Cutting Edge: TREM-Like Transcript-1, a Platelet Immunoreceptor Tyrosine-Based Inhibition Motif Encoding Costimulatory Immunoreceptor that Enhances, Rather than Inhibits, Calcium Signaling via SHP-2

Barrow, Alexander D.; Astoul, Emmanuelle; Floto, A.; Brooke, Gary; Relou, Ingrid A.M.; Jennings, Nicola S.; Smith, Kenneth G. C.; Ouwehand, Willem H.; Farndale, Richard W.; Alexander, Denis R.; Trowsdale, John

doi:10.4049/jimmunol.172.10.5838

Cited by 93 publications

(99 citation statements)

References 16 publications

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“…The latter action is similar to that of G6b-B, which upon crosslinking by a specific antibody inhibits activation of platelets by the GPVI-specific agonist, collagen-related peptide, and the G protein-coupled receptor agonist ADP (13). In contrast, the ITIM receptor, TREM-1, which is present on platelet intracellular granules, is translocated to the surface of activated platelets and reinforces platelet activation (16).…”

mentioning

confidence: 83%

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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mentioning

confidence: 83%

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 potential biological significance of the sTLT-1 fragment is reinforced by the existence of 2 splice variants with limited or absent intracellular domains. The first is the most abundant TLT-1 mRNA species and possesses an extracellular domain identical to that of full-length TLT-1 but only a 16-aa cytoplasmic domain (18). The second form was recently identified in our laboratory and encodes only the TLT-1 extracellular domain (A.V.…”

Section: Discussionmentioning

confidence: 99%

TREM-like transcript-1 protects against inflammation-associated hemorrhage by facilitating platelet aggregation in mice and humans

Washington¹,

Gibot²,

Acevedo³

et al. 2009

J. Clin. Invest.

108

142

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Triggering receptor expressed on myeloid cells-like (TREM-like) transcript-1 (TLT-1), a type 1 single Ig domain orphan receptor specific to platelet and megakaryocyte α-granules, relocates to the platelet surface upon platelet stimulation. We found here that patients diagnosed with sepsis, in contrast to healthy individuals, had substantial levels of soluble TLT-1 (sTLT-1) in their plasma that correlated with the presence of disseminated intravascular coagulation. sTLT-1 bound to fibrinogen and augmented platelet aggregation in vitro. Furthermore, the cytoplasmic domain of TLT-1 could also bind ezrin/radixin/moesin family proteins, suggesting its ability to link fibrinogen to the platelet cytoskeleton. Accordingly, platelets of Treml1 -/-mice failed to aggregate efficiently, extending tail-bleeding times. Lipopolysaccharide-treated Treml1 -/-mice developed higher plasma levels of TNF and D-dimers than wild-type mice and were more likely to succumb during challenge. Finally, Treml1 -/-mice were predisposed to hemorrhage associated with localized inflammatory lesions. Taken together, our findings suggest that TLT-1 plays a protective role during inflammation by dampening the inflammatory response and facilitating platelet aggregation at sites of vascular injury. Therefore, therapeutic modulation of TLT-1-mediated effects may provide clinical benefit to patients with hypercoagulatory conditions, including those associated with inflammation.

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“…Other receptors encoded within the TREM gene cluster such as TLT1 lack the conserved transmembrane lysine residue, but contain within their own cytoplasmic domain tyrosinebased signaling motifs (11). In the case of TLT1, there is an ITIM, which mediates recruitment of SHP1 and SHP2 (11,12).…”

Section: Discussionmentioning

confidence: 99%

“…TLT1 is stored in the ␣-granules of platelets and is quickly redistributed to their surface upon activation. It has also been reported that ligation of this receptor promotes rather than inhibits Ca 2ϩ mobilization through an interaction with SHP2, although the physiological relevance of this, as well as the natural ligand responsible, have yet to be determined (12).…”

Section: Trem-like Transcript 2 Is Expressed On Cells Of the Myeloid/mentioning

confidence: 99%

Trem-Like Transcript 2 Is Expressed on Cells of the Myeloid/Granuloid and B Lymphoid Lineage and Is Up-Regulated in Response to Inflammation

King

Herrin

Justement

2006

The Journal of Immunology

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The triggering receptor expressed on myeloid cells (TREM) gene cluster encodes a group of transmembrane proteins that are emerging as important components in innate and adaptive immunity. In both mice and humans, the TREM gene cluster encodes eight receptors; only four of these, however, are direct homologs: TREM-1, TREM-2, TREM-like transcript 1 (TLT1), and TLT2. Of the transmembrane receptors encoded by the four conserved genes within this cluster, TLT2 has not been studied previously. Data presented in this study demonstrate that TLT2 is expressed early in B cell development in conjunction with B220 and is detected on all developing mouse B cell populations as well as B cells in the periphery. TLT2 expression on B cells in the periphery exhibits a distinct hierarchy with the highest detectable levels observed on B1 B cells in the peritoneum. The overall gradation of TLT2 expression on B cells is: B1 > marginal zone/transitional 2 > transitional 1 > follicular. Additionally, TLT2 expression was observed on mouse neutrophils throughout the body. Although monocytes were not observed to express TLT2, resident peritoneal and lung macrophages do express TLT2, suggesting that it is up-regulated in association with terminal differentiation of monocytes. Finally, both neutrophils and macrophages were observed to up-regulate TLT2 expression in vivo in response to inflammatory stimuli, whereas TLT2 expression on B cells remained unchanged. In conclusion, the data suggest that TLT2 may be involved in the innate immune response based on its expression profile and the fact that it is up-regulated in response to inflammation.

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Cutting Edge: TREM-Like Transcript-1, a Platelet Immunoreceptor Tyrosine-Based Inhibition Motif Encoding Costimulatory Immunoreceptor that Enhances, Rather than Inhibits, Calcium Signaling via SHP-2

Cited by 93 publications

References 16 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

TREM-like transcript-1 protects against inflammation-associated hemorrhage by facilitating platelet aggregation in mice and humans

Trem-Like Transcript 2 Is Expressed on Cells of the Myeloid/Granuloid and B Lymphoid Lineage and Is Up-Regulated in Response to Inflammation

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