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The Toll-like receptor 2/1 (TLR2/1) complex initiates human platelet activation via the src/Syk/LAT/PLC gamma 2 signalling cascade
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Biomedicine; Dept Clin & Expt Med, Linköping Univ, Linköping, Sweden.ORCID iD: 0000-0003-2519-203X
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Biomedicine.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Biomedicine.
Dept Clin & Expt Med, Linköping Univ, Linköping, Sweden.
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2014 (English)In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 26, no 2, p. 279-286Article in journal (Refereed) Published
Abstract [en]

The specific TLR2/1 complex activator Pam3CSK4 has been shown to provoke prominent activation and aggregation of human non-nucleated platelets. As Pam3CSK4-evoked platelet activation does not employ the major signalling pathway established in nucleated immune cells, we investigated if the TLR2/1 complex on platelets may initiate signalling pathways known to be induced by physiological agonists such as collagen via GPVI or thrombin via PARs. We found that triggering TLR2/1 complex-signalling with Pam3CSK4, in common with that induced via GPVI, and in contrast to that provoked by PARS, involves tyrosine phosphorylation of the adaptor protein LAT as well as of PLC gamma 2 in a src- and Syk-dependent manner. In this respect, we provide evidence that Pam3CSK4 does not cross-activate GPVI. Further, by the use of platelets from a Glanzmann's thrombasthenia patient lacking beta(3), in contrast to findings in nucleated immune cells, we show that the initiation of platelet activation by Pam3CSK4 does not involve integrin beta(3) signalling; whereas the latter, subsequent to intermediate TXA2 synthesis and signalling, was found to be indispensable for proper dense granule secretion and full platelet aggregation. Together, our findings reveal that triggering the TLR2/1 complex with Pam3CSK4 initiates human platelet activation by engaging tyrosine kinases of the src family and Syk, the adaptor protein LAT, as well as the key mediator PLC gamma 2. (C) 2013 Elsevier Inc. All rights reserved.

Place, publisher, year, edition, pages
New York, USA: Elsevier, 2014. Vol. 26, no 2, p. 279-286
Keywords [en]
Human platelets, TLR2, Pam3CSK4, Syk, LAT, PLC gamma 2
National Category
Medical and Health Sciences Cell Biology
Research subject
Cell Research
Identifiers
URN: urn:nbn:se:oru:diva-34261DOI: 10.1016/j.cellsig.2013.11.011ISI: 000330922800012PubMedID: 24240055Scopus ID: 2-s2.0-84889605890OAI: oai:DiVA.org:oru-34261DiVA, id: diva2:704734
Funder
Swedish Research CouncilSwedish Heart Lung Foundation
Note

Funding Agencies:

Foundation of Olle Engkvist

Medical Faculty of the University of Linkoping through Forsknings- och Forskarutbildningsnamnden (FUN)

Available from: 2014-03-13 Created: 2014-03-13 Last updated: 2019-03-26Bibliographically approved

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Fälker, KnutKlarström-Engström, KristinBengtsson, TorbjörnGrenegård, Magnus

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Fälker, KnutKlarström-Engström, KristinBengtsson, TorbjörnGrenegård, Magnus
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