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Blood, 15 January 2006, Vol. 107, No. 2, pp. 542-549.
Prepublished online as a Blood First Edition Paper on September 20, 2005; DOI 10.1182/blood-2005-05-1994.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2
Katsue Suzuki-Inoue,
Gemma L. J. Fuller,
Ángel García,
Johannes A. Eble,
Stefan Pöhlmann,
Osamu Inoue,
T. Kent Gartner,
Sascha C. Hughan,
Andrew C. Pearce,
Gavin D. Laing,
R. David G. Theakston,
Edina Schweighoffer,
Nicole Zitzmann,
Takashi Morita,
Victor L. J. Tybulewicz,
Yukio Ozaki, and
Steve P. Watson
From the Department of Clinical and Laboratory Medicine, University of Yamanashi, Japan; Centre for Cardiovascular Sciences, Institute of Biomedical Research, University of Birmingham, United Kingdom; Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, United Kingdom; Institute for Physiological Chemistry and Pathobiochemistry, Muenster University Hospital, Germany; Institute for Clinical and Molecular Virology and Nikolaus-Fiebiger-Center of Molecular Medicine, University of Erlangen-Nürnberg, Erlangen, Germany; Department of Microbiology and Molecular Cell Sciences, University of Memphis, TN; Venom Research Unit, Liverpool School of Tropical Medicine, Liverpool, United Kingdom; Division of Immune Cell Biology, National Institute for Medical Research, London, United Kingdom; and Department of Biochemistry, Meiji Pharmaceutical University, Tokyo, Japan.
The snake venom rhodocytin has been reported to bind to integrin  2 1 and glycoprotein (GP) Ib 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 PLC 2, 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 PLC2. CLEC-2 is the first C-type lectin receptor to be found on platelets which signals through this novel pathway.
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