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The snake venom rhodocytin has been reported to bind to integrin alpha2beta1 and glycoprotein (GP) Ibalpha on platelets, but it is also able to induce activation independent of the 2 receptors and of GPVI. Using rhodocytin affinity chromatography, we have identified a novel C-type lectin receptor, CLEC-2, in platelets that confers signaling responses to rhodocytin when expressed in a cell line. CLEC-2 has a single tyrosine residue in a YXXL motif in its cytosolic tail, which undergoes tyrosine phosphorylation upon platelet activation by rhodocytin or an antibody to CLEC-2, but not to collagen, thrombin receptor agonist peptide (TRAP), or convulxin. Tyrosine phosphorylation of CLEC-2 and other signaling proteins by rhodocytin is inhibited by the Src family kinase inhibitor PP2. Further, activation of murine platelets by rhodocytin is abolished in the absence of Syk and PLCgamma2, and partially reduced in the absence of LAT, SLP-76, and Vav1/Vav3. These findings define a novel signaling pathway in platelets whereby activation of CLEC-2 by rhodocytin leads to tyrosine phosphorylation of its cytosolic tail, binding of Syk and initiation of downstream tyrosine phosphorylation events, and activation of PLCgamma2. CLEC-2 is the first C-type lectin receptor to be found on platelets which signals through this novel pathway.

Original publication

DOI

10.1182/blood-2005-05-1994

Type

Journal article

Journal

Blood

Publication Date

15/01/2006

Volume

107

Pages

542 - 549

Keywords

Adaptor Proteins, Signal Transducing, Animals, Antibodies, Monoclonal, Blotting, Western, Collagen, Crotalid Venoms, Cytosol, Enzyme Precursors, Flow Cytometry, Guanine Nucleotide Exchange Factors, Humans, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, Lectins, C-Type, Membrane Proteins, Mice, Mice, Knockout, Peptide Fragments, Phospholipase C gamma, Phosphoproteins, Phosphorylation, Platelet Activation, Platelet Aggregation, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-vav, Pyrimidines, Receptors, Gastrointestinal Hormone, Receptors, Immunologic, Receptors, Neuropeptide Y, Receptors, Thrombin, Signal Transduction, Syk Kinase, Tyrosine, Viper Venoms