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Comparison of CLEC-2 and GPVI signaling in platelets: the role of adaptor proteins

Hughes, Craig Edward (2010)
Ph.D. thesis, University of Birmingham.

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Abstract

GPVI activates platelets through an ITAM pathway by activation of Src and Syk kinases leading to activation of PLC\(_y\)2. CLEC-2 has been shown to activate platelets using an ITAM-like sequence in its cytoplasmic tail that is also dependent on Src and Syk kinases, but shows a partial rather than an absolute dependence on adapter SLP-76 for activation of PLC\(_y\)2. The aim of this thesis is to understand some of the key differences in these signalling pathways. GPVI is in complex with FcRwhich contains the ITAM sequence (Yxx(L/I)x\(_{6-12}\)Yxx(L/I)). These two tyrosines provide a docking site for the tandem-SH2 domains of Syk. In this thesis I show that CLEC-2 signalling through Syk is mediated by phosphorylation of the CLEC-2 YxxL sequence, receptor dimerisation and cross-linking by the Syk SH2 domains. I also show that the differential requirement for SLP-76 is not mediated by Gads. Both signalling pathways also show partial dependency for LAT. I also show that a novel protein, G6f, is not able to substitute for LAT in this signalling pathway and also exclude the LAT-family proteins PAG, LIME, LAX and NTAL as potential LAT replacements in platelet activation by GPVI. These results extend our understanding of platelet activation by CLEC-2.

Type of Work:Ph.D. thesis.
Supervisor(s):Watson, Steve P. and Tomlinson, Michael G
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:Centre for Cardiovascular Sciences
Subjects:RB Pathology
Institution:University of Birmingham
ID Code:1204
This unpublished thesis/dissertation is copyright of the author and/or third parties.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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