Vögtle, Timo, Sharma, Sumana, Mori, Jun et al. (25 more authors) (2019) Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B. eLife. e46840. ISSN 2050-084X
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. © 2019, Vögtle et al.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Keywords: | parasites and microbes,staffpaper |
Dates: |
|
Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Biology (York) The University of York > Faculty of Sciences (York) > Hull York Medical School (York) |
Depositing User: | Pure (York) |
Date Deposited: | 20 Oct 2020 15:20 |
Last Modified: | 16 Oct 2024 17:01 |
Published Version: | https://doi.org/10.7554/eLife.46840 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.7554/eLife.46840 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:166966 |