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Signalling through the platelet GPIb-V-IX complex Volume 14, issue 4, Juillet-août 2008

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Authors
INSERM U311, EFS-Alsace, 10 rue Spielmann, 67065 Strasbourg Cedex

The platelet GPIb-V-IX complex is a multisubunit receptor, assembled from the GPIbα, GPIbβ, GPIX and GPV transmembrane subunits, which plays en essential role in haemostasis by its ability to interact with von Willebrand factor, ensuring the recruitment of platelets from the circulation at the site of vessel injury. This unique function, carried by the GPIbα subunit, allows the transient adhesion of platelets under high shear conditions found in arteries and the microcirculation. This rolling step is followed by the stable adhesion and aggregation of platelets. This adhesive function is accompanied by an ability to transduce an intracellular signal in response to von Willebrand factor. This signalling function has been mainly studied in in vitro systems. A specific activation has been observed following platelet adhesion on matrix-immobilized von Willebrand factor inducing a typical shape change whereby discoid platelets become spheric and extend numerous filopodia. The signalling pathway involves a Src family kinase, PLCγ2 activation, IP 3 production, and mobilization of intracellular Ca 2+. This weak signalling event is amplified to result in the activation of the α IIbβ 3 integrin, and the stable attachment and spreading of platelets. Most studies of GPIb-dependent signalling have been performed under conditions of platelet aggregation in suspension in the presence of soluble von Willebrand factor. In these systems, the responses are not due to the GPIb-V-IX complex itself but reflect amplification by agonists secreted (ADP) or synthesized (TxA2) by the platelets and depend on the engagement of the α IIbβ 3 integrin. The signalling pathways and effectors, such as PI3 kinase, MAP kinases, and PKC, reported in these studies are therefore not specifically triggered by the GPIb-V-IX complex. The cytoplasmic domains of the GPIb-V-IX complex involved in the early signalling events are still unknown. The intracellular segments do not exhibit enzymatic activity but partners have been identified in GPIbα and GPIbβ interacting directly (filamin, 14-3-3, and calmodulin) or indirectly (PI3kinase, SHIP-2 and α-actinin), and for which the signalling function remains to be established. The physiological significance of the signalling triggered by the GPIb-V-IX is still unknown but the fact that it takes place at an early stage of the haemostatic plug or thrombus formation, makes it a potentially interesting pharmacological target. Its blockade could, by inactivating the first layer of platelets adhering at the lesion site, slow down thrombus growth while maintaining sufficient initial adhesion to support haemostasis.