Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B

Research output: Contribution to journalArticle

Authors

  • Sumana Sharma
  • Daniela Semeniak
  • Cyril Scandola
  • Mitchell Geer
  • Jordan Lane
  • Scott Pollack
  • Riitta Lassila
  • Annukka Jouppila
  • Alastair J. Barr
  • Derek J Ogg
  • Tina D Howard
  • Helen McMiken
  • Juli Warwicker
  • Catherine Geh
  • Rachel Rowlinson
  • W. Mark Abbott
  • Anita Eckly
  • Harold Schulze
  • Gavin J Wright
  • Klaus Futterer
  • Rajesh Sundaresan
  • Michael Douglas
  • Yotis Senis

External organisations

  • Sygnature Discovery Limited
  • Wellcome Trust Sanger Institute
  • University Hospital Würzburg
  • Université de Strasbourg
  • University of Helsinki
  • Helsinki University Hospital
  • University of Westminster
  • Peak Proteins Limited

Abstract

The immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor G6b-B is critical for platelet production and activation. Loss of G6b-B results in severe macrothrombocytopenia, myelofibrosis and aberrant platelet function in mice and humans. Using a combination of immunohistochemistry, affinity chromatography and proteomics, we identified the extracellular matrix heparan sulfate (HS) proteoglycan perlecan as a G6b-B binding partner. Subsequent in vitro biochemical studies and a cell-based genetic screen demonstrated that the interaction is specifically mediated by the HS chains of perlecan. Biophysical analysis revealed that heparin forms a high-affinity complex with G6b-B and mediates dimerization. Using platelets from humans and genetically-modified mice, we demonstrate that binding of G6b-B to HS and multivalent heparin inhibits platelet and megakaryocyte function by inducing downstream signaling via the tyrosine phosphatases Shp1 and Shp2. Our findings provide novel insights into how G6b-B is regulated and contribute to our understanding of the interaction of megakaryocytes and platelets with glycans.

Details

Original languageEnglish
Article number46840
Pages (from-to)1-43
Number of pages43
JournalElife
Volume8
Publication statusPublished - 22 Aug 2019

Keywords

  • Platelets, ITIM-Receptor, G6b-B, heparan sulfate, heparin, perlecan, signaling, tyrosine phosphatases, platelets, ITIM-receptor, mouse, cell biology, chemical biology, biochemistry, human