title: Wdr1-Dependent Actin Reorganization in Platelet Activation.
abstract: 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 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 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.
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, United States of America.|Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, United States of America.
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Dasgupta
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, United States of America.|Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, United States of America.
authors.forename: Anhquyen
authors.initials: A
authors.lastname: Le
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America.|Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, United States of America.
authors.forename: Qi
authors.initials: Q
authors.lastname: Da
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America.|Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, United States of America.
authors.forename: Miguel
authors.initials: M
authors.lastname: Cruz
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America.|Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, United States of America.
authors.forename: Rolando E
authors.initials: RE
authors.lastname: Rumbaut
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, United States of America.|Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, United States of America.
authors.forename: Perumal
authors.initials: P
authors.lastname: Thiagarajan
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D001777:Blood Coagulation / Q000502:physiology; D005455:Fluorescent Antibody Technique; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000502:physiology*; D015539:Platelet Activation / Q000502:physiology*; D010974:Platelet Aggregation / Q000502:physiology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000502:physiology; D016608:Talin / Q000502:physiology
chemical_list: D000199:Actins; D008840:Microfilament Proteins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D016608:Talin; C524014:Wdr1 protein, mouse