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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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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. |
format | Online Article Text |
id | pubmed-5023164 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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