Src family tyrosine kinase Lyn mediates VWF/GPIb-IX–induced platelet activation via the cGMP signaling pathway
Open Access
- 15 August 2008
- journal article
- Published by American Society of Hematology in Blood
- Vol. 112 (4), 1139-1146
- https://doi.org/10.1182/blood-2008-02-140970
Abstract
The platelet receptor for von Willebrand factor (VWF), glycoprotein (GP) Ib-IX, mediates initial platelet adhesion and transmits signals leading to platelet activation. Src family tyrosine kinases (SFKs) play an important role in VWF-induced GPIb-IX signaling. However, the SFK-dependent downstream signaling pathway is unclear but is thought to involve thromboxane A2 (TXA2) synthesis. Here we show that, although platelets deficient in SFK members, Lyn or Fyn, were defective in the TXA2-dependent second wave of platelet aggregation induced by botrocetin/VWF, only Lyn-knockout platelets were also defective in stable platelet adhesion to VWF under shear stress that is independent of the TXA2 pathway. Lyn-knockout platelets also spread poorly on VWF but spread normally on fibrinogen, indicating an important role for Lyn in VWF-mediated GPIb signaling but not in integrin outside-in signaling. Importantly, Lyn knockout abrogated VWF-induced cGMP elevation. Addition of low concentrations of 8-bromo-cGMP, however, corrected the defective stable adhesion of Lyn-knockout platelets or PP2-treated platelets on VWF. These results demonstrate an important role for Lyn in VWF/GPIb-IX–induced integrin activation mediated via the cGMP signaling pathway independently of TXA2 synthesis and also indicate that Lyn is critically important in GPIb-IX–mediated activation of the cGMP pathway.Keywords
This publication has 45 references indexed in Scilit:
- Analysis of Fyn function in hemostasis and αIIbβ3-integrin signalingJournal of Cell Science, 2008
- A functional 14-3-3ζ–independent association of PI3-kinase with glycoprotein Ibα, the major ligand-binding subunit of the platelet glycoprotein Ib-IX-V complexBlood, 2008
- The role of Akt in the signaling pathway of the glycoprotein Ib-IX–induced platelet activationBlood, 2008
- A molecular switch that controls cell spreading and retractionThe Journal of cell biology, 2007
- Src family kinase–mediated and Erk-mediated thromboxane A2 generation are essential for VWF/GPIb-induced fibrinogen receptor activation in human plateletsBlood, 2005
- Glycoprotein VI is associated with GPIb-IX-V on the membrane of resting and activated plateletsThrombosis and Haemostasis, 2005
- The roles of ADP and TXA2 in botrocetin/VWF‐induced aggregation of washed plateletsJournal of Thrombosis and Haemostasis, 2004
- Signaling through GP Ib-IX-V activates αIIbβ3 independently of other receptorsBlood, 2004
- Identification of aspartic acid 514 through glutamic acid 542 as a glycoprotein Ib-IX complex receptor recognition sequence in von Willebrand factor. Mechanism of modulation of von Willebrand factor by ristocetin and botrocetinBiochemistry, 1992
- Factor VIII/von Willebrand Factor has potent lectin activityBiochemical and Biophysical Research Communications, 1984