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Title: The Regulation and Role of Novel PKC Isoforms in Platelets
Author: Hall, Kellie Joann
ISNI:       0000 0001 3526 7387
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2008
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Platelets are central to physiological haemostasis and respond to stimulation by a variety of soluble and insoluble agonists. Most platelet activatory agonists couple to activation of protein kinase C (PKC) isoforms, including PKC8 and PKCe, members of the novel PKC family. So far the role of PKC8 in platelets has been fairly well characterised although its regulation in platelets, particularly by phosphorylation, is less well understood. Conversely the role of PKCe is less well understood due to a lack of selective inhibitors. This thesis aimed to investigate the regulation ofPKC8 by tyrosine phosphorylation and the role ofPKCe in platelets to improve our understanding of the signalling pathways leading to platelet activation. PKCo was found to be phosphorylated on T~11 and T~65 following thrombin stimulation of human platelets, downstream ofSrc family kinases and phospholipase C signalling. PKCo required membrane recruitment and allosteric modulation (by DAG or PMA) for tyrosine phosphorylation to occur. Tyrosine phosphorylation of PKCo was not required for membrane recruitment of the kinase but was able to potentiate the kinase activity. The presence of the two identified phosphorylation sites in the hinge region (fy(3l1) and the kinase domain (f~6~ suggests that phosphorylation of these sites may stabilise the active conformation ofthe kinase. The role ofPKCe in platelet functional responses is less well characterised than that of PKCo. Using platelets from PKCe-l- mice it was f~und that PKCe negatively regulated integrin activation and a-granule release downstream of GPVI signalling. Interestingly PKce positively regulated thrombin-induced integrin activation however this effect was not seen when using the PAR4 agonist AYPGKF. PKCe was found to positively regulate dense granule secretion downstream of PAR4 but negatively regulate it downstream of TxA2 although the mechanism by which this occurred was not investigated. The findings from this study suggest that PKCe plays a distinct role in platelet activation in an agonist-specific manner.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available