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• W2106292009 abstract "Blood platelets are tiny cell fragments derived from megakaryocytes. Their primary function is to control blood vessel integrity and ensure hemostasis if a vessel wall is damaged. Circulating quiescent platelets have a flat, discoid shape maintained by a circumferential microtubule bundle, called the marginal band (MB). In the case of injury platelets are activated and rapidly adopt a spherical shape due to microtubule motor‐induced elongation and subsequent coiling of the MB. Platelet activation and shape change can be transient or become irreversible. This depends on the strength of the activation stimulus, which is translated into a cytoskeletal crosstalk between microtubules, their motors and the actomyosin cortex, ensuring stimulus‐response coupling. Following microtubule motor‐driven disc‐to‐sphere transition, a strong stimulus will lead to compression of the sphere through actomyosin cortex contraction. This will concentrate the granules in the center of the platelet and accelerate their exocytosis. Once granules are released, platelets have crossed the point of no return to irreversible activation. This review summarizes the current knowledge of the molecular mechanism leading to platelet shape change, with a special emphasis on microtubules, and refers to previously published observations, which have been essential for generating an integrated view of cytoskeletal rearrangements during platelet activation. Blood platelets are tiny cell fragments derived from megakaryocytes. Their primary function is to control blood vessel integrity and ensure hemostasis if a vessel wall is damaged. Circulating quiescent platelets have a flat, discoid shape maintained by a circumferential microtubule bundle, called the marginal band (MB). In the case of injury platelets are activated and rapidly adopt a spherical shape due to microtubule motor‐induced elongation and subsequent coiling of the MB. Platelet activation and shape change can be transient or become irreversible. This depends on the strength of the activation stimulus, which is translated into a cytoskeletal crosstalk between microtubules, their motors and the actomyosin cortex, ensuring stimulus‐response coupling. Following microtubule motor‐driven disc‐to‐sphere transition, a strong stimulus will lead to compression of the sphere through actomyosin cortex contraction. This will concentrate the granules in the center of the platelet and accelerate their exocytosis. Once granules are released, platelets have crossed the point of no return to irreversible activation. This review summarizes the current knowledge of the molecular mechanism leading to platelet shape change, with a special emphasis on microtubules, and refers to previously published observations, which have been essential for generating an integrated view of cytoskeletal rearrangements during platelet activation. Vertebrates have developed an efficient blood circulatory system to provide all parts of the body with nutrients and to evacuate cytotoxic products. They thereby expose themselves to life threatening danger if blood is lost by injury. Thus, during evolution a quality control and first aid repair system for blood vessels had to evolve, which has to respond to several essential criteria. First, the integrity of the whole circulatory system has to be constantly monitored. Second, vessel damage should give an alert signal to trigger use of a repair kit. Third, ideally the repair tools should be already in place at the site of injury. In non‐mammalian vertebrates, nucleated thrombocytes are the specialized cell type able to fulfill this functional role. During evolution the cells involved in hemostasis have become more sophisticated 1.Levin J. Chapter 1 ‐ The Evolution of Mammalian Platelets.in: Michelson AD Platelets. 3rd. Academic Press, 2013: 3-25Crossref Scopus (36) Google Scholar. Mammalian thrombocytes, called platelets, are generated by fragmentation of megakaryocytes 2.Thon J.N. Italiano J.E. Platelet formation.Semin Hematol. 2010; 47: 220-6Crossref PubMed Scopus (102) Google Scholar. They are tiny cell fragments devoid of a nucleus but equipped with all the necessary components for vessel repair, prefabricated and stored in the cytoplasm and in their granules. Most surprisingly, despite these fundamental differences between nucleated thrombocytes of lower vertebrates and mammalian platelets the principal features of cytoskeletal reorganizations during activation are conserved as discussed below. Platelets circulate in the blood and control vessel integrity as small, discoid particles. Their small size and flat, discoid form allow them to pass through narrow spaces where large, round cells would get stuck. On vessel injury, platelets are activated and rapidly change shape. They become spherical and extend filopodia 3.Hartwig J.H. The platelet: form and function.Semin Hematol. 2006; 43: S94-100Crossref PubMed Scopus (70) Google Scholar. Blood flow simulations have shown that spherical platelets are transported more quickly to the vessel wall than disc‐shaped platelets, giving them a better chance to adhere near the injured site 4.Reasor Jr, D.A. Mehrabadi M. Ku D.N. Aidun C.K. Determination of critical parameters in platelet margination.Ann Biomed Eng. 2013; 41: 238-49Crossref PubMed Scopus (95) Google Scholar. They almost simultaneously secrete the content of their granules, releasing substances for the activation of surrounding platelets, cytokines for endothelial cells and coagulation factors. An important field of investigation is the characterization of the molecular mechanisms leading to this rapid shape change during platelet activation and the concomitant exocytosis of platelet granules. The precise regulation of these processes is also extensively studied, with the aim of developing new strategies against pathological thrombus formation. This section focuses on microtubules and actin filaments, because their reorganization is particularly important for the shape changes observed during platelet activation. Additionally, a detailed list of other structural components of the platelet cytoskeleton identified in the platelet proteome is shown in Table 1.Table 1Structural constituents of the platelet cytoskeleton. Members of different cytoskeletal families identified in a proteomic study by Burkhart et al. 21.Burkhart J.M. Vaudel M. Gambaryan S. Radau S. Walter U. Martens L. Geiger J. Sickmann A. Zahedi R.P. The first comprehensive and quantitative analysis of human platelet protein composition allows the comparative analysis of structural and functional pathways.Blood. 2012; 120: e73-82Crossref PubMed Scopus (503) Google Scholar are listed and the relative expression levels are indicated according to the color code shown below the table (no color in the case of unavailable copy number estimations) Open table in a new tab Microtubules are composed of heterodimers of α‐ and β‐tubulin subunits, which polymerize in a head to tail fashion to form a protofilament (Fig. 1A). In most cells, 13 protofilaments assemble laterally to form a polar, hollow tube with the α‐subunits exposed at one end (minus end) and the β‐subunits at the other (plus end) 5.Wade R.H. On and around microtubules: an overview.Mol Biotechnol. 2009; 43: 177-91Crossref PubMed Scopus (157) Google Scholar. Microtubule polymerization is mainly initiated at the centrosome, the major microtubule organizing center (MTOC) of animal cells, and subunit addition occurs essentially at the plus end, extending to the cell periphery. Microtubules alternate between growth and shrink phases, referred to as dynamic instability. The overall assembly rate depends on growth and shrink velocities as well as on the frequency of catastrophe (disassembly) and rescue (reassembly) events and the length of pausing periods and is highly regulated by several microtubule associated proteins (MAPs) 6.Subramanian R. Kapoor T.M. Building complexity: insights into self‐organized assembly of microtubule‐based architectures.Dev Cell. 2012; 23: 874-85Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar. At least six isoforms of α‐ and β‐tubulins have been described, which are variably expressed in different tissues 5.Wade R.H. On and around microtubules: an overview.Mol Biotechnol. 2009; 43: 177-91Crossref PubMed Scopus (157) Google Scholar. The main β‐isoform in platelets is the hematopoietic β1‐tubulin 7.Wang D. Villasante A. Lewis S.A. Cowan N.J. The mammalian beta‐tubulin repertoire: hematopoietic expression of a novel, heterologous beta‐tubulin isotype.J Cell Biol. 1986; 103: 1903-10Crossref PubMed Scopus (211) Google Scholar. Microtubule properties are not only influenced by their isoform composition, but also by post‐translational modifications (only those detected on platelet microtubules will be discussed in more detail here) 8.Janke C. Bulinski J.C. Post‐translational regulation of the microtubule cytoskeleton: mechanisms and functions.Nat Rev Mol Cell Biol. 2011; 12: 773-86Crossref PubMed Scopus (615) Google Scholar. With time long‐lived microtubules become modified by both lysine 40 acetylation and detyrosination of the C‐terminus of the α‐subunit (Fig. 1A). Lysine acetylation is catalyzed by the tubulin acetyltransferase, α‐TAT1 9.Kalebic N. Sorrentino S. Perlas E. Bolasco G. Martinez C. Heppenstall P.A. AlphaTAT1 is the major alpha‐tubulin acetyltransferase in mice.Nat Commun. 2013; 4: 1962Crossref PubMed Scopus (136) Google Scholar, 10.Akella J.S. Wloga D. Kim J. Starostina N.G. Lyons‐Abbott S. Morrissette N.S. Dougan S.T. Kipreos E.T. Gaertig J. MEC‐17 is an alpha‐tubulin acetyltransferase.Nature. 2010; 467: 218-22Crossref PubMed Scopus (336) Google Scholar, while the carboxypeptidase hydrolyzing the C‐terminal peptide bond of α‐tubulin is yet to be identified. Both modifications are reversible and the reverse reaction takes place on the free tubulin dimer rapidly after microtubule depolymerization. The acetyl‐group is removed by the major tubulin deacetylase, HDAC6 11.Zhang Y. Kwon S. Yamaguchi T. Cubizolles F. Rousseaux S. Kneissel M. Cao C. Li N. Cheng H.L. Chua K. Lombard D. Mizeracki A. Matthias G. Alt F.W. Khochbin S. Matthias P. Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally.Mol Cell Biol. 2008; 28: 1688-701Crossref PubMed Scopus (423) Google Scholar, while the tyrosine residue is added by the tubulin tyrosine ligase, TTL 12.MacRae T.H. Tubulin post‐translational modifications–enzymes and their mechanisms of action.Eur J Biochem. 1997; 244: 265-78Crossref PubMed Scopus (262) Google Scholar. Thus, newly polymerizing microtubules have tyrosinated α‐subunits and lack acetylation, because they are formed from this pool of ‘remodified’ free heterodimers 8.Janke C. Bulinski J.C. Post‐translational regulation of the microtubule cytoskeleton: mechanisms and functions.Nat Rev Mol Cell Biol. 2011; 12: 773-86Crossref PubMed Scopus (615) Google Scholar. In the resting platelet about half of the total tubulin content is in the polymerized state forming several microtubules organized in a peripheral ring structure called the marginal band (MB) (Fig. 1B) 13.Steiner M. Ikeda Y. Quantitative assessment of polymerized and depolymerized platelet microtubules. Changes caused by aggregating agents.J Clin Invest. 1979; 63: 443-8Crossref PubMed Scopus (38) Google Scholar. Platelets don't have a MTOC and microtubules are nucleated from γ‐tubulin seeds within the MB 14.Patel‐Hett S. Richardson J.L. Schulze H. Drabek K. Isaac N.A. Hoffmeister K. Shivdasani R.A. Bulinski J.C. Galjart N. Hartwig J.H. Italiano Jr, J.E. Visualization of microtubule growth in living platelets reveals a dynamic marginal band with multiple microtubules.Blood. 2008; 111: 4605-16Crossref PubMed Scopus (110) Google Scholar. The MB is responsible for the discoid resting shape because platelets become spherical when microtubules are depolymerized by nocodazole, colchicine, vincristine or cold treatment 15.White J.G. Rao G.H. Microtubule coils versus the surface membrane cytoskeleton in maintenance and restoration of platelet discoid shape.Am J Pathol. 1998; 152: 597-609PubMed Google Scholar. Interestingly, platelets deficient or mutated in the hematopoietic β1‐tubulin isoform have an altered organization of the MB and a spherical shape 16.Freson K. De Vos R. Wittevrongel C. Thys C. Defoor J. Vanhees L. Vermylen J. Peerlinck K. van Geet C. The TUBB1 Q43P functional polymorphism reduces the risk of cardiovascular disease in men by modulating platelet function and structure.Blood. 2005; 106: 2356-62Crossref PubMed Scopus (81) Google Scholar, 17.Italiano Jr, J.E. Bergmeier W. Tiwari S. Falet H. Hartwig J.H. Hoffmeister K.M. Andre P. Wagner D.D. Shivdasani R.A. Mechanisms and implications of platelet discoid shape.Blood. 2003; 101: 4789-96Crossref PubMed Scopus (131) Google Scholar. Besides these genetic alterations directly affecting microtubules, there are several other inherited diseases characterized by pathologically abnormal platelets with altered MBs as reviewed by Thon and Italiano 18.Thon J.N. Italiano Jr, J.E. Does size matter in platelet production?.Blood. 2012; 120: 1552-61Crossref PubMed Scopus (67) Google Scholar. The MB surrounds the platelet organelles and has a length of about 9 μm 14.Patel‐Hett S. Richardson J.L. Schulze H. Drabek K. Isaac N.A. Hoffmeister K. Shivdasani R.A. Bulinski J.C. Galjart N. Hartwig J.H. Italiano Jr, J.E. Visualization of microtubule growth in living platelets reveals a dynamic marginal band with multiple microtubules.Blood. 2008; 111: 4605-16Crossref PubMed Scopus (110) Google Scholar, 19.Severin S. Gaits‐Iacovoni F. Allart S. Gratacap M.P. Payrastre B. A confocal‐based morphometric analysis shows a functional crosstalk between the actin filament system and microtubules in thrombin‐stimulated platelets.J Thromb Haemost. 2013; 11: 183-6Crossref PubMed Scopus (15) Google Scholar, 20.Diagouraga B. Grichine A. Fertin A. Wang J. Khochbin S. Sadoul K. Motor‐driven marginal band coiling promotes cell shape change during platelet activation.J Cell Biol. 2014; 204: 177-85Crossref PubMed Scopus (56) Google Scholar. It is composed of long‐lived, acetylated/detyrosinated microtubules and 8–12 dynamic/tyrosinated microtubules, which polymerize in both directions within the MB. The actively polymerizing microtubules have been visualized by Patel‐Hett et al. 14.Patel‐Hett S. Richardson J.L. Schulze H. Drabek K. Isaac N.A. Hoffmeister K. Shivdasani R.A. Bulinski J.C. Galjart N. Hartwig J.H. Italiano Jr, J.E. Visualization of microtubule growth in living platelets reveals a dynamic marginal band with multiple microtubules.Blood. 2008; 111: 4605-16Crossref PubMed Scopus (110) Google Scholar in living platelets using the green fluorescent protein (GFP) fused to the plus‐end binding protein EB3, which associates specifically with growing microtubule ends. It is not completely clear whether there are 8–12 microtubules acetylated near their minus ends and decorated at their growing ends with end‐binding proteins or whether there are a few stable, acetylated microtubules that co‐exist with 8–12 shorter, growing microtubules. Another important part of the cytoskeleton is composed of actin filaments, polar, ropelike polymers of globular actin subunits. Actin is the most abundant protein in platelets 21.Burkhart J.M. Vaudel M. Gambaryan S. Radau S. Walter U. Martens L. Geiger J. Sickmann A. Zahedi R.P. The first comprehensive and quantitative analysis of human platelet protein composition allows the comparative analysis of structural and functional pathways.Blood. 2012; 120: e73-82Crossref PubMed Scopus (503) Google Scholar. In resting platelets about 60% is stored in the monomeric globular form (G‐actin) 22.Fox J.E. Boyles J.K. Reynolds C.C. Phillips D.R. Actin filament content and organization in unstimulated platelets.J Cell Biol. 1984; 98: 1985-91Crossref PubMed Scopus (76) Google Scholar, while filamentous actin (F‐actin) is mostly localized beneath the plasma membrane 23.Boyles J. Fox J.E. Phillips D.R. Stenberg P.E. Organization of the cytoskeleton in resting, discoid platelets: preservation of actin filaments by a modified fixation that prevents osmium damage.J Cell Biol. 1985; 101: 1463-72Crossref PubMed Scopus (70) Google Scholar. These cortical actin fibers are in close association with another part of the platelet cytoskeleton formed by a 2D‐network of spectrin molecules 24.Fox J.E. Reynolds C.C. Morrow J.S. Phillips D.R. Spectrin is associated with membrane‐bound actin filaments in platelets and is hydrolyzed by the Ca2+‐dependent protease during platelet activation.Blood. 1987; 69: 537-45Crossref PubMed Google Scholar. The main spectrin isoforms in platelets are the αII and βII subunits, which associate to form hetero‐tetramers 25.Patel‐Hett S. Wang H. Begonja A.J. Thon J.N. Alden E.C. Wandersee N.J. An X. Mohandas N. Hartwig J.H. Italiano Jr, J.E. The spectrin‐based membrane skeleton stabilizes mouse megakaryocyte membrane systems and is essential for proplatelet and platelet formation.Blood. 2011; 118: 1641-52Crossref PubMed Scopus (57) Google Scholar. The submembranous organization of the cytoskeleton appears to be particularly important in platelets for the stabilization and flexibility of the membrane cortex 26.Fox J.E. Boyles J.K. Berndt M.C. Steffen P.K. Anderson L.K. Identification of a membrane skeleton in platelets.J Cell Biol. 1988; 106: 1525-38Crossref PubMed Scopus (118) Google Scholar. In fact, much of the plasma membrane in resting platelets is invaginated. This peculiar membrane organization constitutes the open canalicular system and is clearly visible in cryo‐electron tomography 27.van Nispen tot Pannerden H. de Haas F. Geerts W. Posthuma G. van Dijk S. Heijnen H.F. The platelet interior revisited: electron tomography reveals tubular alpha‐granule subtypes.Blood. 2010; 116: 1147-56Crossref PubMed Scopus (137) Google Scholar. It is thought to serve as a membrane reservoir for rapid spreading during platelet activation. Resting platelets circulate in the blood for about 5–10 days and may be cleared in the spleen or liver without ever having rearranged their cytoskeleton 28.Dowling M.R. Josefsson E.C. Henley K.J. Hodgkin P.D. Kile B.T. Platelet senescence is regulated by an internal timer, not damage inflicted by hits.Blood. 2010; 116: 1776-8Crossref PubMed Scopus (45) Google Scholar. However, when a vessel is damaged, platelets adhere to the exposed extracellular matrix (ECM) and rapidly change from the discoid to a spherical shape due to a dramatic reorganization of their cytoskeleton 3.Hartwig J.H. The platelet: form and function.Semin Hematol. 2006; 43: S94-100Crossref PubMed Scopus (70) Google Scholar. They then spread on the ECM and release substances into the bloodstream to activate surrounding platelets, which undergo a similar disc‐to‐sphere transition, this time in suspension 29.Brass L.F. Tomaiuolo M. Stalker T.J. Harnessing the platelet signaling network to produce an optimal hemostatic response.Hematol Oncol Clin North Am. 2013; 27: 381-409Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar. In pathological situations, platelets may be activated by shear stress through a stenosed blood vessel 30.Holme P.A. Orvim U. Hamers M.J. Solum N.O. Brosstad F.R. Barstad R.M. Sakariassen K.S. Shear‐induced platelet activation and platelet microparticle formation at blood flow conditions as in arteries with a severe stenosis.Arterioscler Thromb Vasc Biol. 1997; 17: 646-53Crossref PubMed Scopus (384) Google Scholar or by adhesion to an atherosclerotic plaque 31.Penz S. Reininger A.J. Brandl R. Goyal P. Rabie T. Bernlochner I. Rother E. Goetz C. Engelmann B. Smethurst P.A. Ouwehand W.H. Farndale R. Nieswandt B. Siess W. Human atheromatous plaques stimulate thrombus formation by activating platelet glycoprotein VI.FASEB J. 2005; 19: 898-909Crossref PubMed Scopus (132) Google Scholar. Whatever the activation stimulus (mechanical shear stress, adhesion to the ECM or soluble agonists), it is the strength of the signal that determines whether platelets are only transiently activated (just undergoing disc‐to‐sphere transition) or release their granules to become irreversibly activated. The strength of the activation stimulus depends on the number and type of agonists binding to their corresponding receptors at the plasma membrane of a given platelet. Although initially different, most of the signaling events triggered by individual agonist/receptor interactions ultimately converge in common reactions, for instance a rise in intracellular calcium, an early, essential step during platelet activation 32.Li Z. Delaney M.K. O'Brien K.A. Du X. Signaling during platelet adhesion and activation.Arterioscler Thromb Vasc Biol. 2010; 30: 2341-9Crossref PubMed Scopus (585) Google Scholar. The speed of activation is also strongly dependent on the strength of the stimulus. At agonist concentrations used in standard aggregation assays, the kinetics of the cytoskeletal reorganizations are extremely fast, precluding the elucidation of the early steps during platelet activation leading to the spherical shape. Recently, new light has been shed on the molecular mechanism by analyzing platelets present in freshly drawn blood, which are transiently activated due to the mechanical stress during blood sampling 20.Diagouraga B. Grichine A. Fertin A. Wang J. Khochbin S. Sadoul K. Motor‐driven marginal band coiling promotes cell shape change during platelet activation.J Cell Biol. 2014; 204: 177-85Crossref PubMed Scopus (56) Google Scholar. This mechanical activation stimulus is strong enough to promote and maintain the round, spherical shape for several minutes but is sufficiently mild to allow platelets to go back to the resting state. Tubulin immunofluorescence studies have revealed that transiently activated platelets, present in freshly drawn blood, have elongated MBs in a three‐dimensional coiled form, like the seam of a tennis ball, giving them their characteristic spherical shape (Fig. 1C) 20.Diagouraga B. Grichine A. Fertin A. Wang J. Khochbin S. Sadoul K. Motor‐driven marginal band coiling promotes cell shape change during platelet activation.J Cell Biol. 2014; 204: 177-85Crossref PubMed Scopus (56) Google Scholar. These observations are in agreement with earlier studies showing that microtubule depolymerization is not necessary for platelets to attain a spherical shape during activation 33.White J.G. Rao G.H. Influence of a microtubule stabilizing agent on platelet structural physiology.Am J Pathol. 1983; 112: 207-17PubMed Google Scholar. Without an additional stimulus, coiled MBs relax to the flat resting state after a recovery period (Fig. 2A). In a resting platelet population, only a small percentage of sporadically activated platelets with coiled MBs can be observed. Cross‐sections of such platelets have been illustrated by Xu and Afzelius 34.Xu Z. Afzelius B.A. The substructure of marginal bundles in human blood platelets.J Ultrastruct Mol Struct Res. 1988; 99: 244-53Crossref PubMed Scopus (12) Google Scholar using electron microscopy (Fig. 3A). Their interpretation was, however, that there were two perpendicular microtubule bundles (Fig. 3B) instead of one bundle in the coiled conformation (Fig. 3C). In transiently activated platelets with strongly coiled MBs, the curvature of the microtubule bundle becomes critical for newly polymerizing microtubules within the bundle. The growing microtubules cannot follow the coiled bundle anymore and diverge from the original path by switching to the opposite side of the coiled structure 20.Diagouraga B. Grichine A. Fertin A. Wang J. Khochbin S. Sadoul K. Motor‐driven marginal band coiling promotes cell shape change during platelet activation.J Cell Biol. 2014; 204: 177-85Crossref PubMed Scopus (56) Google Scholar. This will generate a new, flat microtubule ring in addition to the coiled bundle (Fig. 2B). Platelets with such a microtubule organization have been described by Behnke and Forer in a population of freshly prepared platelets 35.Behnke O. Forer A. From megakaryocytes to platelets: platelet morphogenesis takes place in the bloodstream.Eur J Haematol Suppl. 1998; 61: 3-23PubMed Google Scholar. When the activation stimulus is not maintained, these platelets can still return to the resting state by disassembly of the coiled part, leaving the flat microtubule bundle in the periphery as the new resting MB (Fig. 2B). This new MB is formed of the pool of deacetylated, tyrosinated α‐tubulin subunits (mentioned above) and may be gradually reacetylated and detyrosinated with time. The heterogeneity of MB acetylation within a resting platelet population 14.Patel‐Hett S. Richardson J.L. Schulze H. Drabek K. Isaac N.A. Hoffmeister K. Shivdasani R.A. Bulinski J.C. Galjart N. Hartwig J.H. Italiano Jr, J.E. Visualization of microtubule growth in living platelets reveals a dynamic marginal band with multiple microtubules.Blood. 2008; 111: 4605-16Crossref PubMed Scopus (110) Google Scholar could thus be explained by recent transient activation events.Figure 3Cross‐sectioned microtubule bundles in a human platelet. (A) Transmission electron microscopy of a platelet in freshly drawn blood with microtubules cross‐sectioned at four locations as indicated by red arrowheads (original figure 5 from 34.Xu Z. Afzelius B.A. The substructure of marginal bundles in human blood platelets.J Ultrastruct Mol Struct Res. 1988; 99: 244-53Crossref PubMed Scopus (12) Google Scholar reprinted with permission from Elsevier). (B) A possible explanation for the cross‐sectioned microtubule bundles observed in A: two perpendicular rings are cross‐sectioned; section plane indicated in blue. (C) An alternative explanation for the cross‐sectioned microtubule bundles observed in A: a coiled ring is cross‐sectioned at the section plane indicated in blue.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Coiled MBs are not only observed in transiently activated platelets. In fact, MB coiling is always observed as an early step during platelet activation for all activation pathways so far tested 20.Diagouraga B. Grichine A. Fertin A. Wang J. Khochbin S. Sadoul K. Motor‐driven marginal band coiling promotes cell shape change during platelet activation.J Cell Biol. 2014; 204: 177-85Crossref PubMed Scopus (56) Google Scholar. For instance, when platelets are activated by contact with a glass surface, the MB coils just before platelet spreading. White and colleagues may have been the first to observe twisted marginal bands after contact of platelets with a glass surface 36.White J.G. Krumwiede M. Burris S.M. Heagan B. Isolation of microtubule coils from platelets after exposure to aggregating agents.Am J Pathol. 1986; 125: 319-26PubMed Google Scholar. MB coiling is also seen when platelets are activated in suspension with very low‐dose agonists, such as 5–10 μm arachidonic acid, 25–100 nm ADP or 0.01–0.02 U mL−1 thrombin 20.Diagouraga B. Grichine A. Fertin A. Wang J. Khochbin S. Sadoul K. Motor‐driven marginal band coiling promotes cell shape change during platelet activation.J Cell Biol. 2014; 204: 177-85Crossref PubMed Scopus (56) Google Scholar. At these threshold concentrations, which are close to physiological concentrations 37.Brash A.R. Arachidonic acid as a bioactive molecule.J Clin Invest. 2001; 107: 1339-45Crossref PubMed Scopus (436) Google Scholar, 38.Shen J. DiCorleto P.E. ADP stimulates human endothelial cell migration via P2Y1 nucleotide receptor‐mediated mitogen‐activated protein kinase pathways.Circ Res. 2008; 102: 448-56Crossref PubMed Scopus (68) Google Scholar, 39.Deranleau D.A. Luthy R. Luscher E.F. Stochastic response of human blood platelets to stimulation of shape changes and secretion.Proc Natl Acad Sci U S A. 1986; 83: 2076-80Crossref PubMed Scopus (10) Google Scholar, the steps leading to platelet activation are slow enough to be studied over time and MBs reorganize from the flat, resting to the coiled state within 30–60 s. This time period is similar to the time needed for MB coiling during platelet spreading on a glass surface and suggests that this might be the time necessary for physiological platelet activation 20.Diagouraga B. Grichine A. Fertin A. Wang J. Khochbin S. Sadoul K. Motor‐driven marginal band coiling promotes cell shape change during platelet activation.J Cell Biol. 2014; 204: 177-85Crossref PubMed Scopus (56) Google Scholar. An early step during platelet activation is the formation of membrane protrusions or tethers observed on discoid platelets under flow conditions. This process is actin polymerization independent 40.Maxwell M.J. Westein E. Nesbitt W.S. Giuliano S. Dopheide S.M. Jackson S.P. Identification of a 2‐stage platelet aggregation process mediating shear‐dependent thrombus formation.Blood. 2007; 109: 566-76Crossref PubMed Scopus (171) Google Scholar. In contrast, once disc‐to‐sphere transition is completed, the polymerization of actin filaments and their association into bundles drive the extension of filopodia on the surface of spherical platelets, leading to the spiny sphere morphology 41.Kuwahara M. Sugimoto M. Tsuji S. Matsui H. Mizuno T. Miyata S. Yoshioka A. Platelet shape changes and adhesion under high shear flow.Arterioscler Thromb Vasc Biol. 2002; 22: 329-34Crossref PubMed Scopus (65) Google Scholar. Incubation of platelets at low temperatures leads also to actin assembly, formation of filopodia and an activated state of platelets 42.Winokur R. Hartwig J.H. Mechanism of shape change in chilled human platelets.Blood. 1995; 85: 1796-804Crossref PubMed Google Scholar. It has been suggeste" @default.
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• W2106292009 date "2015-03-01" @default.
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• W2106292009 title "New explanations for old observations: marginal band coiling during platelet activation" @default.
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