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First published online July 13, 2004
doi: 10.1242/10.1242/jcs.01325

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Platelet adhesion signalling and the regulation of thrombus formation

School of Animal and Microbial Sciences, The University of Reading, Whiteknights, PO Box 228, Reading, Berkshire, RG6 6AJ, UK

View larger version (50K): [in a new window]   Fig. 1. Stages in the development of a platelet thrombus on collagen exposed at sites of injury. The initial interaction of platelets with subendothelial collagens under high shear conditions present in the arterial circulation is indirectly mediated by von Willebrand factor, which binds collagen and platelet GPIb. This unstable interaction facilitates transient tethering and rolling. GPIb-mediated adhesion is superseded by more-stable binding to collagen by GPVI and integrin 2ß1. This, together with GPIb, stimulates platelet signalling that results in shape change and spreading, and the secretion and release of multiple prothrombotic factors. Integrin affinity becomes upregulated through inside-out signalling, resulting in fibrinogen-mediated platelet aggregation through binding to integrin IIbß3, and adhesion is stabilized by enhanced binding of collagen and von Willebrand factor to integrins 2ß1 and IIbß3, respectively.

View larger version (51K): [in a new window]   Fig. 2. Model of platelet signalling stimulated by collagen and von Willebrand factor (VWF). Collagen binding results in GPVI clustering and tyrosine phosphorylation of the Fc receptor -chain (FcR) by the Src-family kinases Lyn and Fyn. This results in the binding of the tyrosine kinase Syk, which becomes tyrosine phosphorylated and activated. This leads to the tyrosine phosphorylation of the transmembrane adaptor protein LAT, which functions to assemble a complex of signalling proteins. Phosphoinositide 3-kinase (PI3K) is recruited to LAT and, through the generation of, among other products, phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3, PIP3 in figure], influences the recruitment and activation of phospholipase C2 (PLC2). PLC2 cleaves phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2, PIP2 in figure] to generate inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] and diacylglycerol (DAG). Ins(1,4,5)P3 and DAG are responsible for the mobilization of calcium from intracellular stores and the activation of isoforms of protein kinase C (PKC), respectively, both of which lead to secretion and aggregation. PI3K activity also results in the regulation of protein kinase B (PKB), phosphoinositide-dependent kinase 1 (PDK1) and integrin-linked kinase (ILK), which are believed to be involved in integrin regulation. PKB also inhibits glycogen synthase kinase 3 (GSK3), which might contribute to a negative-feedback pathway mediated by PKB. The adaptor proteins Gads, SLP-76 and SLAP-130, and the Rho GTP exchange factor Vav, are also recruited to LAT, although the significance of this is unclear. The binding of VWF to GPIb-V-IX results in calcium fluxes that lead to the upregulation of integrin IIbß3 affinity, although the signalling pathway underlying this has not yet been defined. A proposed model based upon current data implicates several molecules involved in GPVI signalling in this process. These include FcR, Fyn, Lyn, Syk, LAT, PLC2, SLP-76, PI3K and PKC. It is possible that a signalling complex similar to that formed in GPVI signalling might mediate GPIb-V-IX signalling as shown, although this model is not confirmed. The roles of other GPIb-V-IX-binding proteins such as filamin, 14-3-3 and calmodulin (CAM) have yet to be determined.