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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 publication

DOI

10.7554/eLife.46840

Type

Journal article

Journal

Elife

Publication Date

22/08/2019

Volume

8

Keywords

G6b-B, ITIM-receptor, biochemistry, cell biology, chemical biology, heparan sulfate, heparin, human, mouse, perlecan, platelets, Animals, Blood Platelets, Heparitin Sulfate, Humans, Megakaryocytes, Mice, Inbred C57BL, Mice, Knockout, Protein Binding, Protein Multimerization, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Receptors, Immunologic, Signal Transduction