Tonic B‐cell and viral ITAM signaling: context is everything

Grande, Shannon; Bannish, Gregory; Fuentes‐Pananá, Ezequiel M.; Katz, Elad; Monroe, John G.

doi:10.1111/j.1600-065x.2007.00535.x

Cited by 16 publications

(12 citation statements)

References 160 publications

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“…The B cell antigen receptor also signals independently of ligand engagement and this provides functionally relevant signals in immature B lymphocytes (49) and in diffuse large B-cell lymphoma (50). Significantly, this constitutive signaling is mediated through the B cell receptor ITAMs (51,52). Thus, constitutive signaling appears to be a common feature of YXXL-containing receptors.…”

Section: Discussionmentioning

confidence: 99%

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

Mori

Pearce

Spalton

et al. 2008

Journal of Biological Chemistry

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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.The GPVI-FcR ␥-chain complex is the major signaling receptor for collagen on platelets and megakaryocytes (1, 2). Crosslinking of GPVI leads to Src-dependent phosphorylation of a tandem YXXL sequence on the FcR ␥-chain known as an immunoreceptor tyrosine-based activation motif (ITAM). 4 In turn, this leads to recruitment and activation of the tyrosine kinase Syk through its tandem SH2 domains. Syk initiates a signaling cascade that generates a linker for activation of T (LAT) cell-dependent signalosome, which mediates activation of phospholipase C␥2 (PLC␥-2) (3, 4). This pathway initiates a rise in intracellular Ca 2ϩ and activation of protein kinase C leading to platelet aggregation.CLEC-2 is a 32-kDa C-type lectin-like receptor that functions as a platelet receptor for the snake venom toxin rhodocytin and the lymphatic endothelial marker, podoplanin (5-7). Like glycoprotein (GP) VI, CLEC-2 signals via sequential activation of Src and Syk tyrosine kinases leading to activation of PLC␥2 (5). The regulation of PLC␥2 by CLEC-2 is distinct from that of GPVI in that it uses a single YXXL sequence and is only partially dependent on the adapter SLP-76 (5, 8).G6b is a recently identified member of the immunoglobulin superfamily that exists in several splice variants (9). G6b-B is the only one of these variants to contain both a transmembrane region and two immunoreceptor tyrosine-based inhibit...

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Section: Discussionmentioning

confidence: 99%

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

Mori

Pearce

Spalton

et al. 2008

Journal of Biological Chemistry

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“…The expression of the BCR is essential for the survival of B cells at all developmental stages, leading to the hypothesis that the BCR must provide constitutive low-level ‘tonic’ signals that promote survival, either spontaneously or on interaction with ligands in the environment 8,9 . Recent genetic and biochemical analyses have shed light on the nature of the tonic signalling pathway, suggesting that the initiation of tonic signalling may not be identical to that of antigen-induced signalling, and may bypass the requirement for the phosphorylation of BCR ITAMs.…”

Section: The Bcr In Resting Cellsmentioning

confidence: 99%

The tipping points in the initiation of B cell signalling: how small changes make big differences

2010

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B cells are selected by the binding of antigen to clonally distributed B cell receptors (BCRs), triggering signalling cascades that result in B cell activation. With the recent application of high-resolution live-cell imaging, we are gaining an understanding of the events that initiate BCR signalling within seconds of its engagement with antigen. These observations are providing a molecular explanation for fundamental aspects of B cell responses, including antigen affinity discrimination and the value of class switching, as well as insights into the underlying causes of B cell tumorigenesis. Advances in our understanding of the earliest molecular events that follow antigen binding to the BCR may provide a general framework for the initiation of signalling in the adaptive immune system.

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“…The phosphorylation of the two tyrosines within the ITAM leads to the physical recruitment of Syk to the site of the clustered receptor in an interaction mediated by its tandem pair of SH2 domains [37,38,39]. Interestingly, a number of virally encoded proteins also contain ITAM sequences, which they use to co-opt Syk for their own nefarious purposes [35,40,41]. …”

Section: Activation Of Syk In B Lymphocytes By Binding To the Antimentioning

confidence: 99%

Syk and pTyr'd: Signaling through the B cell antigen receptor

Geahlen

2009

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

154

208

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The B cell receptor (BCR) transduces antigen binding into alterations in the activity of intracellular signaling pathways through its ability to recruit and activate the cytoplasmic protein-tyrosine kinase Syk. The recruitment of Syk to the receptor, its activation and its subsequent interactions with downstream effectors are all regulated by its phosphorylation on tyrosine. This review discusses our current understanding of how this phosphorylation regulates the activity of Syk and its participation in signaling through the BCR.

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Tonic B‐cell and viral ITAM signaling: context is everything

Cited by 16 publications

References 160 publications

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

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

The tipping points in the initiation of B cell signalling: how small changes make big differences

Syk and pTyr'd: Signaling through the B cell antigen receptor

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