Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B
Year: 2019
Type: article
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.
Source: eLife
DOI: 10.7554/elife.46840
Authors: 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
Institutions: University of Birmingham, Wellcome Sanger Institute, Universitätsklinikum Würzburg, Inserm, Biologie et pharmacologie des plaquettes sanguines : hémostase, thrombose, transfusion, Université de Strasbourg, University of Helsinki, Helsinki University Hospital, University of Westminster, Aston University, Dudley Group NHS Foundation Trust
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,500
Awards: G1304440978, Deciphering interactions between megakaryocytes and their bone marrow environment, a prerequisite to implement in vitro platelet production for transfusion, Regulation of platelet activation and thrombosis by the G6b-B-Shp1/2 signalling complex, Regulation of platelet homeostasis and thrombosis by the kinase-phosphatase pair Csk-CD148, Wellcome Trust Sanger Institute - generic account for deposition of all core- funded research papers., A novel mechanism controlling platelet production involving suppression of ERK1/2 by DUSP1/6
OpenAlex ID: W2969611248