| First Author | Vögtle T | Year | 2019 |
| Journal | Elife | Volume | 8 |
| PubMed ID | 31436532 | Mgi Jnum | J:281749 |
| Mgi Id | MGI:6379487 | Doi | 10.7554/eLife.46840 |
| Citation | Vogtle T, et al. (2019) Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B. Elife 8:e46840 |
| abstractText | 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. |
