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

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

eLife (2019-08-23)
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, Gavin J Wright, Alexandra Mazharian, Klaus Fütterer, Sundaresan Rajesh, Michael R Douglas, Yotis A Senis
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.

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Streptavidin from Streptomyces avidinii, essentially salt-free, lyophilized powder, ≥13 units/mg protein