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

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 AbbottAnita Eckly, Harald Schulze, Gavin J. Wright, Alexandra Mazharian, Klaus Fütterer, Sundaresan Rajesh, Michael R. Douglas, Yotis A. Senis

Research output: Contribution to journalArticle

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

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Keywords

  • biochemistry
  • cell biology
  • chemical biology
  • G6b-B
  • heparan sulfate
  • heparin
  • human
  • ITIM-receptor
  • mouse
  • perlecan
  • platelets

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  • Cite this

    Vögtle, T., Sharma, S., Mori, J., Nagy, Z., Semeniak, D., Scandola, C., Geer, M. J., Smith, C. W., Lane, J., Pollack, S., Lassila, R., Jouppila, A., Barr, A. J., Ogg, D. J., Howard, T. D., McMiken, H. J., Warwicker, J., Geh, C., Rowlinson, R., ... Senis, Y. A. (2019). Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B. eLife, 8, [e46840]. https://doi.org/10.7554/eLife.46840