SLAP/SLAP2 prevent excessive platelet (hem)ITAM signaling in thrombosis and ischemic stroke in mice

Research output: Contribution to journalArticle

Authors

  • Deya Cherpokova
  • Markus Bender
  • Martina Morowski
  • Peter Kraft
  • Michael K Schuhmann
  • Sarah M Akbar
  • Cheryl S Sultan
  • Christoph Kleinschnitz
  • Guido Stoll
  • Leonard L Dragone
  • Bernhard Nieswandt

Colleges, School and Institutes

Abstract

Glycoprotein VI and C-type lectin-like receptor 2 are essential platelet activating receptors in hemostasis and thrombo-inflammatory disease, which signal through a (hem)immunoreceptor tyrosine-based activation motif (ITAM)-dependent pathway. The adapter molecules Src-like adapter proteins (SLAP and SLAP2) are involved in the regulation of immune cell surface expression and signaling, but their function in platelets is unknown. In this study, we show that platelets expressed both SLAP isoforms and that overexpression of either protein in a heterologous cell line almost completely inhibited glycoprotein VI and C-type lectin-like receptor 2 signaling. In mice, single deficiency of SLAP or SLAP2 had only moderate effects on platelet function, whereas double deficiency of both adapters resulted in markedly increased signal transduction, integrin activation, granule release, aggregation, procoagulant activity, and thrombin generation in response to (hem)ITAM-coupled, but not G protein-coupled, receptor activation. In vivo, constitutive SLAP/SLAP2 knockout mice displayed accelerated occlusive arterial thrombus formation and a dramatically worsened outcome after focal cerebral ischemia. This was attributed to the absence of both adapter proteins in platelets, as demonstrated by adoptive transfer of Slap(-/-)/Slap2(-/-) platelets into wild-type mice. Our results establish SLAP and SLAP2 as critical inhibitors of platelet (hem)ITAM signaling in the setting of arterial thrombosis and ischemic stroke.

Bibliographic note

© 2015 by The American Society of Hematology.

Details

Original languageEnglish
Pages (from-to)185-194
Number of pages10
JournalBlood
Volume125
Issue number1
Early online date19 Oct 2014
Publication statusPublished - 1 Jan 2015

Keywords

  • Adaptor Proteins, Signal Transducing, Amino Acid Motifs, Animals, Blood Platelets, Brain Infarction, Carotid Arteries, Cell Membrane, Crotalid Venoms, Inflammation, Intracellular Signaling Peptides and Proteins, Lectins, C-Type, Membrane Proteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Middle Cerebral Artery, Phosphoproteins, Platelet Activation, Platelet Membrane Glycoproteins, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-cbl, Proto-Oncogene Proteins pp60(c-src), Signal Transduction, Snake Venoms, Thrombosis