A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2

Suzuki-Inoue, K., Fuller, G. L. J., Garcia, A., Eble, J. A., Pohlmann, S., Inoue, O., Gartner, T. K., Hughan, S. C., Pearce, A. C., Laing, Gavin, Theakston, R.David G., Schweighoffer, E., Zitzmann, N., Morita, T., Tybulewicz, V. L. J., Ozaki, Y. and Watson, S. P. (2006) 'A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2'. Blood, Vol 107, Issue 2, pp. 542-549.

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Abstract

The snake venom rhodocytin has been reported to bind to integrin alpha 2 beta 1 and glycoprotein (GP) Ib alpha 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 tall, 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 gamma 2, and partially reduced in the absence of LAT, SLP-76, and Vav2/Vav3. These findings define a novel signaling pathway in platelets whereby activation of CLEC-2 by rhodocytin leads to tyrosine phosphorylation of its cytosolic tall, binding of Sylk and initiation of downstream tyrosine phosphorylation events, and activation of PLCy2. CLEC-2 is the first C-type lectin receptor to be found on platelets which signals through this novel pathway.

Item Type:	Article
Uncontrolled Keywords:	glycoprotein-vi collagen receptor tyrosine phosphorylation gamma-chain integrin alpha(2)beta(1) phospholipase c-gamma-2 asialoglycoprotein receptor venom agonist aggregation
Subjects:	QU Biochemistry > QU 4 General works WD Disorders of Systemic, Metabolic or Environmental Origin, etc > Animal Poisons > WD 400 General works WD Disorders of Systemic, Metabolic or Environmental Origin, etc > Animal Poisons > WD 410 Reptiles
Faculty: Department:	Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI):	https://doi.org/10.1182/blood-2005-05-1994
Depositing User:	Sarah Lewis-Newton
Date Deposited:	06 Apr 2011 09:56
Last Modified:	06 Feb 2018 13:02
URI:	https://archive.lstmed.ac.uk/id/eprint/1605

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