G6b-B inhibits constitutive and agonist-induced signaling by glycoprotein VI and CLEC-2

  • 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.

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Author:Jun Mori, Andrew C. Pearce, Jennifer C. Spalton, Beata Grygielska, Johannes A. EbleORCiDGND, Michael G. Tomlinson, Yotis A. Senis, Steve P. Watson
URN:urn:nbn:de:hebis:30:3-255571
URL:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2602894/
DOI:https://doi.org/10.1074/jbc.M806895200
ISSN:0021-9258
ISSN:1083-351X
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/18955485
Parent Title (English):The journal of biological chemistry
Publisher:American Soc. for Biochemistry and Molecular Biology
Place of publication:Bethesda, Md.
Document Type:Article
Language:English
Date of Publication (online):2008/10/27
Date of first Publication:2008/10/27
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2013/02/21
Volume:283
Issue:51
Page Number:9
First Page:35419
Last Page:35427
Note:
© 2008 by The American Society for Biochemistry and Molecular Biology, Inc
HeBIS-PPN:332010449
Institutes:Medizin / Medizin
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Sammlung Biologie / Sondersammelgebiets-Volltexte
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell 3.0