{"data":{"id":"10.6084/m9.figshare.c.2132603.v1","type":"dois","attributes":{"doi":"10.6084/m9.figshare.c.2132603.v1","prefix":"10.6084","suffix":"m9.figshare.c.2132603.v1","identifiers":[],"alternateIdentifiers":[],"creators":[{"name":"Vandenbriele, Christophe","givenName":"Christophe","familyName":"Vandenbriele","affiliation":[],"nameIdentifiers":[]},{"name":"Sun, Yi","givenName":"Yi","familyName":"Sun","affiliation":[],"nameIdentifiers":[]},{"name":"Criel, Maarten","givenName":"Maarten","familyName":"Criel","affiliation":[],"nameIdentifiers":[]},{"name":"Cludts, Katrien","givenName":"Katrien","familyName":"Cludts","affiliation":[],"nameIdentifiers":[]},{"name":"Van kerckhoven, Soetkin","givenName":"Soetkin","familyName":"Van kerckhoven","affiliation":[],"nameIdentifiers":[]},{"name":"Izzi, Benedetta","givenName":"Benedetta","familyName":"Izzi","affiliation":[],"nameIdentifiers":[]},{"name":"Vanassche, Thomas","givenName":"Thomas","familyName":"Vanassche","affiliation":[],"nameIdentifiers":[]},{"name":"Verhamme, Peter","givenName":"Peter","familyName":"Verhamme","affiliation":[],"nameIdentifiers":[]},{"name":"F. Hoylaerts, Marc","givenName":"Marc","familyName":"F. Hoylaerts","affiliation":[],"nameIdentifiers":[]}],"titles":[{"title":"Dextran sulfate triggers platelet aggregation via direct activation of PEAR1"}],"publisher":"Taylor \u0026 Francis","container":{},"publicationYear":2015,"subjects":[{"subject":"Biochemistry"},{"subject":"Space Science"},{"subject":"Medicine"},{"subject":"Cell Biology"},{"subject":"Neuroscience"},{"subject":"Physiology"},{"subject":"FOS: Biological sciences","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"Pharmacology"},{"subject":"Immunology"},{"subject":"FOS: Clinical medicine","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"Hematology"},{"subject":"Infectious Diseases"},{"subject":"FOS: Health sciences","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"Plant Biology"}],"contributors":[],"dates":[{"date":"2015-12-05","dateType":"Created"},{"date":"2019-08-19","dateType":"Updated"},{"date":"2015","dateType":"Issued"}],"language":null,"types":{"ris":"GEN","bibtex":"misc","citeproc":"article","schemaOrg":"Collection","resourceType":"Collection","resourceTypeGeneral":"Collection"},"relatedIdentifiers":[{"relationType":"IsIdenticalTo","relatedIdentifier":"10.6084/m9.figshare.c.2132603","relatedIdentifierType":"DOI"}],"relatedItems":[],"sizes":[],"formats":[],"version":null,"rightsList":[{"rights":"Creative Commons Attribution 4.0 International","rightsUri":"https://creativecommons.org/licenses/by/4.0/legalcode","schemeUri":"https://spdx.org/licenses/","rightsIdentifier":"cc-by-4.0","rightsIdentifierScheme":"SPDX"}],"descriptions":[{"description":"Dextran sulfate (DxS; Mr 500 kD) induces fibrinogen receptor (α\u003csub\u003eIIb\u003c/sub\u003eβ\u003csub\u003e3\u003c/sub\u003e) 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 \u003ci\u003ePear1\u003csup\u003e−/−\u003c/sup\u003e\u003c/i\u003e platelets, but Akt-phosphorylation was largely abolished. As a result, the aggregation of \u003ci\u003ePear1\u003csup\u003e−/−\u003c/sup\u003e\u003c/i\u003e platelets was reduced and reversible, i.e. aggregates were less stable compared to wild-type platelet aggregates. Moreover, DxS-induced \u003ci\u003ePear1\u003csup\u003e−/−\u003c/sup\u003e\u003c/i\u003e platelet aggregation was fully abrogated by Syk inhibition, indicating that the remaining platelet aggregation of \u003ci\u003ePear1\u003csup\u003e−/−\u003c/sup\u003e\u003c/i\u003e 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. \u003cb\u003e\u003ci\u003eConclusion\u003c/i\u003e\u003c/b\u003e. 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.","descriptionType":"Abstract"}],"geoLocations":[],"fundingReferences":[],"xml":"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