Signaling through GP Ib-IX-V activates αIIbβ3 independently of other receptors

Ana Kasirer-Friede, Maria Rita Cozzi, Mario Mazzucato, Luigi De Marco, Zaverio M. Ruggeri, Sanford J. Shattil

Research output: Contribution to journalArticle

Abstract

Platelet adhesion to von Willebrand factor (VWF) activates αIIbβ3, a prerequisite for thrombus formation. However, it is unclear whether the primary VWF receptor, glycoprotein (GP) Ib-IX-V, mediates αIIbβ3 activation directly or through other signaling proteins physically associated with it (eg, FcR γ-chain), possibly with the contribution of other agonist receptors and of VWF signaling through αIIbβ3. To resolve this question, human and GP Ibα transgenic mouse platelets were plated on dimeric VWF A1 domain (dA1VWF), which engages only GP Ib-IX-V, in the presence of inhibitors of other agonist receptors. Platelet adhesion to dA1VWF induced Src kinase-dependent tyrosine phosphorylation of the FcR γ-chain and the adapter molecule, ADAP, and triggered intracellular Ca2+ oscillations and αIIbβ3 activation. Inhibition of Ca2+ oscillations with BAPTA-AM prevented αIIbβ3 activation but not tyrosine phosphorylation. Pharmacologic inhibition of protein kinase C (PKC) or phosphatidylinositol 3-kinase (PI 3-kinase) prevented αIIbβ3 activation but not Ca2+ oscillations. Inhibition of Src with 2 distinct compounds blocked all responses downstream of GP Ib-IX-V under static or flow conditions. However, dA1VWF-induced responses were reduced only slightly in GP Ibα transgenic platelets lacking FcR γ-chain. These data establish that GP Ib-IX-V itself can signal to activate αIIbβ3, through sequential actions of Src kinases, Ca2+ oscillations, and PI 3-kinase/PKC.

Original languageEnglish
Pages (from-to)3403-3411
Number of pages9
JournalBlood
Volume103
Issue number9
DOIs
Publication statusPublished - May 1 2004

ASJC Scopus subject areas

  • Hematology

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    Kasirer-Friede, A., Cozzi, M. R., Mazzucato, M., De Marco, L., Ruggeri, Z. M., & Shattil, S. J. (2004). Signaling through GP Ib-IX-V activates αIIbβ3 independently of other receptors. Blood, 103(9), 3403-3411. https://doi.org/10.1182/blood-2003-10-3664