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J Biol Chem, Vol. 273, Issue 32, 20317-20322, August 7, 1998

A Sequence within the Cytoplasmic Tail of GpIIb Independently Activates Platelet Aggregation and Thromboxane Synthesis

Gillian Stephens, Niamh O'Luanaigh, Dermot Reilly, Patrick HarriottDagger , Brian WalkerDagger , Desmond Fitzgerald, and Niamh Moran

From the Centre for Cardiovascular Science, Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland and Dagger  Department of Biochemistry, Queens University, Belfast, BT9 7BL, Northern Ireland

All integrin alpha  subunits contain a highly conserved KXGFFKR motif in their cytoplasmic domains that plays a crucial role in the regulation of integrin affinity for their ligands. We show that a lipid-modified peptide corresponding to the cytoplasmic region, 989-995, of the platelet integrin subunit glycoprotein GpIIb (alpha IIb), palmitoyl-KVGFFKR (Ppep; 10 µM), but not a similarly modified scrambled peptide (palmitoyl-FKFVRGK), can specifically induce platelet activation and aggregation equivalent to that of strong agonists such as thrombin. Ppep-induced aggregation is also associated with indices of platelet activation including thromboxane A2 (TXA2) synthesis (EC50 = 45 ± 5 µM), secretion of alpha -granules detected as enhanced surface expression of P-selectin (EC50 = 52 ± 8 µM), and conformational changes in GpIIb/IIIa measured by the monoclonal antibody, PAC-1 (EC50 = 3.7 ± 1 µM). The TXA2 receptor antagonist, SQ29548, PGE1, and the ADP scavenger, apyrase, differentially inhibit the aggregation response and TXA2 synthesis in response to Ppep. Similarly, GpIIb/IIIa antagonists (RO-449883 and integrelin), which inhibit aggregation by greater than 90%, have little effect on peptide-induced TXA2 synthesis, suggesting that this event is independent of fibrinogen binding to GpIIb/IIIa. Alanine-stepping of the Ppep sequence identifies GFFK(991-994) as the critical residues in all peptide-mediated events. We conclude that this peptide can imitate the cytoplasmic domain of GpIIb and initiate parallel but independent signaling pathways, one leading to ligand binding and platelet aggregation and the other to intracellular signaling events such as TXA2 synthesis and secretion.

Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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