This study investigates three aspects of the adhesive interaction operating between platelet glycoprotein Ib/IX and integrin Œ±IIbŒ≤3. These include the following: 1) examining the sufficiency of GPIb/IX and integrin Œ±IIbŒ≤3 to mediate irreversible cell adhesion on immobilized von Willebrand factor (vWf) under flow; 2) the ability of the vWf-GPIb interaction to induce integrin Œ±IIbŒ≤3 activation independent of endogenous platelet stimuli; and 3) the identification of key second messengers linking the vWf-GPIb/IX interaction to integrin Œ±IIbŒ≤3 activation. By using Chinese hamster ovary cells transfected with GPIb/IX and integrin Œ±IIbŒ≤3, we demonstrate that these receptors are both necessary and sufficient to mediate irreversible cell adhesion under flow, wherein GPIb/IX mediates cell tethering and rolling on immobilized vWf, and integrin Œ±IIbŒ≤3mediates cell arrest. Moreover, we demonstrate direct signaling between GPIb/IX and integrin Œ±IIbŒ≤3. Studies on human platelets demonstrated that vWf binding to GPIb/IX is able to induce integrin Œ±IIbŒ≤3 activation independent of endogenous platelet stimuli under both static and physiological flow conditions (150‚Äì1800 s‚àí 1). Analysis of the key second messengers linking the vWf-GPIb interaction to integrin Œ±IIbŒ≤3 activation demonstrated that the first step in the activation process involves calcium release from internal stores, whereas transmembrane calcium influx is a secondary event potentiating integrin Œ±IIbŒ≤3 activation.
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