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

Timo Voegtle, Sumana Sharma, Jun Mori, Zoltan Nagy, Daniela Semeniak, Cyril Scandola, Mitchell Geer, Christopher Smith, 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 AbbottAnita Eckly, Harold Schulze, Gavin J Wright, Alexandra Mazharian, Klaus Futterer, Rajesh Sundaresan, Michael Douglas, Yotis Senis

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)
251 Downloads (Pure)

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.
Original languageEnglish
Article numbere46840
JournaleLife
Volume8
DOIs
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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

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