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Christophe Dubois, Beat Steiner, Sylvie C. Meyer Reigner
Contribution of PAR-1, PAR-4 and GPIb in intracellular signaling leading to the cleavage of the 3 cytoplasmic domain during thrombin-induced platelet aggregation
Integrin IIb3 plays a pivotal role in platelet aggregation by binding to fibrinogen. The 3 cytoplasmic domain of IIb3 interacts with cytoskeletal and signaling proteins and is cleaved by -calpain, a calcium regulated cysteine protease. In the present study, we have investigated in more detail the cleavage of the 3 cytoplasmic domain during platelet aggregation induced by thrombin, TRAP-1 and TRAP-4. Our data show that 3 is cleaved in all three cases. The time course of 3 cleavage and the amount of cleaved 3 depends on the way platelets are activated and on the complete activation of -calpain, with a maximum of 90% of cleaved 3 obtained when thrombin is used. Furthermore, our results also show that the cleaved IIb3 is mainly distributed in the Triton soluble fraction, indicating its inability to bind to the cytoskeleton. Interestingly, in the absence of GPIb or following inhibition of thrombin binding to GPIb, there is a reduction in the thrombin-induced calcium flux, 3 cleavage and -calpain activation. These results suggest that cleavage of the 3 cytoplasmic domain by -calpain might be an important step regulating the link between the cytoskeleton and IIb3 during platelet aggregation, and that GPIb could function as a cofactor for the complete activation of platelets by thrombin.
Thrombosis and Haemostasis, Schattauer
Print ISSN: 0340-6245
Volume: 91, 04/2004
Pages: 733 - 742