Synergistic adhesive interactions and signaling mechanisms operating between platelet glycoprotein Ib/IX and integrin αIIbβ3: Studies in human platelets and transfected Chinese hamster ovary cells

Cindy L. Yap, Sascha C. Hughan, Susan L. Cranmer, Warwick S. Nesbitt, Michael M. Rooney, Simon Giuliano, Suhasini Kulkarni, Sacha M. Dopheide, Yuping Yuan, Hatem H. Salem, Shaun P. Jackson

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Abstract

This study investigates three aspects of the adhesive interaction operating between platelet glycoprotein Ib/IX and integrin αIIbβ3. These include the following: 1) examining the sufficiency of GPIb/IX and integrin αIIbβ3 to mediate irreversible cell adhesion on immobilized von Willebrand factor (vWf) under flow; 2) the ability of the vWf-GPIb interaction to induce integrin αIIbβ3 activation independent of endogenous platelet stimuli; and 3) the identification of key second messengers linking the vWf-GPIb/IX interaction to integrin αIIbβ3 activation. By using Chinese hamster ovary cells transfected with GPIb/IX and integrin αIIbβ3, 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 αIIbβ3 mediates cell arrest. Moreover, we demonstrate direct signaling between GPIb/IX and integrin αIIbβ3. Studies on human platelets demonstrated that vWf binding to GPIb/IX is able to induce integrin αIIbβ3 activation independent of endogenous platelet stimuli under both static and physiological flow conditions (150-1800 s-1). Analysis of the key second messengers lingking the vWf-GPIb interaction to integrin αIIbβ3 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 αIIbβ3 activation.

Original languageEnglish
Pages (from-to)41377-41388
Number of pages12
JournalThe Journal of Biological Chemistry
Volume275
Issue number52
DOIs
Publication statusPublished - 29 Dec 2000

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