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Integrin talin

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https://www.readbyqxmd.com/read/28515282/talin-plays-a-critical-role-in-the-maintenance-of-the-regulatory-t-cell-pool
#1
Jane E Klann, Kelly A Remedios, Stephanie H Kim, Patrick J Metz, Justine Lopez, Lauren A Mack, Ye Zheng, Mark H Ginsberg, Brian G Petrich, John T Chang
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 Tln1(fl/fl)Cd4(Cre) 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...
May 17, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28487468/epigallocatechin-gallate-has-pleiotropic-effects-on-transmembrane-signaling-by-altering-the-embedding-of-transmembrane-domains
#2
Feng Ye, Chansik Yang, Jiyoon Kim, Christopher J MacNevin, Klaus M Hahn, Dongeun Park, Mark H Ginsberg, Chungho Kim
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, integrin αIIbβ3 and epidermal growth factor receptor (EGFR)...
May 9, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28432753/identification-of-indothiazinone-as-a-natural-antiplatelet-agent
#3
Chansik Yang, Sugyeong Kwon, Se-Jong Kim, Minseon Jeong, Ji-Young Park, Dongeun Park, Soon Jun Hong, Jong-Wha Jung, Chungho Kim
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 αIIbβ3 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...
April 22, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28428266/kca1-1-channels-regulate-%C3%AE-1-integrin-function-and-cell-adhesion-in-rheumatoid-arthritis-fibroblast-like-synoviocytes
#4
Mark R Tanner, Michael W Pennington, Teresina Laragione, Pércio S Gulko, Christine Beeton
Large-conductance calcium-activated potassium channel (KCa1.1; BK, Slo1, MaxiK, KCNMA1) is the predominant potassium channel expressed at the plasma membrane of fibroblast-like synoviocytes isolated from the synovium of patients with rheumatoid arthritis (RA-FLS). It is a critical regulator of RA-FLS migration and invasion and therefore represents an attractive target for the therapy of RA. However, the molecular mechanisms by which KCa1.1 regulates RA-FLS invasiveness have remained largely unknown. Here, we demonstrate that KCa1...
April 20, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28428218/gain-of-function-mutation-in-filamin-a-potentiates-platelet-integrin-%C3%AE-iib%C3%AE-3-activation
#5
Eliane Berrou, Frédéric Adam, Marilyne Lebret, Virginie Planche, Patricia Fergelot, Odile Issertial, Isabelle Coupry, Jean-Claude Bordet, Paquita Nurden, Dominique Bonneau, Estelle Colin, Cyril Goizet, Jean-Philippe Rosa, Marijke Bryckaert
OBJECTIVE: Dominant mutations of the X-linked filamin A (FLNA) 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 FLNA allele carrying a stop codon mutation resulting in a 100-amino acid-long FLNa C-terminal extension (NP_001447...
April 20, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28428216/maturation-of-platelet-function-during-murine-fetal-development-in-vivo
#6
Andreas Margraf, Claudia Nussbaum, Ina Rohwedder, Sarah Klapproth, Angela R M Kurz, Annamaria Florian, Volker Wiebking, Joachim Pircher, Monika Pruenster, Roland Immler, Steffen Dietzel, Ludmila Kremer, Friedemann Kiefer, Markus Moser, Andreas W Flemmer, Elizabeth Quackenbush, Ulrich H von Andrian, Markus Sperandio
OBJECTIVE: Platelet function has been intensively studied in the adult organism. However, little is known about the function and hemostatic capacity of platelets in the developing fetus as suitable in vivo models are lacking. APPROACH AND RESULTS: To examine fetal platelet function in vivo, we generated a fetal thrombosis model and investigated light-/dye-induced thrombus formation by intravital microscopy throughout gestation. We observed that significantly less and unstable thrombi were formed at embryonic day (E) 13...
April 20, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28408404/smurf1-inhibits-integrin-activation-by-controlling-kindlin-2-ubiquitination-and-degradation
#7
Xiaofan Wei, Xiang Wang, Jun Zhan, Yuhan Chen, Weigang Fang, Lingqiang Zhang, Hongquan Zhang
Integrin activation is an indispensable step for various integrin-mediated biological functions. Kindlin-2 is known to coactivate integrins with Talin; however, molecules that restrict integrin activation are elusive. Here, we demonstrate that the E3 ubiquitin ligase Smurf1 controls the amount of Kindlin-2 protein in cells and hinders integrin activation. Smurf1 interacts with and promotes Kindlin-2 ubiquitination and degradation. Smurf1 selectively mediates degradation of Kindlin-2 but not Talin, leading to inhibition of αIIbβ3 integrin activation in Chinese hamster ovary cells and β1 integrin activation in fibroblasts...
May 1, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28361943/talin-gets-shanked-in-the-fight-for-integrin-activation
#8
Paul Atherton, Christoph Ballestrem
Genetic mutations in the SHANK family of proteins are linked to multiple neuropsychiatric disorders including autism spectrum disorders. A study now elucidates critical roles for SHANK in regulating integrin-mediated cell-extracellular matrix adhesion, by sequestering integrin activators.
March 31, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28351192/synergistic-effect-of-peptide-inhibitors-derived-from-the-extracellular-and-intracellular-domain-of-%C3%AE-iib-subunit-of-integrin-%C3%AE-iib%C3%AE-3-on-platelet-activation-and-aggregation
#9
Alexia V Gkourogianni, Klytaimnistra Kiouptsi, Vassiliki Koloka, Vassilios Moussis, Vassilios Tsikaris, Christilla Bachelot-Loza, Demokritos C Tsoukatos
αIIbβ3, the major platelet integrin, plays a central role in hemostasis and thrombosis. Upon platelet activation, conformation of αIIbβ3 changes and allows fibrinogen binding and, subsequently, platelet aggregation. It was previously shown that a lipid-modified platelet permeable peptide, which corresponds to the intracellular acidic membrane distal sequence (1000)LEEDDEEGE(1008) of αIIb (pal-K-LEEDDEEGE or pal-K-1000-1008), inhibits thrombin-induced human platelet aggregation, by inhibiting talin association with the integrin...
March 29, 2017: Platelets
https://www.readbyqxmd.com/read/28348273/cutting-edge-loss-of-t-cell-riam-precludes-conjugate-formation-with-apc-and-prevents-immune-mediated-diabetes
#10
Frederic Lagarrigue, Frank B Gertler, Mark H Ginsberg, Joseph M Cantor
Rap1-interacting adaptor molecule (RIAM) is a Rap1 effector that mediates the recruitment of talin to integrins, thereby supporting their activation. In this study, we investigated the role of RIAM in an adoptive transfer model for type I diabetes and report that RIAM expression in T cells is necessary for diabetes development. Loss of RIAM did not prevent lymphocyte recruitment to draining lymph nodes 24 h after transfer, but it was required for Ag-driven proliferation and cytotoxic killing. RIAM is recruited to immune synapses along with talin and LFA-1, and loss of RIAM profoundly suppresses Ag-dependent conjugate formation in primary naive and effector T cells...
May 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28299994/the-changes-of-cytoskeletal-proteins-induced-by-the-fast-effect-of-estrogen-in-mouse-blastocysts-and-its-roles-in-implantation
#11
Shi-Mao Zhang, Lin-Lin Yu, Ting Qu, Ying Hu, Dong-Zhi Yuan, Sheng Zhang, Qian Xu, You-Bo Zhao, Jin-Hu Zhang, Li-Min Yue
It is necessary for estrogen to activate mouse blastocysts, so that they can attach to endometrial epithelium in implantation and in our previous research, we have proved estrogen can induce a fast increase in intracellular calcium of mouse blastocysts through acting on G protein-coupled receptor 30 (GPR30), which further promotes their implantation. Moreover, there has been evidence that cytoskeletal proteins are involved in integrin-mediated adhesion of many kinds of cells, which also plays an important role in implantation...
January 1, 2017: Reproductive Sciences
https://www.readbyqxmd.com/read/28292367/myofibroblast-mediated-contraction
#12
Wae M Al Kattan, Seham F Alarfaj, Bayan M Alnooh, Hadeel F Alsaif, Hayfa S Alabdul Karim, Noha M Al-Qattan, Mohammad M Al-Qattan, Amel A F El-Sayed
Myofibroblast-mediated contraction is viewed as a cycle of four steps. The first step is stimulation of myofibroblasts by lysophospholipids leading to the activation of G proteins and ending with contraction of the actin-myosin complex. The next step is the transmission of the intracellular contractile force at the focal adhesions of myofibroblasts; a step that involves talin, vinculin, paxillin, Hic-5, and the integrin receptors. In the third step, fibronectin will act as the extracellular link between the integrin receptors and the extracellular collagen...
January 2017: Journal of the College of Physicians and Surgeons—Pakistan: JCPSP
https://www.readbyqxmd.com/read/28263956/shank-proteins-limit-integrin-activation-by-directly-interacting-with-rap1-and%C3%A2-r-ras
#13
Johanna Lilja, Thomas Zacharchenko, Maria Georgiadou, Guillaume Jacquemet, Nicola De Franceschi, Emilia Peuhu, Hellyeh Hamidi, Jeroen Pouwels, Victoria Martens, Fatemeh Hassani Nia, Malte Beifuss, Tobias Boeckers, Hans-Juergen Kreienkamp, Igor L Barsukov, Johanna Ivaska
SHANK3, a synaptic scaffold protein and actin regulator, is widely expressed outside of the central nervous system with predominantly unknown function. Solving the structure of the SHANK3 N-terminal region revealed that the SPN domain is an unexpected Ras-association domain with high affinity for GTP-bound Ras and Rap G-proteins. The role of Rap1 in integrin activation is well established but the mechanisms to antagonize it remain largely unknown. Here, we show that SHANK1 and SHANK3 act as integrin activation inhibitors by sequestering active Rap1 and R-Ras via the SPN domain and thus limiting their bioavailability at the plasma membrane...
April 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28252668/aggretin-venom-polypeptide-as-a-novel-anti-angiogenesis-agent-by-targeting-integrin-alpha2beta1
#14
Ching Hu Chung, Chien Hsin Chang, Chun Chieh Hsu, Kung Tin Lin, Hui Chin Peng, Tur Fu Huang
VEGF and VEGFR antibodies have been used as a therapeutic strategy to inhibit angiogenesis in many diseases; however, frequent and repeated administration of these antibodies to patients induces immunogenicity. In previous studies, we demonstrated that aggretin, a heterodimeric snake venom C-type lectin, exhibits pro-angiogenic activities via integrin α2β1 ligation. We hypothesised that small-mass aggretin fragments may bind integrin α2β1 and act as antagonists of angiogenesis. In this study, the anti-angiogenic efficacy of a synthesised aggretin α-chain C-terminus (AACT, residue 106-136) was evaluated in both in vitro and in vivo angiogenesis models...
March 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28183734/skap2-is-required-for-%C3%AE-2-integrin-mediated-neutrophil-recruitment-and-functions
#15
Mark Boras, Stephanie Volmering, Arne Bokemeyer, Jan Rossaint, Helena Block, Bernadette Bardel, Veerle Van Marck, Barbara Heitplatz, Stefanie Kliche, Annegret Reinhold, Clifford Lowell, Alexander Zarbock
Integrin activation is required for neutrophil functions. Impaired integrin activation on neutrophils is the hallmark of leukocyte adhesion deficiency (LAD) syndrome in humans, characterized by impaired leukocyte recruitment and recurrent infections. The Src kinase-associated phosphoprotein 2 (Skap2) is involved in integrin functions in different leukocyte subtypes. However, the role of Skap2 in β2 integrin activation and neutrophil recruitment is unknown. In this study, we demonstrate the crucial role of Skap2 in regulating actin polymerization and binding of talin-1 and kindlin-3 to the β2 integrin cytoplasmic domain, thereby being indispensable for β2 integrin activation and neutrophil recruitment...
March 6, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28157452/activated-%C3%AE-2-integrins-restrict-neutrophil-recruitment-during-murine-acute-pseudomonal-pneumonia
#16
Zachary S Wilson, Lawrence B Ahn, William S Serratelli, Matthew D Belley, Joanne Lomas-Neira, Mehmet Sen, Craig T Lefort
Rapid neutrophil recruitment is critical for the efficient clearance of bacterial pathogens from the lungs. Although β2 integrins and their activation are required for neutrophil recruitment from postcapillary venules of the systemic circulation into inflamed tissues, the involvement of integrins in neutrophil recruitment in response to respiratory infection varies among bacterial pathogens. For stimuli eliciting β2 integrin-dependent neutrophil influx, including Pseudomonas aeruginosa, it remains unclear whether the activation of β2 integrins is an essential step in this process...
May 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/28155884/the-molecular-basis-of-talin2-s-high-affinity-toward-%C3%AE-1-integrin
#17
Yaxia Yuan, Liqing Li, Yanyan Zhu, Lei Qi, Latifeh Azizi, Vesa P Hytönen, Chang-Guo Zhan, Cai Huang
Talin interacts with β-integrin tails and actin to control integrin activation, thus regulating focal adhesion dynamics and cell migration. There are two talin genes, Tln1 and Tln2, which encode talin1 and talin2, and it is generally believed that talin2 functions redundantly with talin1. However, we show here that talin2 has a higher affinity to β1-integrin tails than talin1. Mutation of talin2 S339 to leucine, which can cause Fifth Finger Camptodactyly, a human genetic disease, completely disrupted its binding to β-integrin tails...
February 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28135265/%C3%AE-integrin-de-phosphorylation-by-the-density-enhanced-phosphatase-dep-1-attenuates-egfr-signaling-in-c-elegans
#18
Michael Walser, Christoph Alois Umbricht, Erika Fröhli, Paolo Nanni, Alex Hajnal
Density-Enhanced Phosphatase-1 (DEP-1) de-phosphorylates various growth factor receptors and adhesion proteins to regulate cell proliferation, adhesion and migration. Moreover, dep-1/scc1 mutations have been detected in various types of human cancers, indicating a broad tumor suppressor activity. During C. elegans development, DEP-1 mediates binary cell fate decisions by negatively regulating EGFR signaling. Using a substrate-trapping DEP-1 mutant in a proteomics approach, we have identified the C. elegans β-integrin subunit PAT-3 as a specific DEP-1 substrate...
January 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28117756/talin-modulation-by-a-synthetic-n-acylurea-derivative-reduces-angiogenesis-in-human-endothelial-cells
#19
I-Rang Lim, Hyung Joon Joo, Minseon Jeong, Jong-Ho Kim, Seung-Cheol Choi, Chungho Kim, Jong-Wha Jung, Soon Jun Hong
Talin is a focal adhesion protein that activates integrins and recruits other focal adhesion proteins. Talin regulates the interactions between integrins and the extracellular matrix, which are critical for endothelial cells during angiogenesis. In this study, we successfully synthesized a novel talin modulator, N-((2-(1H-indol-3-yl)ethyl)carbamoyl)-2-(benzo[d][1,3]dioxol-5-yloxy)acetamide, referred to as KCH-1521. KCH-1521 was determined to bind talin and modulate downstream signaling molecules of talin. After 24 h of treatment, KCH-1521 changed the cell morphology of human umbilical vein endothelial cells (HUVECs) and reduced focal adhesion protein expression including vinculin and paxillin...
January 22, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28101696/role-of-the-helix-in-talin-f3-domain-f3-helix-in-talin-mediated-integrin-activation
#20
Ang Li, Qiang Guo, Ailin Wei, Yaliang Zhou, Weiming Hu
Increases in ligand binding to cellular integrins (activation) play an important role in platelet and leukocyte function. Talin is necessary in vivo and sufficient in vitro for integrin αIIbβ3 activation. The precise mechanisms by which talin activates integrin are still being elucidated. In particular, talin undergoes conformational changes (around the F3 helix) and inserts the F3 helix into lipid bilayer; however, the connection between this lipid-inserting mechanism of talin and talin's capacity to activate integrin has never been explored before...
March 2017: Cell Biochemistry and Biophysics
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