GPVI potentiation of platelet activation by thrombin and adhesion molecules independent of Src kinases and Syk

Sascha C. Hughan, Craig E. Hughes, Owen J.T. McCarty, Edina Schweighoffer, Izoumroud Soultanova, Jerry Ware, Victor L.J. Tybulewicz, Steve P. Watson

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

OBJECTIVE - The present study investigates the role of Src and Syk tyrosine kinases in signaling by G-protein coupled and platelet adhesion receptors. METHODS AND RESULTS - Using Syk platelets or the Src kinase inhibitor PP2, we demonstrate a critical role for Src and Syk kinases in mediating lamellipodia formation on VWF, collagen, CRP, fibrinogen, and fibronectin. In all cases, the spreading defect was overcome by addition of thrombin. Conversely, platelet aggregation and αIIbβ3 activation induced by thrombin was similar to controls, arguing against a functional role for Src and Syk in αIIbβ3 activation. Unexpectedly, CRP potentiated integrin αIIbβ3 activation and platelet aggregation induced by subthreshold concentrations of thrombin in Syk platelets or in the presence of the Src kinase inhibitor PP2. Potentiation in the presence of PP2 was lost in the absence of FcRγ-chain or GPVI confirming that it was mediated through the immunoglobulin receptor. Further delineation of this PP2-resistant synergy revealed that PAR4 could trigger the enhanced response in combination with CRP. CONCLUSIONS - We show that Syk is critical for lamellipodia formation on a range of immobilized proteins but that this can be overcome by addition of thrombin. Further, we reveal a novel role for GPVI in supporting thrombin-induced activation, independent of Syk and Src kinases.

Original languageEnglish (US)
Pages (from-to)422-429
Number of pages8
JournalArteriosclerosis, thrombosis, and vascular biology
Volume27
Issue number2
DOIs
StatePublished - Feb 2007

Keywords

  • GPVI signaling
  • Platelets
  • Src kinases
  • Syk
  • Thrombin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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