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CLEC-2 activates Syk through dimerization

Hughes, C. E. and Pollitt, A. Y. and Mori, J. and Eble, J. A. and Tomlinson, Michael G. and Hartwig, J. H. and O'Callaghan, C. A. and Futterer, K. and Watson, Steve P (2010) CLEC-2 activates Syk through dimerization. Blood, 115 (14). p. 2947. ISSN 0006-4971

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URL of Published Version: http://dx.doi.org/10.1182/blood-2009-08-237834

Identification Number/DOI: doi:10.1182/blood-2009-08-237834

The C-type lectin receptor CLEC-2 activates platelets through Src and Syk tyrosine kinases, leading to tyrosine phosphorylation of downstream adapter proteins and effector enzymes, including phospholipase-C 2. Signaling is initiated through phosphorylation of a single conserved tyrosine located in a YxxL sequence in the CLEC-2 cytosolic tail. The signaling pathway used by CLEC-2 shares many similarities with that used by receptors that have 1 or more copies of an immunoreceptor tyrosine-based activation motif, defined by the sequence Yxx(L/I)x6-12Yxx(L/I), in their cytosolic tails or associated receptor chains. Phosphorylation of the conserved immunoreceptor tyrosine-based activation motif tyrosines promotes Syk binding and activation through binding of the Syk tandem SH2 domains. In this report, we present evidence using peptide pull-down studies, surface plasmon resonance, quantitative Western blotting, tryptophan fluorescence measurements, and competition experiments that Syk activation by CLEC-2 is mediated by the cross-linking through the tandem SH2 domains with a stoichiometry of 2:1. In support of this model, cross-linking and electron microscopy demonstrate that CLEC-2 is present as a dimer in resting platelets and converted to larger complexes on activation. This is a unique mode of activation of Syk by a single YxxL-containing receptor

Type of Work:Article
Date:2010 (Publication)
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:Institute for Biomedical Research
Subjects:R Medicine (General)
Institution:University of Birmingham
Copyright Holders:American Society of hematology
ID Code:338
Refereed:YES
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