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Platelet integrin talin

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 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...
September 23, 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...
July 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
Yun Jin, Lemin Wang, Qianglin Duan, Zhu Gong, Fan Yang, Yanli Song
OBJECTIVE: Whole human genome oligo microarrays were employed to systematically investigate the mRNA expression profile of 5-HT synthetase, transporter, receptor, and factors in 5-HT signaling pathway in peripheral blood karyocytes from pulmonary embolism (PE) patients. METHODS: A total of 20 PE patients and 20 healthy subjects matched in gender and age were recruited. The human genome microarrays were performed to detect the mRNA expression profile of 5-HT synthetase, transporter, receptor, and factors in 5-HT signal pathway of two groups...
2015: International Journal of Clinical and Experimental Medicine
Simon Stritt, Karen Wolf, Viola Lorenz, Timo Vögtle, Shuchi Gupta, Michael R Bösl, Bernhard Nieswandt
Platelet aggregation at sites of vascular injury is essential for hemostasis but also thrombosis. Platelet adhesiveness is critically dependent on agonist-induced inside-out activation of heterodimeric integrin receptors by a mechanism involving the recruitment of talin-1 to the cytoplasmic integrin tail. Experiments in heterologous cells have suggested a critical role of Rap1-guanosine triphosphate-interacting adaptor molecule (RIAM) for talin-1 recruitment and thus integrin activation, but direct in vivo evidence to support this has been missing...
January 8, 2015: Blood
A Li, Q Guo, C Kim, W Hu, F Ye
BACKGROUND: Increases in ligand binding to integrins (activation) play critical roles in platelet and leukocyte function. Integrin activation requires talin and kindlin binding to integrin β cytoplasmic tails. Research has focused on the conserved GFFKR motif in integrin αII b tails, integrin β cytoplasmic tails and the binding partners of β tails. However, the roles of αII b tail distal of GFFKR motif are unexplored. OBJECTIVE: To investigate the role of αII b tail distal of GFFKR in talin-mediated inside-out integrin signaling...
July 2014: Journal of Thrombosis and Haemostasis: JTH
Kendra H Oliver, Tammy Jessen, Emily L Crawford, Chang Y Chung, James S Sutcliffe, Ana M Carneiro
The plasma-membrane integrin αIIbβ3 (CD41/CD61, GPIIbIIIa) is a major functional receptor in platelets during clotting. A common isoform of integrin β3, Leu33Pro is associated with enhanced platelet function and increased risk for coronary thrombosis and stroke, although these findings remain controversial. To better understand the molecular mechanisms by which this sequence variation modifies platelet function, we produced transgenic knockin mice expressing a Pro32Pro33 integrin β3. Consistent with reports utilizing human platelets, we found significantly reduced bleeding and clotting times, as well as increased in vivo thrombosis, in Pro32Pro33 homozygous mice...
June 2014: Molecular Pharmacology
Luke A Yates, Robert J C Gilbert
Kindlins are essential coactivators, with talin, of the cell surface receptors integrins and also participate in integrin outside-in signalling, and the control of gene transcription in the cell nucleus. The kindlins are ~75 kDa multidomain proteins and bind to an NPxY motif and upstream T/S cluster of the integrin β-subunit cytoplasmic tail. The hematopoietically-important kindlin isoform, kindlin-3, is critical for platelet aggregation during thrombus formation, leukocyte rolling in response to infection and inflammation and osteoclast podocyte formation in bone resorption...
2014: Journal of Visualized Experiments: JoVE
Davide Provasi, Ana Negri, Barry S Coller, Marta Filizola
Platelet aggregation is the consequence of the binding of extracellular bivalent ligands such as fibrinogen and von Willebrand factor to the high affinity, active state of integrin αIIbβ3. This state is achieved through a so-called "inside-out" mechanism characterized by the membrane-assisted formation of a complex between the F2 and F3 subdomains of intracellular protein talin and the integrin β3 tail. Here, we present the results of multi-microsecond, all-atom molecular dynamics simulations carried on the complete transmembrane (TM) and C-terminal (CT) domains of αIIbβ3 integrin in an explicit lipid-water environment, and in the presence or absence of the talin-1 F2 and F3 subdomains...
December 2014: Proteins
Jing Li, Kyungho Kim, Eunsil Hahm, Robert Molokie, Nissim Hay, Victor R Gordeuk, Xiaoping Du, Jaehyung Cho
Interactions between platelets, leukocytes, and activated endothelial cells are important during microvascular occlusion; however, the regulatory mechanisms of these heterotypic cell-cell interactions remain unclear. Here, using intravital microscopy to evaluate mice lacking specific isoforms of the serine/threonine kinase AKT and bone marrow chimeras, we found that hematopoietic cell-associated AKT2 is important for neutrophil adhesion and crawling and neutrophil-platelet interactions on activated endothelial cells during TNF-α-induced venular inflammation...
April 2014: Journal of Clinical Investigation
Edward F Plow, Julia Meller, Tatiana V Byzova
PURPOSE OF REVIEW: This review considers recent developments concerning the role of integrins in vascular biology with a specific emphasis on integrin activation, and the crosstalk between integrins and growth factor receptors. RECENT FINDINGS: Recent studies have shown leukocytes can mediate direct transfer of molecules into endothelial cells, how specific integrins can be used to transduce signaling events, in particular in vascular beds, and how endothelial cell integrins can be targeted with specific ligands for the delivery of therapeutics...
May 2014: Current Opinion in Hematology
Lucia Stefanini, Feng Ye, Adam K Snider, Kasra Sarabakhsh, Raymond Piatt, David S Paul, Wolfgang Bergmeier, Brian G Petrich
Tight regulation of integrin affinity is critical for hemostasis. A final step of integrin activation is talin binding to 2 sites within the integrin β cytoplasmic domain. Binding of talin to a membrane-distal NPxY sequence facilitates a second, weaker interaction of talin with an integrin membrane-proximal region (MPR) that is critical for integrin activation. To test the functional significance of these distinct interactions on platelet function in vivo, we generated knock-in mice expressing talin1 mutants with impaired capacity to interact with the β3 integrin MPR (L325R) or NPLY sequence (W359A)...
April 24, 2014: Blood
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