TY - JOUR TI - Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B AU - Vögtle, Timo AU - Sharma, Sumana AU - Mori, Jun AU - Nagy, Zoltan AU - Semeniak, Daniela AU - Scandola, Cyril AU - Geer, Mitchell J AU - Smith, Christopher W AU - Lane, Jordan AU - Pollack, Scott AU - Lassila, Riitta AU - Jouppila, Annukka AU - Barr, Alastair J AU - Ogg, Derek J AU - Howard, Tina D AU - McMiken, Helen J AU - Warwicker, Juli AU - Geh, Catherine AU - Rowlinson, Rachel AU - Abbott, W Mark AU - Eckly, Anita AU - Schulze, Harald AU - Wright, Gavin J AU - Mazharian, Alexandra AU - Fütterer, Klaus AU - Rajesh, Sundaresan AU - Douglas, Michael R AU - Senis, Yotis A A2 - Bjorkman, Pamela J A2 - Cole, Philip A VL - 8 PY - 2019 DA - 2019/08/22 SP - e46840 C1 - eLife 2019;8:e46840 DO - 10.7554/eLife.46840 UR - https://doi.org/10.7554/eLife.46840 AB - 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. KW - platelets KW - ITIM-receptor KW - G6b-B KW - heparan sulfate KW - heparin KW - perlecan JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -