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Phosphorylation of CLEC-2 is dependent on lipid rafts, actin polymerization,secondary mediators, and Rac

Pollitt, Alice Y and Grygielska, Beata and Leblond, Bertrand and Désiré, Laurent and Eble, Johannes A. and Watson, Steve P (2010) Phosphorylation of CLEC-2 is dependent on lipid rafts, actin polymerization,secondary mediators, and Rac. Blood, 115 (14). pp. 2983-2946. ISSN 0006-4971

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URL of Published Version: http://dx.doi.org/10.1182/blood-2009-12-257212

Identification Number/DOI: 10.1182/blood-2009-12-257212

The C-type lectin-like receptor 2 (CLEC-2)activates platelets through Src and Syk tyrosine kinases via a single cytoplasmic YxxL motif known as a hem immunoreceptor tyrosine-based activation motif (hemITAM).Here, we demonstrate using sucrose gradient ultracentrifugation and methyl--cyclodextrin treatment that CLEC-2 translocates to lipid rafts upon ligand engagement and that translocation is essential for hemITAM phosphorylation and signal initiation. HemITAM phosphorylation, but not translocation, is also critically dependent on actin polymerization,Rac1 activation, and release of ADP and thromboxane A2 (TxA2). The role of ADP and TxA2 in mediating hosphorylation is dependent on ligand engagement and rac activation but is independent of platelet aggregation. In contrast,tyrosine phosphorylation of the GPVIFcR -chain ITAM, which has 2 YxxL motifs,is independent of actin polymerization and secondary mediators. These results reveal a unique series of proximal events in CLEC-2 phosphorylation involving actin polymerization, secondary mediators,and Rac activation.

Type of Work:Article
Date:12 February 2010 (Publication)
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:Centre for Cardiovascular Sciences, Institute for Biomedical Research
Subjects:R Medicine (General)
Institution:University of Birmingham
Copyright Holders:American Society of Hematology
ID Code:424
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