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

Mori, Jun and Pearce, Andrew C and Spalton, Jennifer C. and Grygielska, Beata and Eble, Johannes A. and Tomlinson, Michael G. and Senis, Yotis A. and Watson, Steve P (2008) G6b-B Inhibits Constitutive and Agonist-induced Signaling by Glycoprotein VI and CLEC-2. The Journal of Biological Chemistry, 283 (51). pp. 35419-35427. ISSN 0021-9258

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URL of Published Version: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18955485

Identification Number/DOI: 10.1074/jbc.M806895200

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 γ-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 Cγ (PLCγ). 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 γ-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.

Type of Work:Article
Date:19 December 2008 (Publication)
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:Centre for Cardiovascular Sciences, Institute of Biomedical Research
Subjects:R Medicine (General)
Institution:University of Birmingham
Copyright Holders:American Society for Biochemistry and Molecular Biology
ID Code:243
Refereed:YES
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