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Jun Mori, Zoltan Nagy, Giada Di Nunzio, Christopher W Smith, Mitchell J Geer, Rashid Al Ghaithi, Johanna P van Geffen, Silke Heising, Luke Boothman, Bibian M E Tullemans, Joao N Correia, Louise Tee, Marijke J E Kuijpers, Paul Harrison, Johan W M Heemskerk, Gavin E Jarvis, Alexander Tarakhovsky, Arthur Weiss, Alexandra Mazharian, Yotis A Senis
Src family kinases (SFKs) coordinate the initiating and propagating activation signals in platelets, but it remains unclear how they are regulated. Here, we show that ablation of C-terminal Src kinase (Csk) and receptor-like protein tyrosine-phosphatase CD148 in mice results in a dramatic increase in platelet SFK activity, demonstrating that these proteins are essential regulators of platelet reactivity. Paradoxically, Csk/CD148-deficient mice exhibit reduced in vivo and ex vivo thrombus formation and increased bleeding following injury rather than a prothrombotic phenotype...
March 8, 2018: Blood
Y-J Li, H-X Zhu, D Zhang, H-C Li, P Ma, L-Y Huang
Platelets are megakaryocyte-derived nuclear-free fragments that participate in cardiovascular diseases including acute myocardial infarction, ischemic stroke, hypertension, and atherosclerosis. At the endothelium damage site, platelets interact with sub-endothelial matrix proteins such as glycoprotein VI/Fc receptor γ-chain (GPVI/FcRγ), G protein-coupled receptor/phospholipase Cγ(β) (GPCR/PLCγ(β)), Rho/RhoK and integrin. The activation of these signaling pathways triggers intracellular calcium increase and causes platelet adhesion, aggregation, granule release and finally thrombus formation...
July 2017: European Review for Medical and Pharmacological Sciences
Carmen H Coxon, Mitchell J Geer, Yotis A Senis
Since their discovery, immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptors have been shown to inhibit signaling from immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors in almost all hematopoietic cells, including platelets. However, a growing body of evidence has emerged demonstrating that this is an oversimplification, and that ITIM-containing receptors are versatile regulators of platelet signal transduction, with functions beyond inhibiting ITAM-mediated platelet activation...
June 29, 2017: Blood
Motasem Melhem, Mohamed Abu-Farha, Dinu Antony, Ashraf Al Madhoun, Chiara Bacchelli, Fadi Alkayal, Irina AlKhairi, Sumi John, Mohamad Alomari, Phillip L Beales, Osama Alsmadi
OBJECTIVE: To characterize the underlying genetic and molecular defects in a consanguineous family with lifelong blood disorder manifested with thrombocytopenia (low platelets count) and anemia. METHODS: Genetic linkage analysis, exome sequencing, and functional genomics were carried out to identify and characterize the defective gene. RESULTS: We identified a novel truncation mutation (p.C108*) in chromosome 6 open reading frame 25 (C6orf25) gene in this family...
March 2017: European Journal of Haematology
Alexandra Mazharian, Jun Mori, Ying-Jie Wang, Silke Heising, Benjamin G Neel, Steve P Watson, Yotis A Senis
The SH2 domain-containing protein-tyrosine phosphatases Shp1 and Shp2 have been implicated in regulating signaling from a variety of platelet and megakaryocyte receptors. In this study, we investigate the functions of Shp1 and Shp2 in megakaryocytes and platelets. Megakaryocyte/platelet (MP)-specific deletion of Shp1 in mice resulted in platelets being less responsive to collagen-related peptide due to reduced GPVI expression and signaling via the Src family kinase (SFK)-Syk-PLCγ2 pathway, and fibrinogen due to reduced SFK activity...
May 16, 2013: Blood
Carmen H Coxon, Amanda J Sadler, Jiandong Huo, R Duncan Campbell
Platelet activation is regulated by both positive and negative signals. G6B-b is an inhibitory platelet receptor with an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). The molecular basis of inhibition by G6B-b is currently unknown but thought to involve the SH2 domain-containing tyrosine phosphatase SHP-1. Here we show that G6B-b also associates with SHP-2, as well as SHP-1, in human platelets. Using a number of biochemical approaches, we found these interactions to be direct and that the tandem SH2 domains of SHP-2 demonstrated a binding affinity for G6B-b 100-fold higher than that of SHP-1...
2012: PloS One
Alexandra Mazharian, Ying-Jie Wang, Jun Mori, Danai Bem, Brenda Finney, Silke Heising, Paul Gissen, James G White, Michael C Berndt, Elizabeth E Gardiner, Bernhard Nieswandt, Michael R Douglas, Robert D Campbell, Steve P Watson, Yotis A Senis
Platelets are highly reactive cell fragments that adhere to exposed extracellular matrix (ECM) and prevent excessive blood loss by forming clots. Paradoxically, megakaryocytes, which produce platelets in the bone marrow, remain relatively refractory to the ECM-rich environment of the bone marrow despite having the same repertoire of receptors as platelets. These include the ITAM (immunoreceptor tyrosine-based activation motif)-containing collagen receptor complex, which consists of glycoprotein VI (GPVI) and the Fc receptor γ-chain, and the ITIM (immunoreceptor tyrosine-based inhibition motif)-containing receptor G6b-B...
October 30, 2012: Science Signaling
Yotis Senis, Angel García
Platelets pose unique challenges to cell biologists due to their lack of nucleus and low levels of messenger RNA. Platelets cannot be cultured in great abundance or manipulated using common recombinant DNA technologies. As a result, platelet research has lagged behind that of nucleated cells. The advent of mass spectrometry and its application to protein biochemistry brought with it great hopes for the platelet community that are now being realized. This technology is ideally suited for identifying low-abundance proteins, protein-protein interactions, and post-translational modifications in complex protein mixtures...
2012: Methods in Molecular Biology
Chris I Jones, Natasha E Barrett, Leonardo A Moraes, Jonathan M Gibbins, Denise E Jackson
The response of platelets to changes in the immediate environment is always a balance between activatory and inhibitory signals, the cumulative effect of which is either activation or quiescence. This is true of platelets in free flowing blood and of their regulation of haemostasis and thrombosis. In this review, we consider the endogenous inhibitory mechanisms that combine to regulate platelet activation. These include those derived from the endothelium (nitric oxide, prostacyclin, CD39), inhibitory receptors on the surface of platelets (platelet endothelial cell adhesion molecule-1, carcinoembryonic antigen cell adhesion molecule 1, G6b-B - including evidence for the role of Ig-ITIM superfamily members in the negative regulation of ITAM-associated GPVI platelet-collagen interactions and GPCR-mediated signalling and in positive regulation of "outside-in" integrin α(IIb)β(3)-mediated signalling), intracellular inhibitory receptors (retinoic X receptor, glucocorticoid receptor, peroxisome proliferator-activated receptors, liver X receptor), and emerging inhibitory pathways (canonical Wnt signalling, Semaphorin 3A, endothelial cell specific adhesion molecule, and junctional adhesion molecule-A)...
2012: Methods in Molecular Biology
Fang Sheng, Alejandra Yep, Lei Feng, Jack Preiss, James H Geiger
Glycogen/starch synthase elongates glucan chains and is the key enzyme in the synthesis of glycogen in bacteria and starch in plants. Cocrystallization of Escherichia coli wild-type glycogen synthase (GS) with substrate ADPGlc and the glucan acceptor mimic HEPPSO produced a closed form of GS and suggests that domain-domain closure accompanies glycogen synthesis. Cocrystallization of the inactive GS mutant E377A with substrate ADPGlc and oligosaccharide results in the first oligosaccharide-bound glycogen synthase structure...
October 27, 2009: Biochemistry
Katherine L Tucker, William J Kaiser, Angela L Bergeron, Hongbo Hu, Jing-fei Dong, Tse-Hua Tan, Jonathan M Gibbins
The platelet surface is a dynamic interface that changes rapidly in response to stimuli to co-ordinate the formation of thrombi at sites of vascular injury. Tight control is essential as loss of organisation may result in the inappropriate formation of thrombi (thrombosis) or excessive bleeding. In this paper we describe the comparative analysis of resting and thrombin-stimulated platelet membrane proteomes and associated proteins to identify proteins important to platelet function. Surface proteins were labelled using a biotin tag and isolated by NeurtrAvidin affinity chromatography...
September 2009: Proteomics
Y A Senis, R Antrobus, S Severin, A F Parguiña, I Rosa, N Zitzmann, S P Watson, A García
BACKGROUND AND OBJECTIVES: Outside-in integrin alphaIIbbeta3 signaling involves a series of tyrosine kinase reactions that culminate in platelet spreading on fibrinogen. The aim of this study was to identify novel tyrosine phosphorylated signaling proteins downstream of alphaIIbbeta3, and explore their role in platelet signaling. METHODS AND RESULTS: Utilizing proteomics to search for novel platelet proteins that contribute to outside-in signaling by the integrin alphaIIbbeta3, we identified 27 proteins, 17 of which were not previously shown to be part of a tyrosine phosphorylation-based signaling complex downstream of alphaIIbbeta3...
October 2009: Journal of Thrombosis and Haemostasis: JTH
Jun Mori, Andrew C Pearce, Jennifer C Spalton, Beata Grygielska, Johannes A Eble, Michael G Tomlinson, Yotis A Senis, Steve P Watson
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 gamma-chain and the C-type lectin-like receptor 2 (CLEC-2), respectively, support constitutive (i...
December 19, 2008: Journal of Biological Chemistry
Jianfeng Li, Martin Cadeiras, Manuel Prinz von Bayern, Lining Zhang, Adriana I Colovai, Russell Dedrick, Eric A Jaffe, Nicole Suciu-Foca, Mario C Deng
The G6b-B gene encodes a novel cell surface receptor of the immunoglobulin superfamily that activates inhibitory signaling pathways by triggering SHP-1/SHP-2 via immunoreceptor tyrosine-based inhibitory motifs (ITIM) in its cytoplasmic domain. We previously identified decreased G6b-B expression in peripheral blood mononuclear cells (PBMC) during acute cellular cardiac allograft rejection. We studied the expression of G6b-B in different human mononuclear cell populations and its regulation. Real-time polymerase chain reaction (PCR) revealed that G6b-B mRNA is higher in CD4+ T cells or monocytes, but is not different between CD25+ CD4+ T cells and CD25- CD4+ T cells...
August 2007: Human Immunology
Stephen A Newland, Iain C Macaulay, Andres R Floto, Edwin C de Vet, Willem H Ouwehand, Nicholas A Watkins, Paul A Lyons, Duncan R Campbell
The G6B cell-surface receptor, which contains a single Ig-like domain, has been shown to bind to SHP-1 and SHP-2 after phosphorylation of 2 immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in its cytoplasmic tail, classifying this protein as a new member of the family of inhibitory receptors. In this study, we demonstrate by real-time polymerase chain reaction (PCR) and Western-blot analysis that G6B is expressed on platelets. Cross-linking of G6B with polyclonal antisera has a significant inhibitory effect on platelet aggregation and activation by agonists such as ADP and collagen-related peptide (CRP)...
June 1, 2007: Blood
Iain C Macaulay, Marloes R Tijssen, Daphne C Thijssen-Timmer, Arief Gusnanto, Michael Steward, Philippa Burns, Cordelia F Langford, Peter D Ellis, Frank Dudbridge, Jaap-Jan Zwaginga, Nicholas A Watkins, C Ellen van der Schoot, Willem H Ouwehand
To identify previously unknown platelet receptors we compared the transcriptomes of in vitro differentiated megakaryocytes (MKs) and erythroblasts (EBs). RNA was obtained from purified, biologically paired MK and EB cultures and compared using cDNA microarrays. Bioinformatical analysis of MK-up-regulated genes identified 151 transcripts encoding transmembrane domain-containing proteins. Although many of these were known platelet genes, a number of previously unidentified or poorly characterized transcripts were also detected...
April 15, 2007: Blood
Yotis A Senis, Michael G Tomlinson, Angel García, Stephanie Dumon, Victoria L Heath, John Herbert, Stephen P Cobbold, Jennifer C Spalton, Sinem Ayman, Robin Antrobus, Nicole Zitzmann, Roy Bicknell, Jon Frampton, Kalwant S Authi, Ashley Martin, Michael J O Wakelam, Stephen P Watson
The platelet surface is poorly characterized due to the low abundance of many membrane proteins and the lack of specialist tools for their investigation. In this study we identified novel human platelet and mouse megakaryocyte membrane proteins using specialist proteomics and genomics approaches. Three separate methods were used to enrich platelet surface proteins prior to identification by liquid chromatography and tandem mass spectrometry: lectin affinity chromatography, biotin/NeutrAvidin affinity chromatography, and free flow electrophoresis...
March 2007: Molecular & Cellular Proteomics: MCP
Edwin C J M de Vet, Stephen A B Newland, Paul A Lyons, Begoña Aguado, R Duncan Campbell
The G6b gene, located in the human Major Histocompatibility Complex, encodes a receptor of the immunoglobulin (Ig) superfamily. In this study, we show using a variety of techniques that the extracellular domain of the G6b protein, containing a single Ig-like domain, binds to heparin with high affinity. In an ELISA assay, this binding was displaceable with soluble heparin with an IC50 value of approximately 0.5 microg/ml. Other sulfated glycans showed weaker or no competition. The observed interaction between G6b and heparin is strongly salt dependent suggesting a mainly electrostatic interaction...
April 25, 2005: FEBS Letters
E C de Vet, B Aguado, R D Campbell
The G6b gene, located in the class III region of the human major histocompatibility complex, has been suggested to encode a putative receptor of the immunoglobulin superfamily. Genomic sequence information was used as a starting point to clone the corresponding cDNA. Reverse transcriptase polymerase chain reaction showed that expression of the gene is restricted to certain hematopoietic cell lines including K562, Molt 4, and Jurkat. Several splice variants were detected, varying only in their C-terminal parts...
November 9, 2001: Journal of Biological Chemistry
G Ribas, M J Neville, R D Campbell
The class III region of the human major histocompatibility complex (MHC) contains approximately 59 genes, many of which encode polypeptides with a variety of different functions. Eight of these genes are of particular interest because they encode novel surface molecules that could be involved in immune and/or inflammatory responses and are excellent candidates as disease susceptibility loci. These molecules are members of two different superfamilies, the immunoglobulin superfamily (1C7, G6B, and G6F genes) and the leucocyte antigen-6 superfamily (G6C, G6D, G6E, G5C, and G5B genes)...
July 2001: Immunogenetics
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