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      Platelet secretion: From haemostasis to wound healing and beyond

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          Abstract

          Upon activation, platelets secrete more than 300 active substances from their intracellular granules. Platelet dense granule components, such as ADP and polyphosphates, contribute to haemostasis and coagulation, but also play a role in cancer metastasis. α-Granules contain multiple cytokines, mitogens, pro- and anti-inflammatory factors and other bioactive molecules that are essential regulators in the complex microenvironment of the growing thrombus but also contribute to a number of disease processes. Our understanding of the molecular mechanisms of secretion and the genetic regulation of granule biogenesis still remains incomplete. In this review we summarise our current understanding of the roles of platelet secretion in health and disease, and discuss some of the hypotheses that may explain how platelets may control the release of its many secreted components in a context-specific manner, to allow platelets to play multiple roles in health and disease.

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          Membrane fusion: grappling with SNARE and SM proteins.

          The two universally required components of the intracellular membrane fusion machinery, SNARE and SM (Sec1/Munc18-like) proteins, play complementary roles in fusion. Vesicular and target membrane-localized SNARE proteins zipper up into an alpha-helical bundle that pulls the two membranes tightly together to exert the force required for fusion. SM proteins, shaped like clasps, bind to trans-SNARE complexes to direct their fusogenic action. Individual fusion reactions are executed by distinct combinations of SNARE and SM proteins to ensure specificity, and are controlled by regulators that embed the SM-SNARE fusion machinery into a physiological context. This regulation is spectacularly apparent in the exquisite speed and precision of synaptic exocytosis, where synaptotagmin (the calcium-ion sensor for fusion) cooperates with complexin (the clamp activator) to control the precisely timed release of neurotransmitters that initiates synaptic transmission and underlies brain function.
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            The platelet contribution to cancer progression.

            Traditionally viewed as major cellular components in hemostasis and thrombosis, the contribution of platelets to the progression of cancer is an emerging area of research interest. Complex interactions between tumor cells and circulating platelets play an important role in cancer growth and dissemination, and a growing body of evidence supports a role for physiologic platelet receptors and platelet agonists in cancer metastases and angiogenesis. Platelets provide a procoagulant surface facilitating amplification of cancer-related coagulation, and can be recruited to shroud tumor cells, thereby shielding them from immune responses, and facilitate cancer growth and dissemination. Experimental blockade of key platelet receptors, such as GP1b/IX/V, GPIIbIIIa and GPVI, has been shown to attenuate metastases. Platelets are also recognized as dynamic reservoirs of proangiogenic and anti-angiogenic proteins that can be manipulated pharmacologically. A bidirectional relationship between platelets and tumors is also seen, with evidence of 'tumor conditioning' of platelets. The platelet as a reporter of malignancy and a targeted delivery system for anticancer therapy has also been proposed. The development of platelet inhibitors that influence malignancy progression and clinical testing of currently available antiplatelet drugs represents a promising area of targeted cancer therapy. © 2011 International Society on Thrombosis and Haemostasis.
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              The incredible journey: From megakaryocyte development to platelet formation

              Circulating blood platelets are specialized cells that prevent bleeding and minimize blood vessel injury. Large progenitor cells in the bone marrow called megakaryocytes (MKs) are the source of platelets. MKs release platelets through a series of fascinating cell biological events. During maturation, they become polyploid and accumulate massive amounts of protein and membrane. Then, in a cytoskeletal-driven process, they extend long branching processes, designated proplatelets, into sinusoidal blood vessels where they undergo fission to release platelets. Given the need for platelets in many pathological situations, understanding how this process occurs is an active area of research with important clinical applications.
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                Author and article information

                Contributors
                Journal
                Blood Rev
                Blood Rev
                Blood Reviews
                Elsevier
                0268-960X
                1532-1681
                1 May 2015
                May 2015
                : 29
                : 3
                : 153-162
                Affiliations
                Medical Sciences Building, School of Physiology and Pharmacology, University of Bristol, University Walk, BS8 1TD Bristol, UK
                Author notes
                [* ]Corresponding author at: School of Physiology & Pharmacology, Medical Sciences Building, University Walk, Bristol BS8 1TD, UK. Tel.: + 44 117 331 1435; fax: + 44 117 331 2288. a.poole@ 123456bris.ac.uk
                Article
                S0268-960X(14)00085-X
                10.1016/j.blre.2014.10.003
                4452143
                25468720
                035487c7-9644-4eff-a15e-8235d17173ad
                © 2014 The Authors. Published by Elsevier Ltd.

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

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                Categories
                Review

                platelets,secretion,snare proteins,thrombosis,haemostasis,cancer metastasis,inflammation

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