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

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Author(s)

  • Timo Vögtle
  • Sumana Sharma
  • Jun Mori
  • Zoltan Nagy
  • Daniela Semeniak
  • Cyril Scandola
  • Mitchell J Geer
  • Christopher W Smith
  • Jordan Lane
  • Scott Pollack
  • Riitta Lassila
  • Annukka Jouppila
  • Alastair J Barr
  • Derek J Ogg
  • Tina D Howard
  • Helen J McMiken
  • Juli Warwicker
  • Catherine Geh
  • Rachel Rowlinson
  • W Mark Abbott
  • Anita Eckly
  • Harald Schulze
  • Alexandra Mazharian
  • Klaus Fütterer
  • Sundaresan Rajesh
  • Michael R Douglas
  • Yotis A Senis

Department/unit(s)

Publication details

JournaleLife
DateAccepted/In press - 21 Aug 2019
DatePublished (current) - 22 Aug 2019
Volume8
Number of pages43
Original languageEnglish

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. © 2019, Vögtle et al.

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  • parasites and microbes, staffpaper

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