-1.
[So] Source:Nat Methods;14(11):1090-1096, 2017 Nov.
[Is] ISSN:1548-7105
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Förster resonance energy transfer (FRET)-based tension sensor modules (TSMs) are available for investigating how distinct proteins bear mechanical forces in cells. Yet, forces in the single piconewton (pN) regime remain difficult to resolve, and tools for multiplexed tension sensing are lacking. Here, we report the generation and calibration of a genetically encoded, FRET-based biosensor called FL-TSM, which is characterized by a near-digital force response and increased sensitivity at 3-5 pN. In addition, we present a method allowing the simultaneous evaluation of coexpressed tension sensor constructs using two-color fluorescence lifetime microscopy. Finally, we introduce a procedure to calculate the fraction of mechanically engaged molecules within cells. Application of these techniques to new talin biosensors reveals an intramolecular tension gradient across talin-1 that is established upon integrin-mediated cell adhesion. The tension gradient is actomyosin- and vinculin-dependent and sensitive to the rigidity of the extracellular environment.
[Mh] Termos MeSH primário: Talina/química
[Mh] Termos MeSH secundário: Calibragem
Transferência Ressonante de Energia de Fluorescência
Adesões Focais/química
Microscopia de Fluorescência
Miosinas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (TLN1 protein, human); 0 (Talin); EC 3.6.4.1 (Myosins)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170926
[St] Status:MEDLINE
[do] DOI:10.1038/nmeth.4431


  3 / 1041 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


  4 / 1041 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


  5 / 1041 MEDLINE  
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[PMID]:28591616
[Au] Autor:Bell S; Terentjev EM
[Ad] Endereço:Cavendish Laboratory, University of Cambridge, Cambridge, United Kingdom.
[Ti] Título:Focal Adhesion Kinase: The Reversible Molecular Mechanosensor.
[So] Source:Biophys J;112(11):2439-2450, 2017 Jun 06.
[Is] ISSN:1542-0086
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sensors are the first element of the pathways that control the response of cells to their environment. Protein complexes that produce or enable a chemical signal in response to a mechanical stimulus are called "mechanosensors". In this work, we develop a theoretical model describing the physical mechanism of a reversible single-molecule stiffness sensor. Although this has the potential for general application, here we apply the model to focal adhesion kinase, which initiates the chemical signal in its active phosphorylated conformation, but can spontaneously return to its closed folded conformation. We find how the rates of conformation changes depend on the substrate stiffness and the pulling force applied from the cell cytoskeleton. We find the sensor is homeostatic, spontaneously self-adjusting to reach a state where its range of maximum sensitivity matches the substrate stiffness. The results compare well with the phenotype observations of cells on different substrates.
[Mh] Termos MeSH primário: Proteína-Tirosina Quinases de Adesão Focal/metabolismo
Adesões Focais/metabolismo
Mecanotransdução Celular/fisiologia
[Mh] Termos MeSH secundário: Actinas/metabolismo
Animais
Citoesqueleto/metabolismo
Elasticidade
Matriz Extracelular/metabolismo
Retroalimentação Fisiológica/fisiologia
Homeostase/fisiologia
Integrinas/metabolismo
Modelos Biológicos
Processos Estocásticos
Talina/metabolismo
Viscosidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (Integrins); 0 (Talin); EC 2.7.10.2 (Focal Adhesion Protein-Tyrosine Kinases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170608
[St] Status:MEDLINE


  6 / 1041 MEDLINE  
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[PMID]:28515282
[Au] Autor:Klann JE; Remedios KA; Kim SH; Metz PJ; Lopez J; Mack LA; Zheng Y; Ginsberg MH; Petrich BG; Chang JT
[Ad] Endereço:Department of Medicine, University of California San Diego, La Jolla, CA 92093.
[Ti] Título:Talin Plays a Critical Role in the Maintenance of the Regulatory T Cell Pool.
[So] Source:J Immunol;198(12):4639-4651, 2017 Jun 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Talin, a cytoskeletal protein essential in mediating integrin activation, has been previously shown to be involved in the regulation of T cell proliferation and function. In this study, we describe a role for talin in maintaining the homeostasis and survival of the regulatory T (Treg) cell pool. T cell-specific deletion of talin in mice resulted in spontaneous lymphocyte activation, primarily due to numerical and functional deficiencies of Treg cells in the periphery. Peripheral talin-deficient Treg cells were unable to maintain high expression of IL-2Rα, resulting in impaired IL-2 signaling and ultimately leading to increased apoptosis through downregulation of prosurvival proteins Bcl-2 and Mcl-1. The requirement for talin in maintaining high IL-2Rα expression by Treg cells was due, in part, to integrin LFA-1-mediated interactions between Treg cells and dendritic cells. Collectively, our data suggest a critical role for talin in Treg cell-mediated maintenance of immune homeostasis.
[Mh] Termos MeSH primário: Homeostase
Ativação Linfocitária
Transdução de Sinais
Linfócitos T Reguladores/imunologia
Talina/metabolismo
[Mh] Termos MeSH secundário: Animais
Apoptose
Células Dendríticas/imunologia
Genes bcl-2
Interleucina-2/imunologia
Interleucina-2/metabolismo
Subunidade alfa de Receptor de Interleucina-2/genética
Subunidade alfa de Receptor de Interleucina-2/imunologia
Antígeno-1 Associado à Função Linfocitária/imunologia
Antígeno-1 Associado à Função Linfocitária/metabolismo
Camundongos
Proteína de Sequência 1 de Leucemia de Células Mieloides/genética
Linfócitos T Reguladores/fisiologia
Talina/deficiência
Talina/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Interleukin-2); 0 (Interleukin-2 Receptor alpha Subunit); 0 (Lymphocyte Function-Associated Antigen-1); 0 (Mcl1 protein, mouse); 0 (Myeloid Cell Leukemia Sequence 1 Protein); 0 (Talin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170927
[Lr] Data última revisão:
170927
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170519
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1601165


  7 / 1041 MEDLINE  
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[PMID]:28487468
[Au] Autor:Ye F; Yang C; Kim J; MacNevin CJ; Hahn KM; Park D; Ginsberg MH; Kim C
[Ad] Endereço:From the Department of Medicine, University of California San Diego School of Medicine, La Jolla, California 92093.
[Ti] Título:Epigallocatechin gallate has pleiotropic effects on transmembrane signaling by altering the embedding of transmembrane domains.
[So] Source:J Biol Chem;292(24):9858-9864, 2017 Jun 16.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Epigallocatechin gallate (EGCG) is the principal bioactive ingredient in green tea and has been reported to have many health benefits. EGCG influences multiple signal transduction pathways related to human diseases, including redox, inflammation, cell cycle, and cell adhesion pathways. However, the molecular mechanisms of these varying effects are unclear, limiting further development and utilization of EGCG as a pharmaceutical compound. Here, we examined the effect of EGCG on two representative transmembrane signaling receptors, integrinαIIbß3 and epidermal growth factor receptor (EGFR). We report that EGCG inhibits talin-induced integrin αIIbß3 activation, but it activates αIIbß3 in the absence of talin both in a purified system and in cells. This apparent paradox was explained by the fact that the activation state of αIIbß3 is tightly regulated by the topology of ß3 transmembrane domain (TMD); increases or decreases in TMD embedding can activate integrins. Talin increases the embedding of integrin ß3 TMD, resulting in integrin activation, whereas we observed here that EGCG decreases the embedding, thus opposing talin-induced integrin activation. In the absence of talin, EGCG decreases the TMD embedding, which can also disrupt the integrin α-ß TMD interaction, leading to integrin activation. EGCG exhibited similar paradoxical behavior in EGFR signaling. EGCG alters the topology of EGFR TMD and activates the receptor in the absence of EGF, but inhibits EGF-induced EGFR activation. Thus, this widely ingested polyphenol exhibits pleiotropic effects on transmembrane signaling by modifying the topology of TMDs.
[Mh] Termos MeSH primário: Antioxidantes/metabolismo
Catequina/análogos & derivados
Integrina beta3/metabolismo
Bicamadas Lipídicas/metabolismo
Modelos Moleculares
Receptor do Fator de Crescimento Epidérmico/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Antioxidantes/química
Antioxidantes/uso terapêutico
Células CHO
Catequina/química
Catequina/metabolismo
Catequina/uso terapêutico
Cricetulus
Suplementos Nutricionais
Dimerização
Seres Humanos
Integrina alfa2/química
Integrina alfa2/genética
Integrina alfa2/metabolismo
Integrina beta3/química
Integrina beta3/genética
Ligantes
Bicamadas Lipídicas/química
Mutação
Fragmentos de Peptídeos/antagonistas & inibidores
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/metabolismo
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/agonistas
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/química
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genética
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo
Domínios e Motivos de Interação entre Proteínas
Receptor do Fator de Crescimento Epidérmico/agonistas
Receptor do Fator de Crescimento Epidérmico/química
Receptor do Fator de Crescimento Epidérmico/genética
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Talina/antagonistas & inibidores
Talina/química
Talina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (ITGA2B protein, human); 0 (ITGB3 protein, human); 0 (Integrin alpha2); 0 (Integrin beta3); 0 (Ligands); 0 (Lipid Bilayers); 0 (Peptide Fragments); 0 (Platelet Glycoprotein GPIIb-IIIa Complex); 0 (Recombinant Fusion Proteins); 0 (Talin); 8R1V1STN48 (Catechin); BQM438CTEL (epigallocatechin gallate); EC 2.7.10.1 (EGFR protein, human); EC 2.7.10.1 (Receptor, Epidermal Growth Factor)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170706
[Lr] Data última revisão:
170706
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170511
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.C117.787309


  8 / 1041 MEDLINE  
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[PMID]:28432753
[Au] Autor:Yang C; Kwon S; Kim SJ; Jeong M; Park JY; Park D; Hong SJ; Jung JW; Kim C
[Ad] Endereço:Department of Life Sciences, Korea University, Seoul, Korea.
[Ti] Título:Identification of indothiazinone as a natural antiplatelet agent.
[So] Source:Chem Biol Drug Des;90(5):873-882, 2017 Nov.
[Is] ISSN:1747-0285
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cardiovascular disease, which is caused by unregulated platelet aggregation, is one of the main causes of deaths worldwide. Many studies have focused on natural products with antiplatelet effects as a safe alternative therapy to prevent the disease. In this context, an in-house chemical library was screened to find natural products capable of inhibiting the interaction between platelet integrin αIIbß3 and fibrinogen, which is an essential step in platelet aggregation. On the basis of the screening results, indothiazinone, an alkaloid found in microbial cultures, was identified as a potential antiplatelet agent. Specifically, indothiazinone treatment significantly inhibited the binding of fibrinogen to Chinese hamster ovary cells expressing integrin αIIbß3. It also restricted thrombin- and adenosine diphosphate-dependent spreading of human platelets on a fibrinogen matrix. More importantly, surface plasmon resonance and molecular dynamics studies suggested that indothiazinone suppressed talin-induced activation of integrin αIIbß3 presumably by inhibiting talin-integrin interaction. In conclusion, these results suggest that indothiazinone can be used as a lead compound for the development of antiplatelet drugs with a novel mode of action.
[Mh] Termos MeSH primário: Plaquetas/efeitos dos fármacos
Indóis/farmacologia
Inibidores da Agregação de Plaquetas/farmacologia
Tiazóis/farmacologia
[Mh] Termos MeSH secundário: Animais
Plaquetas/citologia
Plaquetas/metabolismo
Células CHO
Cricetulus
Seres Humanos
Indóis/química
Modelos Moleculares
Inibidores da Agregação de Plaquetas/química
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo
Talina/metabolismo
Tiazóis/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Indoles); 0 (Platelet Aggregation Inhibitors); 0 (Platelet Glycoprotein GPIIb-IIIa Complex); 0 (Talin); 0 (Thiazoles); 0 (indothiazinone)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170423
[St] Status:MEDLINE
[do] DOI:10.1111/cbdd.13008


  9 / 1041 MEDLINE  
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[PMID]:28428218
[Au] Autor:Berrou E; Adam F; Lebret M; Planche V; Fergelot P; Issertial O; Coupry I; Bordet JC; Nurden P; Bonneau D; Colin E; Goizet C; Rosa JP; Bryckaert M
[Ad] Endereço:From the INSERM UMR_S 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin Bicêtre, France (E.B., F.A., M.L., V.P., O.I., J.-P.R., M.B.); INSERM UMR_S 1211, Université de Bordeaux, CHU Bordeaux UNIV EA 4576, Place Aurélie Raba-Léon, France (P.F., I.C., C.G.); CHU Bordeaux, Centre de Référ
[Ti] Título:Gain-of-Function Mutation in Filamin A Potentiates Platelet Integrin α ß Activation.
[So] Source:Arterioscler Thromb Vasc Biol;37(6):1087-1097, 2017 Jun.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Dominant mutations of the X-linked filamin A ( ) gene are responsible for filaminopathies A, which are rare disorders including brain periventricular nodular heterotopia, congenital intestinal pseudo-obstruction, cardiac valves or skeleton malformations, and often macrothrombocytopenia. APPROACH AND RESULTS: We studied a male patient with periventricular nodular heterotopia and congenital intestinal pseudo-obstruction, his unique X-linked allele carrying a stop codon mutation resulting in a 100-amino acid-long FLNa C-terminal extension (NP_001447.2: ). Platelet counts were normal, with few enlarged platelets. FLNa was detectable in all platelets but at 30% of control levels. Surprisingly, all platelet functions were significantly upregulated, including platelet aggregation and secretion, as induced by ADP, collagen, or von Willebrand factor in the presence of ristocetin, as well as thrombus formation in blood flow on a collagen or on a von Willebrand factor matrix. Most importantly, patient platelets stimulated with ADP exhibited a marked increase in α ß integrin activation and a parallel increase in talin recruitment to ß , contrasting with normal Rap1 activation. These results are consistent with the mutant FLNa affecting the last step of α ß activation. Overexpression of mutant FLNa in the HEL megakaryocytic cell line correlated with an increase (compared with wild-type FLNa) in PMA-induced fibrinogen binding to and in talin and kindlin-3 recruitment by α ß . CONCLUSIONS: Altogether, our results are consistent with a less binding of mutant FLNa to ß and the facilitated recruitment of talin by ß on platelet stimulation, explaining the increased α ß activation and the ensuing gain-of-platelet functions.
[Mh] Termos MeSH primário: Plaquetas/metabolismo
Filaminas/genética
Integrina alfa2/sangue
Integrina beta3/sangue
Pseudo-Obstrução Intestinal/genética
Mutação
Heterotopia Nodular Periventricular/genética
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo
[Mh] Termos MeSH secundário: Adulto
Plaquetas/ultraestrutura
Linhagem Celular
Análise Mutacional de DNA
Filaminas/sangue
Predisposição Genética para Doença
Hereditariedade
Seres Humanos
Pseudo-Obstrução Intestinal/sangue
Pseudo-Obstrução Intestinal/diagnóstico
Masculino
Heterotopia Nodular Periventricular/sangue
Heterotopia Nodular Periventricular/diagnóstico
Fenótipo
Ativação Plaquetária
Testes de Função Plaquetária
Ligação Proteica
Transdução de Sinais
Talina/sangue
Proteínas de Ligação a Telômeros/sangue
Transfecção
Fator de von Willebrand/metabolismo
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (FLNA protein, human); 0 (Filamins); 0 (ITGA2B protein, human); 0 (ITGB3 protein, human); 0 (Integrin alpha2); 0 (Integrin beta3); 0 (Platelet Glycoprotein GPIIb-IIIa Complex); 0 (TERF2IP protein, human); 0 (Talin); 0 (Telomere-Binding Proteins); 0 (von Willebrand Factor)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170620
[Lr] Data última revisão:
170620
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170422
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.117.309337


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[PMID]:28375585
[Au] Autor:Chen P; Lei L; Wang J; Zou X; Zhang D; Deng L; Wu D
[Ad] Endereço:Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
[Ti] Título:Downregulation of Talin1 promotes hepatocellular carcinoma progression through activation of the ERK1/2 pathway.
[So] Source:Cancer Sci;108(6):1157-1168, 2017 Jun.
[Is] ISSN:1349-7006
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Talin1 is an adaptor protein that conjugates integrins to the cytoskeleton and regulates integrins and focal adhesion signaling. Several studies have found that Talin1 is overexpressed in several tumor types and promotes tumor progression. However, the explicit role of Talin1 in hepatocellular carcinoma (HCC) progression is still unclear and its functional mechanism remains largely unknown. In this study, we showed a trend of gradually decreasing expression of Talin1 from normal liver tissues to hepatocirrhosis, liver hyperplasia, the corresponding adjacent non-tumor, primary HCC, and eventually metastatic foci, indicating that Talin1 may correlate with HCC initiation to progression. Talin1 was significantly downregulated in HCC tissues compared with adjacent non-tumor tissues and low Talin1 expression was associated with HCC progression and poor prognosis. Furthermore, Talin1 knockdown induced epithelial-mesenchymal transition and promoted migration and invasion in SK-Hep-1 cells and HepG2 cells. Mechanistically, we found that the ERK pathway was responsible for these promoting effects of Talin1 knockdown in HCC cells. The promoting effects of Talin1 knockdown on epithelial-mesenchymal transition, migration, and invasion were reversed by U0126, a specific ERK1/2 inhibitor. Taken together, our results suggested that Talin1 might serve as a tumor suppressor in HCC and a potential prognostic biomarker for HCC patients.
[Mh] Termos MeSH primário: Carcinoma Hepatocelular/genética
Carcinoma Hepatocelular/patologia
Regulação para Baixo/genética
Neoplasias Hepáticas/genética
Neoplasias Hepáticas/patologia
Sistema de Sinalização das MAP Quinases/genética
Talina/genética
[Mh] Termos MeSH secundário: Linhagem Celular
Linhagem Celular Tumoral
Movimento Celular/genética
Progressão da Doença
Transição Epitelial-Mesenquimal/genética
Feminino
Regulação Neoplásica da Expressão Gênica/genética
Células Hep G2
Seres Humanos
Masculino
Meia-Idade
Transdução de Sinais/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (TLN1 protein, human); 0 (Talin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170915
[Lr] Data última revisão:
170915
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170405
[St] Status:MEDLINE
[do] DOI:10.1111/cas.13247



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