Glycoprotein Ib-V-IX, a Receptor for von Willebrand Factor, Couples Physically and Functionally to the Fc Receptor y-Chain, Fyn, and Lyn to Activate Human Platelets
The adhesion molecule von Willebrand factor (vWF) activates platelets upon binding 2 surface receptors, glycoprotein (GP) Ib-V-IX and integrin aIIbb3. We have used 2 approaches to selectively activate GP Ib using either the snake venom lectin alboaggregin-A or mutant recombinant forms of vWF (DA1-vWF and RGGS-vWF) with selective binding properties to its 2 receptors. We show that activation of GP Ib induces platelet aggregation, secretion of 5-hydroxy tryptamine (5-HT), and an increase in cytosolic calcium. Syk becomes tyrosine phosphorylated and activated downstream of GP Ib, and associates with several tyrosinephosphorylated proteins including the Fc receptor g-chain through interaction with Syk SH2 domains. GP Ib physically associates with the g-chain in GST-Syk-SH2 precipitates from platelets stimulated through GP Ib, and 2 Src family
kinases, Lyn and Fyn, also associate with this signaling complex. In addition, GP Ib stimulation couples to tyrosine phosphorylation of phospholipase Cg2. The Src familyspecific inhibitor PP1 dose-dependently inhibits phosphorylation of Syk, its association with tyrosine-phosphorylated g-chain, phosphorylation of PLCg2, platelet aggregation, and 5-HT release. The results indicate that, upon activation, GP Ib is physically associated with FcR g-chain and members of the Src family kinases, leading to phosphorylation of the g-chain, recruitment, and activation of Syk. Phosphorylation of PLCg2 also lies downstream of Src kinase activation and may critically couple early signaling events to functional platelet responses.
Falati, Shahrokh; Edmead, Christine E.; and Poole, Alastair W., "Glycoprotein Ib-V-IX, a Receptor for von Willebrand Factor, Couples Physically and Functionally to the Fc Receptor y-Chain, Fyn, and Lyn to Activate Human Platelets" (1999). Articles & Chapters. 1533.
Blood, Vol 94, No 5 (September 1), 1999: pp 1648-1656