| First Author | Dasgupta SK | Year | 2016 |
| Journal | PLoS One | Volume | 11 |
| Issue | 9 | Pages | e0162897 |
| PubMed ID | 27627652 | Mgi Jnum | J:251339 |
| Mgi Id | MGI:6100276 | Doi | 10.1371/journal.pone.0162897 |
| Citation | Dasgupta SK, et al. (2016) Wdr1-Dependent Actin Reorganization in Platelet Activation. PLoS One 11(9):e0162897 |
| abstractText | In resting platelets, the integrin alphaIIbbeta3 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 alphaIIbbeta3 activation. We investigated the role of the actin interacting protein Wdr1 in alphaIIbbeta3 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 FeCl3 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 alphaIIbbeta3) was significantly less in Wdr1-hypomorphic platelets at various concentrations of collagen, indicating impaired inside-out activation of alphaIIbbeta3, 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 alphaIIbbeta3 during platelet activation. |
