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Wdr1-Dependent Actin Reorganization in Platelet Activation

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 pla...

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Autores principales: Dasgupta, Swapan K., Le, Anhquyen, Da, Qi, Cruz, Miguel, Rumbaut, Rolando E., Thiagarajan, Perumal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5023164/
https://www.ncbi.nlm.nih.gov/pubmed/27627652
http://dx.doi.org/10.1371/journal.pone.0162897
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author Dasgupta, Swapan K.
Le, Anhquyen
Da, Qi
Cruz, Miguel
Rumbaut, Rolando E.
Thiagarajan, Perumal
author_facet Dasgupta, Swapan K.
Le, Anhquyen
Da, Qi
Cruz, Miguel
Rumbaut, Rolando E.
Thiagarajan, Perumal
author_sort Dasgupta, Swapan K.
collection PubMed
description 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 (2.1 ± 0.7 minutes). Their platelets had impaired aggregation to collagen and thrombin. In a FeCl(3) induced carotid artery thrombosis model, vessel occlusion in Wdr1-hypomorphic mice was prolonged significantly compared to wild-type mice (9.0 ± 10.5 minutes versus 5.8 ± 12.6 minutes (p = 0.041). Activation-induced binding of JON/A (a conformation-specific antibody to activated αIIbβ3) was significantly less in Wdr1-hypomorphic platelets at various concentrations of collagen, indicating impaired inside-out activation of αIIbβ3, despite a normal calcium response. Actin turnover, assessed by measuring F-actin and G-actin ratios during collagen- and thrombin-induced platelet aggregation, was highly impaired in Wdr1-hypomorphic platelets. Furthermore, talin failed to redistribute and translocate to the cytoskeleton following activation in Wdr1-hypomorphic platelets. These studies show that Wdr1 is essential for talin-induced activation of αIIbβ3 during platelet activation.
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spelling pubmed-50231642016-09-27 Wdr1-Dependent Actin Reorganization in Platelet Activation Dasgupta, Swapan K. Le, Anhquyen Da, Qi Cruz, Miguel Rumbaut, Rolando E. Thiagarajan, Perumal PLoS One Research Article 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 (2.1 ± 0.7 minutes). Their platelets had impaired aggregation to collagen and thrombin. In a FeCl(3) induced carotid artery thrombosis model, vessel occlusion in Wdr1-hypomorphic mice was prolonged significantly compared to wild-type mice (9.0 ± 10.5 minutes versus 5.8 ± 12.6 minutes (p = 0.041). Activation-induced binding of JON/A (a conformation-specific antibody to activated αIIbβ3) was significantly less in Wdr1-hypomorphic platelets at various concentrations of collagen, indicating impaired inside-out activation of αIIbβ3, despite a normal calcium response. Actin turnover, assessed by measuring F-actin and G-actin ratios during collagen- and thrombin-induced platelet aggregation, was highly impaired in Wdr1-hypomorphic platelets. Furthermore, talin failed to redistribute and translocate to the cytoskeleton following activation in Wdr1-hypomorphic platelets. These studies show that Wdr1 is essential for talin-induced activation of αIIbβ3 during platelet activation. Public Library of Science 2016-09-14 /pmc/articles/PMC5023164/ /pubmed/27627652 http://dx.doi.org/10.1371/journal.pone.0162897 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
Dasgupta, Swapan K.
Le, Anhquyen
Da, Qi
Cruz, Miguel
Rumbaut, Rolando E.
Thiagarajan, Perumal
Wdr1-Dependent Actin Reorganization in Platelet Activation
title Wdr1-Dependent Actin Reorganization in Platelet Activation
title_full Wdr1-Dependent Actin Reorganization in Platelet Activation
title_fullStr Wdr1-Dependent Actin Reorganization in Platelet Activation
title_full_unstemmed Wdr1-Dependent Actin Reorganization in Platelet Activation
title_short Wdr1-Dependent Actin Reorganization in Platelet Activation
title_sort wdr1-dependent actin reorganization in platelet activation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5023164/
https://www.ncbi.nlm.nih.gov/pubmed/27627652
http://dx.doi.org/10.1371/journal.pone.0162897
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