Cross-talk between glycoprotein Ib and the collagen receptor GPVI in human platelets

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The interaction between immobilized von Willebrand factor (VWF) and the platelet membrane glycoprotein (GP) Ib -IX/V complex is important in platelet arrest and subsequent thrombus formation. Binding of VWF to the GPIb-IX/V complex initiates a number of intracellular signaling events that lead to platelet activation. Our recent studies revealed that the interaction by VWF-botrocetin mediates platelet activation signals in a manner similar to that of the collagen receptor, GPVI, namely through tyrosine phosphorylation of the Fc receptor γ-chain, Syk and phospholipase C γ2 (PLCγ2). We found that GPIb formed a complex with Src and PI3-kinase in resting platelets, and the amount of GPIb-associated Src increased in response to VWF and botrocetin. PI3-kinase inhibitors, wortmannin and Ly294002 had no effects on VWF-mediated platelet aggregation, as well as Src activation and tyrosine phosphorylation of the FcRγ-chain. In this study, we have also found that a portion of GPIb constitutively associates with GPVI, where they have been localized in part to glycolipid-enriched membrane domains (GEMs). Here we provide several lines of evidence that GPIb-mediated signaling pathways interacts with GPVI, and that the interaction between these two receptors is dependent on GEM-organized signaling in human platelets.