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Abstract
ADP-induced thromboxane generation depends on Src family kinases (SFKs) and is enhanced with pan-protein kinase C (PKC) inhibitors, but it is not clear how these two events are linked. The aim of the current study is to investigate the role of Y311 phosphorylated PKCδ in regulating ADP-induced platelet activation. In the current study, we employed various inhibitors and murine platelets from mice deficient in specific molecules to evaluate the role of PKCδ in ADP-induced platelet responses. We show that, upon stimulation of platelets with 2MeSADP, Y311 on PKCδ is phosphorylated in a P2Y1/Gq and Lyn-dependent manner. By using PKCδ and Lyn knockout murine platelets, we also show that tyrosine phosphorylated PKCδ plays a functional role in mediating 2MeSADP-induced thromboxane generation. 2MeSADP-induced PKCδ Y311 phosphorylation and thromboxane generation were potentiated in human platelets pre-treated with either a pan-PKC inhibitor, GF109203X or a PKC α/β inhibitor and in PKC α or β knockout murine platelets compared to controls. Furthermore, we show that PKC α/β inhibition potentiates the activity of SFK, which further hyper-phosphorylates PKCδ and potentiates thromboxane generation. These results show for the first time that tyrosine phosphorylated PKCδ regulates ADP-induced thromboxane generation independent of its catalytic activity and that classical PKC isoforms α/β regulate the tyrosine phosphorylation on PKCδ and subsequent thromboxane generation through tyrosine kinase, Lyn, in platelets.
Original language | English |
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Pages (from-to) | 558-68 |
Number of pages | 11 |
Journal | Thrombosis and Haemostasis |
Volume | 114 |
Issue number | 3 |
Early online date | 7 May 2015 |
DOIs | |
Publication status | Published - Sept 2015 |
Keywords
- platelet physiology
- thromboxane A2
- ADP receptors
- protein kinase C
- protein tyrosine kinases
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Dive into the research topics of 'Cross talk between serine/threonine and tyrosine kinases regulates ADP-induced thromboxane generation in platelets'. Together they form a unique fingerprint.Projects
- 2 Finished
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Investigation of Molecular Mechanisms Regulating Megakaryocyte and Platelet Hyperactivity and Prothrombotic Disorders in LAIR-1 and PECAM-1-Deficient Mice
Mazharian, A., Senis, Y. & Watson, S.
1/04/14 → 31/03/17
Project: Research
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Regulation of Platelet Activation and Thrombosis by the G6b-B-Shp1/2 Signalling Complex
Senis, Y.
1/01/13 → 31/12/17
Project: Research