Src family kinase–mediated and Erk-mediated thromboxane A2 generation are essential for VWF/GPIb-induced fibrinogen receptor activation in human platelets
Open Access
- 15 November 2005
- journal article
- Published by American Society of Hematology in Blood
- Vol. 106 (10), 3410-3414
- https://doi.org/10.1182/blood-2005-05-1933
Abstract
The binding of von Willebrand factor (VWF) to the platelet membrane glycoprotein Ib-IX (GPIb-IX) results in platelet activation. In this study, we sought to clarify previous conflicting reports and to elucidate the mechanism of activation and the precise role of extracellular signal-regulated kinase (Erk) in VWF-induced platelet activation. Erk2 is activated in platelets on stimulation with VWF/ristocetin in a time-dependent manner. VWF-induced Erk2 phosphorylation and thromboxane A2 (TXA2) release were completely blocked by PP2, an Src family kinase inhibitor, suggesting that Erk is downstream of Src family kinases. U73122, a phospholipase C inhibitor, also abolished TXA2 generation and Erk phosphorylation. Although VWF fostered the agglutination of platelets regardless of any additional treatment, the inhibition of mitogen-activated protein kinase kinase (MEK) with U0126 abolished VWF-induced platelet aggregation and thromboxane production in non–aspirin-treated washed platelets. However, in platelets treated with aspirin, VWF failed to cause any aggregation. Thus, we conclude that VWF stimulation of platelets results in phospholipase A2 activation through Erk stimulation and that Src family kinases and phospholipase C play essential roles in this event. We further conclude that VWF-induced platelet aggregation does not directly depend on Erk activation but has an absolute requirement for Src/Erk-mediated TXA2 generation.Keywords
This publication has 30 references indexed in Scilit:
- Botrocetin/VWF-induced signaling through GPIb-IX-V produces TxA2 in an αIIbβ3- and aggregation-independent mannerBlood, 2005
- Molecular mechanism and functional implications of thrombin-mediated tyrosine phosphorylation of PKCδ in plateletsBlood, 2005
- Differential requirements for calcium and Src family kinases in platelet GPIIb/IIIa activation and thromboxane generation downstream of different G-protein pathwaysBlood, 2005
- The roles of ADP and TXA2 in botrocetin/VWF‐induced aggregation of washed plateletsJournal of Thrombosis and Haemostasis, 2004
- Signaling Role for Phospholipase Cγ2 in Platelet Glycoprotein Ibα Calcium Flux and Cytoskeletal ReorganizationJournal of Biological Chemistry, 2003
- Sequential cytoplasmic calcium signals in a 2-stage platelet activation process induced by the glycoprotein Ibα mechanoreceptorBlood, 2002
- Glycoprotein IIb-IIIa-dependent aggregation by glycoprotein Ibα is reinforced by a Src family kinase inhibitor (PP1)-sensitive signalling pathwayBiochemical Journal, 2002
- Essential role for phosphoinositide 3-kinase in shear-dependent signaling between platelet glycoprotein Ib/V/IX and integrin αIIbβ3Blood, 2002
- Platelet Activation by von Willebrand Factor Requires Coordinated Signaling through Thromboxane A2 and FcγIIA ReceptorPublished by Elsevier BV ,2001
- Thrombospondin-platelet interactions. Role of divalent cations, wall shear rate, and platelet membrane glycoproteins.JCI Insight, 1993