Cross talk between serine/threonine and tyrosine kinases regulates ADP-induced thromboxane generation in platelets

Dheeraj Bhavanasi, Rachit Badolia, Bhanu Kanth Manne, Sumalaxmi Janapati, Carol T Dangelmaier, Alexandra Mazharian, Jianguo Jin, Soochong Kim, X Zhang, Xiaoyang Chen, Yotis A Senis, Satya P Kunapuli

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

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 languageEnglish
Pages (from-to)558-68
Number of pages11
JournalThrombosis and Haemostasis
Volume114
Issue number3
Early online date7 May 2015
DOIs
Publication statusPublished - Sep 2015

Keywords

  • platelet physiology
  • thromboxane A2
  • ADP receptors
  • protein kinase C
  • protein tyrosine kinases

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