期刊
BLOOD
卷 115, 期 14, 页码 2947-2955出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-08-237834
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资金
- The Wellcome Trust [073107, 088410]
- British Heart Foundation (BHF) [PG/07/116, PG/05/134, FS/08/062, CH/03/003]
- Medical Research Council [G116/165]
- Deutsche Forschungsgemeinschaft [SFB/TR23]
- University of Birmingham
- MRC [G116/165] Funding Source: UKRI
- British Heart Foundation [FS/08/062/25797] Funding Source: researchfish
- Medical Research Council [G116/165] Funding Source: researchfish
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 gamma 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)x(6-12)Yxx(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. (Blood. 2010;115(14):2947-2955)
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