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      Platelet signaling: a complex interplay between inhibitory and activatory networks

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          Summary

          The role of platelets in hemostasis and thrombosis is dependent on a complex balance of activatory and inhibitory signaling pathways. Inhibitory signals released from the healthy vasculature suppress platelet activation in the absence of platelet receptor agonists. Activatory signals present at a site of injury initiate platelet activation and thrombus formation; subsequently, endogenous negative signaling regulators dampen activatory signals to control thrombus growth. Understanding the complex interplay between activatory and inhibitory signaling networks is an emerging challenge in the study of platelet biology, and necessitates a systematic approach to utilize experimental data effectively. In this review, we will explore the key points of platelet regulation and signaling that maintain platelets in a resting state, mediate activation to elicit thrombus formation, or provide negative feedback. Platelet signaling will be described in terms of key signaling molecules that are common to the pathways activated by platelet agonists and can be described as regulatory nodes for both positive and negative regulators.

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          Most cited references103

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          Kindlin-3 is essential for integrin activation and platelet aggregation.

          Integrin-mediated platelet adhesion and aggregation are essential for sealing injured blood vessels and preventing blood loss, and excessive platelet aggregation can initiate arterial thrombosis, causing heart attacks and stroke. To ensure that platelets aggregate only at injury sites, integrins on circulating platelets exist in a low-affinity state and shift to a high-affinity state (in a process known as integrin activation or priming) after contacting a wounded vessel. The shift is mediated through binding of the cytoskeletal protein Talin to the beta subunit cytoplasmic tail. Here we show that platelets lacking the adhesion plaque protein Kindlin-3 cannot activate integrins despite normal Talin expression. As a direct consequence, Kindlin-3 deficiency results in severe bleeding and resistance to arterial thrombosis. Mechanistically, Kindlin-3 can directly bind to regions of beta-integrin tails distinct from those of Talin and trigger integrin activation. We have therefore identified Kindlin-3 as a novel and essential element for platelet integrin activation in hemostasis and thrombosis.
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            Activation of platelet function through G protein-coupled receptors.

            Because of their ability to become rapidly activated at places of vascular injury, platelets are important players in primary hemostasis as well as in arterial thrombosis. In addition, they are also involved in chronic pathological processes including the atherosclerotic remodeling of the vascular system. Although primary adhesion of platelets to the vessel wall is largely independent of G protein-mediated signaling, the subsequent recruitment of additional platelets into a growing platelet thrombus requires mediators such as ADP, thromboxane A(2), or thrombin, which act through G protein-coupled receptors. Platelet activation via G protein-coupled receptors involves 3 major G protein-mediated signaling pathways that are initiated by the activation of the G proteins G(q), G(13), and G(i). This review summarizes recent progress in understanding the mechanisms underlying platelet activation and thrombus extension via G protein-mediated signaling pathways.
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              Transcriptional repression of atherogenic inflammation: modulation by PPARdelta.

              The formation of an atherosclerotic lesion is mediated by lipid-laden macrophages (foam cells), which also establish chronic inflammation associated with lesion progression. The peroxisome proliferator-activated receptor (PPAR) gamma promotes lipid uptake and efflux in these atherogenic cells. In contrast, we found that the closely related receptor PPARdelta controls the inflammatory status of the macrophage. Deletion of PPARdelta from foam cells increased the availability of inflammatory suppressors, which in turn reduced atherosclerotic lesion area by more than 50%. We propose an unconventional ligand-dependent transcriptional pathway in which PPARdelta controls an inflammatory switch through its association and disassociation with transcriptional repressors. PPARdelta and its ligands may thus serve as therapeutic targets to attenuate inflammation and slow the progression of atherosclerosis.
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                Author and article information

                Journal
                J Thromb Haemost
                J. Thromb. Haemost
                10.1111/(ISSN)1538-7836
                JTH
                Journal of Thrombosis and Haemostasis
                John Wiley and Sons Inc. (Hoboken )
                1538-7933
                1538-7836
                09 April 2016
                May 2016
                : 14
                : 5 ( doiID: 10.1111/jth.2016.14.issue-5 )
                : 918-930
                Affiliations
                [ 1 ] Institute of Cardiovascular and Metabolic Research School of Biological SciencesUniversity of Reading ReadingUK
                Author notes
                [*] [* ] Correspondence: Jonathan Gibbins, Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Harborne Building, Reading, RG6 6AS, UK.

                Tel.: +44 118 3787082; fax: +44 118 9310180.

                E‐mail: j.m.gibbins@ 123456reading.ac.uk .

                Article
                JTH13302
                10.1111/jth.13302
                4879507
                26929147
                ad88a5d9-1391-475c-bf30-ef65daf17c1f
                © 2016 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 06 October 2015
                : 11 February 2016
                Page count
                Pages: 13
                Funding
                Funded by: British Heart Foundation
                Award ID: RG/09/011/28094
                Award ID: RG/15/2/31224
                Categories
                Review Article
                Review Articles
                Custom metadata
                2.0
                jth13302
                May 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.1 mode:remove_FC converted:21.06.2016

                Hematology
                blood platelets,hemostasis,platelet activation,review,thrombosis
                Hematology
                blood platelets, hemostasis, platelet activation, review, thrombosis

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