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Platelet integrin talin

Liming Shen, Kaoyuan Zhang, Chengyun Feng, Youjiao Chen, Shuiming Li, Javed Iqbal, Liping Liao, Yuxi Zhao, Jian Zhai
PURPOSE: Autism is a childhood neurological disorder with poorly understood etiology and pathology. This study is designed to identify differentially expressed proteins that might serve as potential biomarkers for autism. EXPERIMENTAL DESIGN: We perform iTRAQ (isobaric tags for relative and absolute quantitation) analysis for normal and autistic children's plasma of the same age group. RESULTS: The results show that 24 differentially expressed proteins were identified between autistic subjects and controls...
December 23, 2017: Proteomics. Clinical Applications
Juan Gao, Ming Huang, Jingjing Lai, Kaijun Mao, Peisen Sun, Zhongyuan Cao, Youpei Hu, Yingying Zhang, Marie L Schulte, Chaozhi Jin, Jian Wang, Gilbert C White, Zhen Xu, Yan-Qing Ma
Kindlins play an important role in supporting integrin activation by cooperating with talin; however, the mechanistic details remain unclear. Here, we show that kindlins interacted directly with paxillin and that this interaction could support integrin αIIbβ3 activation. An exposed loop in the N-terminal F0 subdomain of kindlins was involved in mediating the interaction. Disruption of kindlin binding to paxillin by structure-based mutations significantly impaired the function of kindlins in supporting integrin αIIbβ3 activation...
November 1, 2017: Journal of Cell Science
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...
November 2017: Chemical Biology & Drug Design
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...
June 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
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...
June 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
Alexia V Gkourogianni, Klytaimnistra Kiouptsi, Vassiliki Koloka, Vassilios Moussis, Vassilios Tsikaris, Christilla Bachelot-Loza, Demokritos C Tsoukatos
αIIb β3 , the major platelet integrin, plays a central role in hemostasis and thrombosis. Upon platelet activation, conformation of αIIb β3 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 LEEDDEEGE1008 of αIIb (pal-K-LEEDDEEGE or pal-K-1000-1008), inhibits thrombin-induced human platelet aggregation, by inhibiting talin association with the integrin...
January 2018: Platelets
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
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
James Schiemer, Andrew Bohm, Li Lin, Glenn Merrill-Skoloff, Robert Flaumenhaft, Jin-Sheng Huang, Guy C Le Breton, Athar H Chishti
Integrins function as bi-directional signaling transducers that regulate cell-cell and cell-matrix signals across the membrane. A key modulator of integrin activation is talin, a large cytoskeletal protein that exists in an autoinhibited state in quiescent cells. Talin is a large 235-kDa protein composed of an N-terminal 45-kDa FERM (4.1, ezrin-, radixin-, and moesin-related protein) domain, also known as the talin head domain, and a series of helical bundles known as the rod domain. The talin head domain consists of four distinct lobes designated as F0-F3...
December 23, 2016: Journal of Biological Chemistry
Hisashi Kato, Yozo Nakazawa, Yumi Kurokawa, Hirokazu Kashiwagi, Yoichiro Morikawa, Daisuke Morita, Fumiaki Banno, Shigenori Honda, Yuzuru Kanakura, Yoshiaki Tomiyama
Affinity regulation of integrin αIIbβ3 for fibrinogen by inside-out signaling plays a critical role in hemostasis. Calcium and diacylglycerol (DAG)-regulated guanine nucleotide exchange factor I (CalDAG-GEFI) was identified as a Rap1-activating molecule, and its role in inside-out αIIbβ3 activation was established in CalDAG-GEFI-deficient mice. However, little information regarding CalDAG-GEFI in human platelets is available. Here, we report a 16-year-old girl with CalDAG-GEFI deficiency who has been suffering from severe bleeding tendency...
December 8, 2016: Blood
Swapan K Dasgupta, Anhquyen Le, Qi Da, Miguel Cruz, Rolando E Rumbaut, Perumal Thiagarajan
In resting platelets, the integrin αIIbβ3 is present in a low-affinity "bent" state. During platelet aggregation, intracytoplasmic signals induce conformational changes (inside-out signaling) that result in a "swung-out" conformation competent to bind ligands such as fibrinogen. The cytoskeleton plays an essential role in αIIbβ3 activation. We investigated the role of the actin interacting protein Wdr1 in αIIbβ3 activation. Wdr1-hypomorphic mice had a prolonged bleeding time (> 10 minutes) compared to that of wild-type mice (2...
2016: PloS One
Baiyun Dai, Peng Wu, Feng Xue, Renchi Yang, Ziqiang Yu, Kesheng Dai, Changgeng Ruan, Gang Liu, Peter J Newman, Cunji Gao
Integrin-αIIbβ3-mediated outside-in signalling is widely accepted as an amplifier of platelet activation; accumulating evidence suggests that outside-in signalling can, under certain conditions, also function as an inhibitor of platelet activation. The role of integrin-αIIbβ3-mediated outside-in signalling in platelet activation is disputable. We employed flow cytometry, aggregometry, immunoprecipitation, and immunoblotting to investigate the role of integrin-αIIbβ3-mediated outside-in signalling in platelet activation...
October 28, 2016: Thrombosis and Haemostasis
Giovanni Longo, Caterina Alexandra Ioannidu, Anna Scotto d'Abusco, Fabiana Superti, Carlo Misiano, Robertino Zanoni, Laura Politi, Luca Mazzola, Francesca Iosi, Francesco Mura, Roberto Scandurra
INTRODUCTION: Recently, we introduced a new deposition method, based on Ion Plating Plasma Assisted technology, to coat titanium implants with a thin but hard nanostructured layer composed of titanium carbide and titanium oxides, clustered around graphitic carbon. The nanostructured layer has a double effect: protects the bulk titanium against the harsh conditions of biological tissues and in the same time has a stimulating action on osteoblasts. RESULTS: The aim of this work is to describe the biological effects of this layer on osteoblasts cultured in vitro...
2016: PloS One
Elena O Artemenko, Alena O Yakimenko, Alexey V Pichugin, Fazly I Ataullakhanov, Mikhail A Panteleev
In resting platelets, adhesive membrane glycoproteins are attached to the cytoskeleton. On strong activation, phosphatidylserine(PS)-positive and -negative platelet subpopulations are formed. Platelet activation is accompanied by cytoskeletal rearrangement, although the glycoprotein attachment status in these two subpopulations is not clear. We developed a new, flow cytometry-based, single-cell approach to investigate attachment of membrane glycoproteins to the cytoskeleton in cell subpopulations. In PS-negative platelets, adhesive glycoproteins integrin αIIbβ3, glycoprotein Ib and, as shown for the first time, P-selectin were associated with the cytoskeleton...
February 15, 2016: Biochemical Journal
Sarah Klapproth, Federico A Moretti, Marlis Zeiler, Raphael Ruppert, Ute Breithaupt, Susanna Mueller, Rainer Haas, Matthias Mann, Markus Sperandio, Reinhard Fässler, Markus Moser
Hematopoietic cells depend on integrin-mediated adhesion and signaling, which is induced by kindlin-3 and talin-1. To determine whether platelet and polymorphonuclear neutrophil (PMN) functions require specific thresholds of kindlin-3, we generated mouse strains expressing 50%, 10%, or 5% of normal kindlin-3 levels. We report that in contrast to kindlin-3-null mice, which die perinatally of severe bleeding and leukocyte adhesion deficiency, mice expressing as little as 5% of kindlin-3 were viable and protected from spontaneous bleeding and infections...
December 10, 2015: Blood
Sarah Klapproth, Markus Sperandio, Elaine M Pinheiro, Monika Prünster, Oliver Soehnlein, Frank B Gertler, Reinhard Fässler, Markus Moser
Talin is an integrin adaptor, which controls integrin activity in all hematopoietic cells. How intracellular signals promote talin binding to the integrin tail leading to integrin activation is still poorly understood, especially in leukocytes. In vitro studies identified an integrin activation complex whose formation is initiated by the interaction of active, guanosine triphosphate (GTP)-bound Ras-related protein 1 (Rap1) with the adapter protein Rap1-GTP-interacting adapter molecule (RIAM) followed by the recruitment of talin to the plasma membrane...
December 17, 2015: Blood
Subhashini Srinivasan, James Schiemer, Xiaowei Zhang, Athar H Chishti, Guy C Le Breton
Even though GPCR signaling in human platelets is directly involved in hemostasis and thrombus formation, the sequence of events by which G protein activation leads to αIIbβ3 integrin activation (inside-out signaling) is not clearly defined. We previously demonstrated that a conformationally sensitive domain of one G protein, i.e. Gα13 switch region 1 (Gα13SR1), can directly participate in the platelet inside-out signaling process. Interestingly however, the dependence on Gα13SR1 signaling was limited to PAR1 receptors, and did not involve signaling through other important platelet GPCRs...
October 9, 2015: Journal of Biological Chemistry
Zhang-Biao Long, Jian-Song Huang, Xiao-Feng Shi, Ji-Chun Yang, Zheng Ruan, Bing Xiao, Xiao-Dong Xi
OBJECTIVE: To study the effect of interaction of the talin rod domain integrin binding site 2 with integrin β3 on platelet signal transduction. METHODS: A peptide that mimics the membrane proximal α helix 6 residues R724 KEFAK729 of the integrin β3 cytoplasmic tails was designed and synthesized, to which the myristoylation was covalently linked to the N-terminal of the peptide enabling membrane penetration. The effects of myr-RKEFAK peptide on the typical platelet outside-in signaling ovent (stable adhesion and spreading on immobilized fibrinogen, aggregation, fibrin clot retraction) and inside-out signaling events (soluble fibrinogen binding) were tested...
June 2015: Zhongguo Shi Yan Xue Ye Xue za Zhi
Natalie S Poulter, Alice Y Pollitt, Amy Davies, Dessislava Malinova, Gerard B Nash, Mike J Hannon, Zoe Pikramenou, Joshua Z Rappoport, John H Hartwig, Dylan M Owen, Adrian J Thrasher, Stephen P Watson, Steven G Thomas
The actin nodule is a novel F-actin structure present in platelets during early spreading. However, only limited detail is known regarding nodule organization and function. Here we use electron microscopy, SIM and dSTORM super-resolution, and live-cell TIRF microscopy to characterize the structural organization and signalling pathways associated with nodule formation. Nodules are composed of up to four actin-rich structures linked together by actin bundles. They are enriched in the adhesion-related proteins talin and vinculin, have a central core of tyrosine phosphorylated proteins and are depleted of integrins at the plasma membrane...
2015: Nature Communications
Joel S Bennett
Blood platelets prevent bleeding after trauma by forming occlusive aggregates at sites of vascular injury. Platelet aggregation is mediated by the integrin heterodimer αIIbβ3 and occurs when platelet agonists generated at the injury site convert αIIbβ3 from its resting to its active conformation. Active αIIbβ3 is then able to bind macromolecular ligands such as fibrinogen that crosslink adjacent platelets into hemostatic aggregates. Platelets circulate in a plasma milieu containing high concentrations of the principal αIIbβ3 ligand fibrinogen...
July 2015: Biopolymers
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