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Investigating the role of Src family kinases in αIIbβ3-mediated platelet signalling

Nash, Craig A (2012)
Ph.D. thesis, University of Birmingham.

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αIIbβ3 is the major integrin expressed in platelets and plays a critical role in platelet aggregation and cessation of bleeding. Signalling via this integrin is critically dependent on the Src-family-kinases of which there are eight members, several of which are expressed in platelets. Platelets also express G protein-coupled receptors which signal through their G proteins, however some evidence for dependence on both Src family kinases and other platelet receptors exists. In this thesis, I have demonstrated that there are differential levels of expression of SFKs in mouse and human platelets. Further to this, utilising mouse models, I demonstrate that Src plays a critical positive role in αIIbβ3-mediated spreading on fibrinogen, with Lyn playing a negative role, potentially downstream of Src. In contrast, individual Src-family-kinases do not appear to play a role in clot retraction or tail bleeding assays, despite the Src-family-kinase inhibitor, Dasatinib having a significant effect. Finally, I demonstrate that both Gi-coupled receptors in human platelets are critically dependent on Src family kinases and αIIbβ3 for signalling, Interestingly, neither receptor stimulates tyrosine phosphorylation of Src family kinases in platelets. This suggests a role for the basal phosphorylation of Src-family-kinases which may be dependent on αIIbβ3-mediated signalling.

Type of Work:Ph.D. thesis.
Supervisor(s):Watson, Steve P. and Senis, Yotis
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:Institute of Biomedical Research
Subjects:QR Microbiology
Institution:University of Birmingham
ID Code:3365
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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