Direct interaction of kindlin-3 with integrin αIIbβ3 in platelets is required for supporting arterial thrombosis in mice. Arterioscler Thromb Vasc Biol 2014 Sep;34(9):1961-7
Date
06/28/2014Pubmed ID
24969775Pubmed Central ID
PMC4167429DOI
10.1161/ATVBAHA.114.303851Scopus ID
2-s2.0-84906939916 (requires institutional sign-in at Scopus site) 36 CitationsAbstract
OBJECTIVE: Kindlin-3 is a critical supporter of integrin function in platelets. Lack of expression of kindlin-3 protein in patients impairs integrin αIIbβ3-mediated platelet aggregation. Although kindlin-3 has been categorized as an integrin-binding partner, the functional significance of the direct interaction of kindlin-3 with integrin αIIbβ3 in platelets has not been established. Here, we evaluated the significance of the binding of kindlin-3 to integrin αIIbβ3 in platelets in supporting integrin αIIbβ3-mediated platelet functions.
APPROACH AND RESULTS: We generated a strain of kindlin-3 knockin (K3KI) mice that express a kindlin-3 mutant that carries an integrin-interaction defective substitution. K3KI mice could survive normally and express integrin αIIbβ3 on platelets similar to their wild-type counterparts. Functional analysis revealed that K3KI mice exhibited defective platelet function, including impaired integrin αIIbβ3 activation, suppressed platelet spreading and platelet aggregation, prolonged tail bleeding time, and absence of platelet-mediated clot retraction. In addition, whole blood drawn from K3KI mice showed resistance to in vitro thrombus formation and, as a consequence, K3KI mice were protected from in vivo arterial thrombosis.
CONCLUSIONS: These observations demonstrate that the direct binding of kindlin-3 to integrin αIIbβ3 is involved in supporting integrin αIIbβ3 activation and integrin αIIbβ3-dependent responses of platelets and consequently contributes significantly to arterial thrombus formation.
Author List
Xu Z, Chen X, Zhi H, Gao J, Bialkowska K, Byzova TV, Pluskota E, White GC 2nd, Liu J, Plow EF, Ma YQAuthor
Gilbert C. White MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Amino Acid SubstitutionAnimals
Bleeding Time
Blood Platelets
Carotid Artery Thrombosis
Cell Shape
Chlorides
Clot Retraction
Cytoskeletal Proteins
Disease Models, Animal
Female
Ferric Compounds
Gene Knock-In Techniques
Genes, Reporter
Male
Mice
Mice, Inbred C57BL
Microspheres
Platelet Activation
Platelet Glycoprotein GPIIb-IIIa Complex
Protein Interaction Mapping
Recombinant Fusion Proteins
