Dextran sulfate triggers platelet aggregation via direct activation of PEAR1
| Autor: | Katrien Cludts, Maarten Criel, Yiting Sun, Peter Verhamme, Soetkin Van kerckhoven, Thomas Vanassche, Marc Hoylaerts, Christophe Vandenbriele, Benedetta Izzi |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Blood Platelets Platelet aggregation Platelet Aggregation Platelet Function Tests Fibrinogen receptor Syk Receptors Cell Surface Models Biological environment and public health Cell Line 03 medical and health sciences Mice Medicine Animals Humans Syk Kinase Platelet Lectins C-Type Phosphorylation Receptor PI3K/AKT/mTOR pathway Mice Knockout Membrane Glycoproteins business.industry Dextran Sulfate Hematology General Medicine Platelet Activation enzymes and coenzymes (carbohydrates) 030104 developmental biology Dextran sulfate Immunology Biophysics business Tyrosine kinase Signal Transduction |
| DOI: | 10.6084/m9.figshare.1614827 |
| Popis: | Dextran sulfate (DxS; Mr 500 kD) induces fibrinogen receptor (αIIbβ3) activation via CLEC-2/Syk signaling and via a Syk-independent SFK/PI3K/Akt-dependent tyrosine kinase pathway in human and murine platelets. The platelet surface receptor, responsible for the DxS-induced Syk-independent Akt-activation, has hitherto not been identified. We found that DxS elicited a concentration-dependent aggregation of human platelets resulting from direct PEAR1 activation by DxS. Blocking the PEAR1 receptor, in combination with a selective Syk-inhibitor, completely abrogated the DxS-driven platelet aggregation. The DxS-induced Syk-phosphorylation was not affected in Pear1−/− platelets, but Akt-phosphorylation was largely abolished. As a result, the aggregation of Pear1−/− platelets was reduced and reversible, i.e. aggregates were less stable compared to wild-type platelet aggregates. Moreover, DxS-induced Pear1−/− platelet aggregation was fully abrogated by Syk inhibition, indicating that the remaining platelet aggregation of Pear1−/− platelets was Syk dependent. Hence, the Pear1/c-Src/PI3K/Akt- and CLEC-2/Syk-signaling pathways are independently and additively activated during platelet aggregation by DxS. Conclusion. The DxS-induced aggregation of human and murine platelets is the result of activation of PI3K/Akt through direct PEAR1 phosphorylation and parallel Syk-signaling through CLEC-2. |
| Databáze: | OpenAIRE |
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