scholarly journals Platelet receptor glycoprotein VI

2020 ◽  
Vol 6 (1) ◽  
pp. 1-5
Author(s):  
Rojin Park
Keyword(s):  
Glycoprotein Vi ◽  
Platelet Receptor

Thrombopoietin Initiates Demethylation-Based Transcription of GP6 during Megakaryocyte Differentiation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3520-3520
Author(s):  
Sachiko Kanaji ◽  
Beatrice Jacquelin ◽  
Mei Chang ◽  
Diane J. Nugent ◽  
Norio Komatsu ◽  
...  
Keyword(s):  
Cord Blood ◽  
Cell Lines ◽  
Mononuclear Cells ◽  
Mrna Level ◽  
Methylation Status ◽  
Specific Gene ◽  
Specific Expression ◽  
Glycoprotein Vi ◽  
Platelet Receptor ◽  
Megakaryocyte Differentiation

Abstract Glycoprotein VI (GPVI) is an essential platelet receptor for collagens that is exclusively expressed in the megakaryocytic lineage. Transcription of the human gene GP6 is driven largely by GATA-1, Sp1 and Fli-1. However, the mere presence of these is not sufficient to initiate transcription during megakaryocyte differentiation, and other mechanisms are suggested to be involved in the regulation of megakaryocyte-specific expression of GPVI. In this study, we show that GPVI expression during megakaryocytic differentiation is dependent on CpG demethylation that can be initiated by thrombopoietin (TPO). Sodium bisulfite genomic sequencing established that a CpG-rich island within the GP6 promoter region is fully methylated at 10 CpG sites in GPVI non-expressive cell lines, such as UT-7/EPO and C8161, but completely unmethylated in GPVI expressive cell lines, including UT-7/TPO and CHRF288-11. To further confirm the relationship between CpG demethylation and expression of GPVI in primary cells, we treated human cord blood cells with TPO. The GP6 promoter is highly methylated in cord blood mononuclear cells (progenitors) but not in CD41+enriched cells obtained after TPO differentiation. Furthermore, when UT-7/EPO-Mpl cells, which stably express human c-mpl, were treated with TPO, demethylation of the GP6 promoter was induced. In every case, demethylation of the GP6 promoter correlated with an increase in mRNA level. Thus, megakaryocyte-specific expression of the GP6 gene is regulated, in part, by CpG demethylation which can be directly initiated by TPO. Our results establish, for the first time, a role for TPO in dynamic changes in CpG methylation status that are involved in the epigenetic regulation of megakaryocyte-specific gene expression.

Crystal structure and collagen-binding site of immune inhibitory receptor LAIR-1: unexpected implications for collagen binding by platelet receptor GPVI

Blood ◽  
2010 ◽  
Vol 115 (7) ◽  
pp. 1364-1373 ◽  
Author(s):  
T. Harma C. Brondijk ◽  
Talitha de Ruiter ◽  
Joost Ballering ◽  
Hans Wienk ◽  
Robert Jan Lebbink ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Binding Site ◽  
Cell Activation ◽  
Immune Cell ◽  
Structural Basis ◽  
Collagen Binding ◽  
Glycoprotein Vi ◽  
Platelet Receptor ◽  
Fundamental Insight ◽  
Key Residues

Abstract Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1), one of the most widely spread immune receptors, attenuates immune cell activation when bound to specific sites in collagen. The collagen-binding domain of LAIR-1 is homologous to that of glycoprotein VI (GPVI), a collagen receptor crucial for platelet activation. Because LAIR-1 and GPVI also display overlapping collagen-binding specificities, a common structural basis for collagen recognition would appear likely. Therefore, it is crucial to gain insight into the molecular interaction of both receptors with their ligand to prevent unwanted cross-reactions during therapeutic intervention. We determined the crystal structure of LAIR-1 and mapped its collagen-binding site by nuclear magnetic resonance (NMR) titrations and mutagenesis. Our data identify R59, E61, and W109 as key residues for collagen interaction. These residues are strictly conserved in LAIR-1 and GPVI alike; however, they are located outside the previously proposed GPVI collagen-binding site. Our data provide evidence for an unanticipated mechanism of collagen recognition common to LAIR-1 and GPVI. This fundamental insight will contribute to the exploration of specific means of intervention in collagen-induced signaling in immunity and hemostasis.

scholarly journals Shear-induced platelet receptor shedding by non-physiological high shear stress with short exposure time: Glycoprotein Ibα and glycoprotein VI

2015 ◽  
Vol 135 (4) ◽  
pp. 692-698 ◽  
Author(s):  
Zengsheng Chen ◽  
Nandan K. Mondal ◽  
Jun Ding ◽  
Jingya Gao ◽  
Bartley P. Griffith ◽  
...  
Keyword(s):  
Shear Stress ◽  
Exposure Time ◽  
Short Exposure ◽  
High Shear ◽  
High Shear Stress ◽  
Short Exposure Time ◽  
Glycoprotein Vi ◽  
Platelet Receptor ◽  
Receptor Shedding

Platelet Receptor Glycoprotein VI-Mediated Adhesion to Type I Collagen Under Hydrodynamic Flow

2004 ◽  
Vol 32 (7) ◽  
pp. 970-976 ◽  
Author(s):  
Kendra L. Sarratt ◽  
Hong Chen ◽  
Mark L. Kahn ◽  
Daniel A. Hammer
Keyword(s):  
Type I Collagen ◽  
Hydrodynamic Flow ◽  
Type I ◽  
Glycoprotein Vi ◽  
Platelet Receptor

Glycoprotein VI is not a Functional Platelet Receptor for Fibrin Formed in Plasma or Blood

2020 ◽  
Vol 120 (06) ◽  
pp. 977-993 ◽  
Author(s):  
Danmei Zhang ◽  
Mariam Ebrahim ◽  
Kristin Adler ◽  
Xavier Blanchet ◽  
Janina Jamasbi ◽  
...  
Keyword(s):  
Platelet Adhesion ◽  
Aggregate Formation ◽  
Glycoprotein Vi ◽  
Platelet Receptor ◽  
Platelet Aggregate ◽  
Flowing Blood ◽  
Coated Surfaces ◽  
Long Fibers ◽  
Collagen Receptor

AbstractGlycoprotein VI (GPVI), a platelet collagen receptor, is crucial in mediating atherothrombosis. Besides collagen, injured plaques expose tissue factor (TF) that triggers fibrin formation. Previous studies reported that GPVI also is a platelet receptor for fibrinogen and fibrin. We studied the effect of anti-GPVI antibodies and inhibitors of GPVI signaling kinases (Syk and Btk) on platelet adhesion and aggregate formation onto immobilized fibrinogen and different types of fibrin under arterial flow conditions. Fibrin was prepared from isolated fibrinogen (“pure fibrin”), recombinant fibrinogen (“recombinant fibrin”), or generated more physiologically from endogenous fibrinogen in plasma (“plasma fibrin”) or by exposing TF-coated surfaces to flowing blood (“blood fibrin”). Inhibition of GPVI and Syk did not inhibit platelet adhesion and aggregate formation onto fibrinogen. In contrast anti-GPVI antibodies, inhibitors of Syk and Btk and the anti-GPIb antibody 6B4 inhibited platelet aggregate formation onto pure and recombinant fibrin. However, inhibition of GPVI and GPVI signaling did not significantly reduce platelet coverage of plasma fibrin and blood fibrin. Plasma fibrin contained many proteins incorporated during clot formation. Advanced optical imaging revealed plasma fibrin as a spongiform cushion with thicker, knotty, and long fibers and little activation of adhering platelets. Albumin intercalated in plasma fibrin fibers left only little space for platelet attachment. Pure fibrin was different showing a dense mesh of thin fibers with strongly activated platelets. We conclude that fibrin formed in plasma and blood contains plasma proteins shielding GPVI-activating epitopes. Our findings do not support a role of GPVI for platelet activation by physiologic fibrin.

A Novel Histidine Tyrosine Phosphatase, TULA-2, Associates with Syk and Negatively Regulates GPVI Signaling in Platelets.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1843-1843
Author(s):  
Dafydd H Thomas ◽  
Carol Dangelmaier ◽  
Jianguo Jin ◽  
Alexander Tsygankov ◽  
Satya P. Kunapuli ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Tyrosine Kinase ◽  
Tyrosine Phosphatase ◽  
Dense Granule ◽  
Negative Regulation ◽  
Negative Regulator ◽  
Signaling Cascade ◽  
Glycoprotein Vi ◽  
Platelet Receptor

Abstract Glycoprotein VI (GPVI) is the primary platelet receptor for collagen signaling. Following damage to the vascular endothelium, the GPVI receptor interacts with the exposed sub-endothelial collagen. This interaction initiates a signaling cascade involving phosphorylation of the dual ITAM motif of the FcRγ chain by Fyn and Lyn, followed by the recruitment, phosphorylation and activation of Syk. This leads to the eventual activation of PLCγ2 and the release of calcium from intracellular stores to cause platelet activation. While a lot is known about the activation processes involved in GPVI signaling less is known about its negative regulation. The T-cell ubiquitin ligand (TULA) family of proteins has been implicated in the negative regulation protein tyrosine kinase (PTK)-dependent signaling pathways. More recently, it has been shown the TULA family member, TULA-2, exhibits phosphatase activity towards PTKs, including Syk, and this activity is responsible for the negative regulation of T-cell receptor signaling (Mikhailik et. al. 2007, Agrawal et. al. 2008). Thus, we investigated the role of TULA-2 in the negative regulation of the GPVI signaling cascade. We show that TULA-2 is expressed in both human and murine platelets. Deletion of TULA-2 in murine platelets manifests itself functionally as enhanced aggregation in response to the GPVI agonist convulxin as well as enhanced dense granule secretion when compared to wild type platelets. No difference was witnessed in response to the PAR4 agonist AYPGKF. TULA-2-deficient platelets also exhibit sustained hyperphosphorylation of Syk at tyrosines 525 and 526 as well as hyperphosphorylation of PLCγ2 at tyrosines 753 and 759, indicative of enhanced kinase and phospholipase activity respectively. GST-pulldown experiments suggest that Syk and TULA- 2 are able to associate in resting and convulxin stimulated platelets and in-vitro phosphatase assays demonstrate that TULA-2 can dephosphorylate Syk at tyrosines 525 and 526. Taken together, these data suggest that TULA-2 is a negative regulator of GPVI signaling and this regulation is mediated by an association of TULA-2 with Syk, allowing the dephosphorylation of Syk at catalytically important tyrosine residues.

scholarly journals Lipid Rafts Orchestrate Signaling by the Platelet Receptor Glycoprotein VI

2002 ◽  
Vol 277 (21) ◽  
pp. 18801-18809 ◽  
Author(s):  
Darren Locke ◽  
Hong Chen ◽  
Ying Liu ◽  
Changdong Liu ◽  
Mark L. Kahn
Keyword(s):  
Lipid Rafts ◽  
Glycoprotein Vi ◽  
Platelet Receptor

Cell–collagen interactions: the use of peptide Toolkits to investigate collagen–receptor interactions

2008 ◽  
Vol 36 (2) ◽  
pp. 241-250 ◽  
Author(s):  
Richard W. Farndale ◽  
Ton Lisman ◽  
Dominique Bihan ◽  
Samir Hamaia ◽  
Christiane S. Smerling ◽  
...  
Keyword(s):  
Amino Acids ◽  
Control Cell ◽  
Receptor Interaction ◽  
Glycoprotein Vi ◽  
Basement Membrane Protein ◽  
Platelet Receptor ◽  
Cell Adhesion And Migration ◽  
And Migration ◽  
Von Willebrand ◽  
Collagen Receptor

Fibrillar collagens provide the most fundamental platform in the vertebrate organism for the attachment of cells and matrix molecules. We have identified specific sites in collagens to which cells can attach, either directly or through protein intermediaries. Using Toolkits of triple-helical peptides, each peptide comprising 27 residues of collagen primary sequence and overlapping with its neighbours by nine amino acids, we have mapped the binding of receptors and other proteins on to collagens II or III. Integrin α2β1 binds to several GXX′GER motifs within the collagens, the affinities of which differ sufficiently to control cell adhesion and migration independently of the cellular regulation of the integrin. The platelet receptor, Gp (glycoprotein) VI binds well to GPO (where O is hydroxyproline)-containing model peptides, but to very few Toolkit peptides, suggesting that sequence in addition to GPO triplets is important in defining GpVI binding. The Toolkits have been applied to the plasma protein vWF (von Willebrand factor), which binds to only a single sequence, identified by truncation and amino acid substitution within Toolkit peptides, as GXRGQOGVMGFO in collagens II and III. Intriguingly, the receptor tyrosine kinase, DDR2 (discoidin domain receptor 2) recognizes three sites in collagen II, including its vWF-binding site, although the amino acids that support the interaction differ slightly within this motif. Furthermore, the secreted protein BM-40 (basement membrane protein 40) also binds well to this same region. Thus the availability of extracellular collagen-binding proteins may be important in regulating and facilitating direct collagen–receptor interaction.

Regulation of platelet membrane levels of glycoprotein VI by a platelet-derived metalloproteinase

Blood ◽  
2004 ◽  
Vol 104 (12) ◽  
pp. 3611-3617 ◽  
Author(s):  
Elizabeth E. Gardiner ◽  
Jane F. Arthur ◽  
Mark L. Kahn ◽  
Michael C. Berndt ◽  
Robert K. Andrews
Keyword(s):  
Ethylenediaminetetraacetic Acid ◽  
Ectodomain Shedding ◽  
Platelet Surface ◽  
Glycoprotein Vi ◽  
Calmodulin Binding ◽  
Platelet Receptor ◽  
Cytoplasmic Tails ◽  
Charged Membrane ◽  
Binding Sequence ◽  
Positively Charged

Thrombosis can be initiated when activated platelets adhere to injured blood vessels via the interaction of subendothelial collagen with its platelet receptor, glycoprotein (GP) VI. Here we observed that incubation of platelets with convulxin, collagen, or collagen-related peptide (CRP) resulted in GPVI signaling-dependent loss of surface GPVI and the appearance of an approximately 55-kDa soluble fragment of GPVI as revealed by immunoblotting. Ethylenediaminetetraacetic acid (EDTA) or GM6001 (a metalloproteinase inhibitor with broad specificity) prevented this loss. In other receptor systems, calmodulin binding to membrane-proximal cytoplasmic sequences regulates metalloproteinase-mediated ectodomain shedding. In this regard, we have previously shown that calmodulin binds to a positively charged, membrane-proximal sequence within the cytoplasmic tail of GPVI. Incubation of platelets with calmodulin inhibitor W7 (150 μM) resulted in a time-dependent loss of GPVI from the platelet surface. Both EDTA and GM6001 prevented this loss. Surface plasmon resonance demonstrated that W7 specifically blocked the association of calmodulin with an immobilized synthetic peptide corresponding to the calmodulin-binding sequence of GPVI. These findings suggest that disruption of calmodulin binding to receptor cytoplasmic tails by agonist binding to the receptor triggers metalloproteinase-mediated loss of GPVI from the platelet surface. This process may represent a potential mechanism to regulate GPVI-dependent platelet adhesion.

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