科研之友
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摘要
Objective-Kindlin-3 is a critical supporter of integrin function in platelets. Lack of expression of kindlin-3 protein in patients impairs integrin alpha IIb beta 3-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 alpha IIb beta 3 in platelets has not been established. Here, we evaluated the significance of the binding of kindlin-3 to integrin alpha IIb beta 3 in platelets in supporting integrin alpha IIb beta 3-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 alpha IIb beta 3 on platelets similar to their wild-type counterparts. Functional analysis revealed that K3KI mice exhibited defective platelet function, including impaired integrin alpha IIb beta 3 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 alpha IIb beta 3 is involved in supporting integrin alpha IIb beta 3 activation and integrin alpha IIb beta 3-dependent responses of platelets and consequently contributes significantly to arterial thrombus formation.
