Regulation of blood platelet function by the AGC family of protein kinases

Aburima, Ahmed A.


Thesis or dissertation

© 2010 Ahmed A Aburima. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright holder.

Upon vascular injury, platelets aggregate at the site of blood vessel injury to form a hemostatic plug maintaining the physiological integrity of the vascular system. Platelets respond to a variety of extracellular stimuli to undergo a rapid aggregation response, releasing active granule contents and leading to a rapidly growing thrombus. During the adhesion, activation, and aggregation of platelets at an injured site, the endothelium responds by limiting the size and growth of the hemostatic plug or thrombus, or even reversing platelet reactivity. These responses are defined as endothelial thromboregulation. There are three primary (and functionally independent) pathways during the early stages of thromboregulation by which the endothelium controls platelet reactivity (1) nitric oxide (NO); (2) prostacyclin (PGI₂ ); and (3) the ectonucleotidase CD39. NO and PGI2 stimulate signalling cascades that result in the activation of the AGC family of Ser/Thr protein kinases (PKA, PKG and PKC). Once activated these kinase blunt platelet function through the phosphorylation of signalling proteins requested for activation. In this study, the role of AGC family kinases and their signaling cascades in regulating platelet function was assessed. The experimental data produced during this study demonstrate new insights in to the regulation of these kinases in platelets. More specifically it was found that

1. Peroxynitrite, a derivative of NO, regulated platelet function and particularly cytoskeletal rearrangement through PKC-dependent phosphorylation of VASPSer²³⁹⁄¹⁵⁷

2. NO-mediated signalling in platelets had a requirement for PKC.

3. Multiple forms of PKA are present in platelets, which are differentially localised.

4. The potential regulation of platelet function by PKA is mediated through Akinase anchoring proteins.

5. Lipid rafts may play an important role in platelet regulation by NO and PKG.

In summary, this studies present insights of the factors regulating AGC kinases in blood platelets.

Department of Biomedical Sciences, Hull York Medical School
Naseem, Khalid; Riba, R.
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