Fibrin activates GPVI in human and mouse platelets

Alshehri, Osama M.; Hughes, Craig E.; Montague, Samantha J.; Watson, Steve P.; Frampton, Jonathan; Bender, Markus

doi:10.1182/blood-2015-04-641654

Cited by 195 publications

(174 citation statements)

References 43 publications

(47 reference statements)

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“…Recent data suggest that it can also bind laminin isoforms and fibrin (Alshehri et al, 2015;Inoue et al, 2006). Significantly, its binding to human placenta laminin (a mixture of laminins-211, -411 and -511) is of lower affinity than that to collagen I and relies on α6β1 integrin-mediated activation of GPVI (Inoue et al, 2006;Wondimu et al, 2006).…”

Section: Direct Binding To Collagens: the Non-integrin Collagenbindinmentioning

confidence: 99%

The integrin–collagen connection – a glue for tissue repair?

Zeltz

Gullberg

2016

Journal of Cell Science

173

121

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There was an error published in J. Cell Sci. 129, 653-664.In Fig. 2A, the fibroblasts were incorrectly labelled. The correct annotation should have been α11 −/− fibroblast (left) and α11 +/+ fibroblast (right). The correct Fig. 2 is shown below. We apologise to the readers for any confusion that this error might have caused. Journal of Cell Science COMMENTARYThe integrin-collagen connection -a glue for tissue repair?Cedric Zeltz and Donald Gullberg* ABSTRACTThe α1β1, α2β1, α10β1 and α11β1 integrins constitute a subset of the integrin family with affinity for GFOGER-like sequences in collagens.Integrins α1β1 and α2β1 were originally identified on a subset of activated T-cells, and have since been found to be expressed on a number of cell types including platelets (α2β1), vascular cells (α1β1, α2β1), epithelial cells (α1β1, α2β1) and fibroblasts (α1β1, α2β1).Integrin α10β1 shows a distribution that is restricted to mesenchymal stem cells and chondrocytes, whereas integrin α11β1 appears restricted to mesenchymal stem cells and subsets of fibroblasts. The bulk of the current literature suggests that collagen-binding integrins only have a limited role in adult connective tissue homeostasis, partly due to a limited availability of cell-binding sites in the mature fibrillar collagen matrices. However, some recent data suggest that, instead, they are more crucial for dynamic connective tissue remodeling events -such as wound healing -where they might act specifically to remodel and restore the tissue architecture. This Commentary discusses the recent development in the field of collagen-binding integrins, their roles in physiological and pathological settings with special emphasis on wound healing, fibrosis and tumor-stroma interactions, and include a discussion of the most recently identified newcomers to this subfamilyintegrins α10β1 and α11β1.

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Section: Direct Binding To Collagens: the Non-integrin Collagenbindinmentioning

confidence: 99%

The integrin–collagen connection – a glue for tissue repair?

Zeltz

Gullberg

2016

Journal of Cell Science

173

121

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“…Glycoprotein (GP) VI is the major platelet signaling receptor for collagen and fibrin, 11,12 and GPVI-fibrin engagement may underpin fibrin-related disease pathology. GPVI is expressed only on megakaryocytes and platelets 13 in association with the Fc receptor g-chain containing an immunoreceptor tyrosine-based activation motif (ITAM).…”

Section: Introductionmentioning

confidence: 99%

Soluble GPVI is elevated in injured patients: shedding is mediated by fibrin activation of GPVI

Montague

Delierneux

Lecut³

et al. 2018

Blood Advances

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• Soluble GPVI is elevated in patients with thermal injury with sepsis, and sGPVI levels augment severity score prediction of mortality.• The GPVI ligand, fibrin, induces GPVI shedding without requirement for platelet activation or signaling Soluble glycoprotein VI (sGPVI) is shed from the platelet surface and is a marker of platelet activation in thrombotic conditions. We assessed sGPVI levels together with patient and clinical parameters in acute and chronic inflammatory conditions, including patients with thermal injury and inflammatory bowel disease and patients admitted to the intensive care unit (ICU)for elective cardiac surgery, trauma, acute brain injury, or prolonged ventilation. Plasma sGPVI was measured by enzyme-linked immunosorbent assay and was elevated on day 14 after thermal injury, and was higher in patients who developed sepsis. sGPVI levels were associated with sepsis, and the value for predicting sepsis was increased in combination with platelet count and Abbreviated Burn Severity Index. sGPVI levels positively correlated with levels of D-dimer (a fibrin degradation product) in ICU patients and patients with thermal injury. sGPVI levels in ICU patients at admission were significantly associated with 28-and 90-day mortality independent of platelet count. sGPVI levels in patients with thermal injury were associated with 28-day mortality at days 1, 14, and 21 when adjusting for platelet count. In both cohorts, sGPVI associations with mortality were stronger than D-dimer levels. Mechanistically, release of GPVI was triggered by exposure of platelets to polymerized fibrin, but not by engagement of G protein-coupled receptors by thrombin, adenosine 59-diphosphate, or thromboxane mimetics. Enhanced fibrin production in these patients may therefore contribute to the observed elevated sGPVI levels. sGPVI is an important platelet-specific marker for platelet activation that predicts sepsis progression and mortality in injured patients.

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“…However, platelets also cause thrombosis by aggregating to block blood flow in diseased arteries following the rupture of collagen-rich atherosclerotic plaques, which can lead to heart attack and stroke. Platelet GPVI is established as the major platelet-activating collagen receptor [1–4], but also binds laminin [5] and fibrin [6, 7]. GPVI has only a minor role in haemostasis, but is important in arterial thrombosis, ischaemic stroke and maintaining vascular integrity during inflammation [8, 9].…”

Section: Introductionmentioning

confidence: 99%

Tetraspanin Tspan9 regulates platelet collagen receptor GPVI lateral diffusion and activation

et al. 2016

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The tetraspanins are a superfamily of four-transmembrane proteins, which regulate the trafficking, lateral diffusion and clustering of the transmembrane proteins with which they interact. We have previously shown that tetraspanin Tspan9 is expressed on platelets. Here we have characterised gene-trap mice lacking Tspan9. The mice were viable with normal platelet numbers and size. Tspan9-deficient platelets were specifically defective in aggregation and secretion induced by the platelet collagen receptor GPVI, despite normal surface GPVI expression levels. A GPVI activation defect was suggested by partially impaired GPVI-induced protein tyrosine phosphorylation. In mechanistic experiments, Tspan9 and GPVI co-immunoprecipitated and co-localised, but super-resolution imaging revealed no defects in collagen-induced GPVI clustering on Tspan9-deficient platelets. However, single particle tracking using total internal reflection fluorescence microscopy showed that GPVI lateral diffusion was reduced by approximately 50% in the absence of Tspan9. Therefore, Tspan9 plays a fine-tuning role in platelet activation by regulating GPVI membrane dynamics.

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Fibrin activates GPVI in human and mouse platelets

Cited by 195 publications

References 43 publications

The integrin–collagen connection – a glue for tissue repair?

The integrin–collagen connection – a glue for tissue repair?

Soluble GPVI is elevated in injured patients: shedding is mediated by fibrin activation of GPVI

Tetraspanin Tspan9 regulates platelet collagen receptor GPVI lateral diffusion and activation

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