Localization of the adhesion receptor glycoprotein Ib-IX-V complex to lipid rafts is required for platelet adhesion and activation.
The platelet glycoprotein (GP) Ib-IX-V complex mediates the attachment of platelets to the blood vessel wall by binding von Willebrand factor (VWF), an interaction that also transmits signals for platelet activation and aggregation. Because the complex is extensively palmitoylated, a modification known to target proteins to lipid rafts, we investigated the role of raft localization in GP Ib-IX-V functions. In unstimulated platelets, a minor portion of the complex localized to Triton-insoluble raft fractions; this portion increased three to sixfold with platelet activation by VWF. Raft-associated GP Ib-IX-V was selectively palmitoylated, with GP Ib-IX-V-associated palmitate increasing in the raft fraction on VWF-mediated activation. The raft fraction was also the site of association between GP Ib-IX-V and the Fc receptor FcgammaRIIA. The importance of this association was demonstrated by the ability of the FcgammaRIIA antibody IV.3 to inhibit shear-induced platelet aggregation. Disruption of rafts by depleting membrane cholesterol impaired several GP Ib-IX-V-dependent platelet fractions: aggregation to VWF under static conditions and under shear stress, tyrosine phosphorylation, and adhesion to a VWF surface. Partial restoration of membrane cholesterol content partially restored shear-induced platelet aggregation and tyrosine phosphorylation. Thus, localization of the GP Ib-IX-V complex within rafts is crucial for both platelet adhesion and postadhesion signaling.
Shrimpton
Corie N
CN
Thrombosis Research Section, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Borthakur
Gautam
G
Larrucea
Susana
S
Cruz
Miguel A
MA
Dong
Jing-Fei
JF
López
José A
JA
D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D015539:Platelet Activation / Q000502:physiology*; D010974:Platelet Aggregation / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism* / Q000502:physiology; D017452:Receptors, IgG / Q000378:metabolism
D010980:Platelet Membrane Glycoproteins; D017452:Receptors, IgG; D002784:Cholesterol