{"id":{"repo_id":"birmingham","oai_identifier":"oai:etheses.bham.ac.uk:1204"},"canonical_url":"https://search.dev.ndltd.org/etd/birmingham/oai:etheses.bham.ac.uk:1204","repository":{"repo_id":"birmingham","name":"University of Birmingham","base_url":"https://etheses.bham.ac.uk/cgi/oai2"},"display":{"title":"Comparison of CLEC-2 and GPVI signaling in platelets: the role of adaptor proteins","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.","abstract_html":"GPVI activates platelets through an ITAM pathway by activation of Src and Syk kinases leading to activation of PLC<span class=\"etd-inline-math\"><sub>y</sub></span>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<span class=\"etd-inline-math\"><sub>y</sub></span>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<span class=\"etd-inline-math\"><sub>6-12</sub></span>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.","abstract_has_math":true,"creators":["Hughes, Craig Edward"],"institution":"University of Birmingham","degree_name":"d_ph","degree_level":"d_ph","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2010,"date_issued":"2010-12","date_published":"2010-12","updated_at":"2026-07-24T01:11:26Z","subjects":["RB Pathology"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.sponsor","label":"Sponsor","values":["wellcome_trust"]},{"key":"dc:creator","label":"Author","values":["Hughes, Craig Edward"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2010-12"]},{"key":"dc:date.issued","label":"Date","values":["2010-12"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["College of Medical & Dental Sciences","School of Clinical and Experimental Medicine, Centre for Cardiovascular Sciences"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Birmingham"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["http://etheses.bham.ac.uk//id/eprint/1204/"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["d_ph"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["d_ph"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["RB Pathology"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://etheses.bham.ac.uk//id/eprint/1204/1/hughes_10_PhD.pdf","http://etheses.bham.ac.uk//id/eprint/1204/2/Decl_IS_Hughes10PhD.pdf"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Comparison of CLEC-2 and GPVI signaling in platelets: the role of adaptor proteins"]}]}],"canonical_facts":{"dc:contributor.sponsor":["wellcome_trust"],"dc:creator":["Hughes, Craig Edward"],"dc:date":["2010-12"],"dc:date.issued":["2010-12"],"dc:description.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."],"dc:format":["application/pdf"],"dc:identifier.uri":["http://etheses.bham.ac.uk//id/eprint/1204/1/hughes_10_PhD.pdf","http://etheses.bham.ac.uk//id/eprint/1204/2/Decl_IS_Hughes10PhD.pdf"],"dc:publisher.department":["College of Medical & Dental Sciences","School of Clinical and Experimental Medicine, Centre for Cardiovascular Sciences"],"dc:publisher.institution":["University of Birmingham"],"dc:relation.isreferencedby":["http://etheses.bham.ac.uk//id/eprint/1204/"],"dc:subject":["RB Pathology"],"dc:title":["Comparison of CLEC-2 and GPVI signaling in platelets: the role of adaptor proteins"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["d_ph"],"dc:type.qualificationname":["d_ph"]},"updated_at":"2026-07-24T01:11:26Z"}