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J. Biol. Chem., Vol. 283, Issue 51, 35419-35427, December 19, 2008

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G6b-B Inhibits Constitutive and Agonist-induced Signaling by Glycoprotein VI and CLEC-2^*

Jun Mori, Andrew C. Pearce¹, Jennifer C. Spalton, Beata Grygielska, Johannes A. Eble, Michael G. Tomlinson², Yotis A. Senis, and Steve P. Watson³

From the Centre for Cardiovascular Sciences, Institute of Biomedical Research, University of Birmingham, B15 2TT, United Kingdom and the Center for Molecular Medicine, Department of Vascular Matrix Biology, Excellence Cluster Cardio-Pulmonary System, Frankfurt University Hospital, 60590 Frankfurt am Main, Germany

Platelets play an essential role in wound healing by forming thrombi that plug holes in the walls of damaged blood vessels. To achieve this, platelets express a diverse array of cell surface receptors and signaling proteins that induce rapid platelet activation. In this study we show that two platelet glycoprotein receptors that signal via an immunoreceptor tyrosine-based activation motif (ITAM) or an ITAM-like domain, namely the collagen receptor complex glycoprotein VI (GPVI)-FcR -chain and the C-type lectin-like receptor 2 (CLEC-2), respectively, support constitutive (i.e. agonist-independent) signaling in a cell line model using a nuclear factor of activated T-cells (NFAT) transcriptional reporter assay that can detect low level activation of phospholipase C (PLC). Constitutive and agonist signaling by both receptors is dependent on Src and Syk family kinases, and is inhibited by G6b-B, a platelet immunoglobulin receptor that has two immunoreceptor tyrosine-based inhibitory motifs in its cytosolic tail. Mutation of the conserved tyrosines in the two immunoreceptor tyrosine-based inhibitory motifs prevents the inhibitory action of G6b-B. Interestingly, the inhibitory activity of G6b-B is independent of the Src homology 2 (SH2)-domain containing tyrosine phosphatases, SHP1 and SHP2, and the inositol 5'-phosphatase, SHIP. Constitutive signaling via Src and Syk tyrosine kinases is observed in platelets and is associated with tyrosine phosphorylation of GPVI-FcR -chain and CLEC-2. We speculate that inhibition of constitutive signaling through Src and Syk tyrosine kinases by G6b-B may help to prevent unwanted platelet activation.

Received for publication, September 5, 2008

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^* This work was supported in part by the British Heart Foundation, The Wellcome Trust, and Deutsche Forschungsgemeinschaft Grant Eb177/5-1 (to J. A. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ Present address: Novartis Horsham Research Centre, Horsham RH12 5AB, United Kingdom.

² Medical Research Council New Investigator Award Research Fellow.

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³ British Heart Foundation Professor. To whom correspondence should be addressed. Tel.: 44-121-415-8678; Fax: 44-121-415-8817; E-mail: s.p.watson{at}bham.ac.uk.

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