A novel interaction between FlnA and Syk regulates platelet ITAM-mediated receptor signaling and function

Falet, Hervé; Pollitt, Alice Y.; Begonja, Antonija Jurak; Weber, Sarah; Duerschmied, Daniel; Watson, Steve P.; Hartwig, John H.

doi:10.1083/jcb1904oia11

Cited by 21 publications

(54 citation statements)

References 51 publications

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“…PLT number and size are often inversely proportional, and others have shown that the PLT cytoskeleton can regulate PLT size and numbers through specific transmembrane receptor interactions. GPIb, for example, is complexed to the actin-binding protein filamin A and is known to have an important role in maintaining the normal cytoskeletal architecture of resting PLTs 17,18 . In Bernard Soulier Syndrome genetic abnormalities of the GPIb-IX-V complex, particularly the GPIbα subunit that contains the Von Willebrand factor and thrombin-binding sites, results in fewer and larger PLTs 1 .…”

Section: Discussionmentioning

confidence: 99%

Microtubule and cortical forces determine platelet size during vascular platelet production

et al. 2012

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megakaryocytes release large preplatelet intermediates into the sinusoidal blood vessels. Preplatelets convert into barbell-shaped proplatelets in vitro to undergo repeated abscissions that yield circulating platelets. These observations predict the presence of circular-preplatelets and barbell-proplatelets in blood, and two fundamental questions in platelet biology are what are the forces that determine barbell-proplatelet formation, and how is the final platelet size established. Here we provide insights into the terminal mechanisms of platelet production. We quantify circular-preplatelets and barbell-proplatelets in human blood in high-resolution fluorescence images, using a laser scanning cytometry assay. We demonstrate that force constraints resulting from cortical microtubule band diameter and thickness determine barbellproplatelet formation. Finally, we provide a mathematical model for the preplatelet to barbell conversion. We conclude that platelet size is limited by microtubule bundling, elastic bending, and actin-myosin-spectrin cortex forces.

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Section: Discussionmentioning

confidence: 99%

Microtubule and cortical forces determine platelet size during vascular platelet production

et al. 2012

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“…Filamin A functions in Mks and platelets include connection of cytoplasmic tail of GPIba with F-actin (Fig. 2) and transduction of Syk-mediated signaling [55,56]. Nurden and colleagues described three female patients with thrombocytopenia caused by monoallelic FLNA mutations.…”

Section: Defective Ppf From Mature Mksmentioning

confidence: 99%

Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists

Pecci

2013

Int J Hematol

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Knowledge in the field of inherited thrombocytopenias (ITs) has considerably improved over the recent years. In the last 5 years, nine new genes whose mutations are responsible for thrombocytopenia have been identified, and this also led to the recognition of several novel nosographic entities, such as thrombocytopenias deriving from mutations in CYCS, TUBB1, FLNA, ITGA2B/ITGB3, ANKRD26 and ACTN1. The identification of novel molecular alterations causing thrombocytopenia together with improvement of methodologies to study megakaryopoiesis led to considerable advances in understanding pathophysiology of ITs, thus providing the background for proposing new treatments. Thrombopoietin-receptor agonists (TPO-RAs) represent an appealing therapeutic hypothesis for ITs and have been tested in a limited number of patients. In this review, we provide an updated description of pathogenetic mechanisms of thrombocytopenia in the different forms of ITs and recapitulate the current management of these disorders. Moreover, we report the available clinical and preclinical data about the role of TPO-RAs in ITs and discuss the rationale for the use of these molecules in view of pathogenesis of the different forms of thrombocytopenia of genetic origin.

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“…Filamin A plays a critical role in platelet morphology and signaling, as it cross-links actin filaments, tethers the von Willebrand factor receptor glycoprotein Ib-IX-V complex and integrins to the underlying actin cytoskeleton, and serves as a scaffold for signaling intermediates, e.g. the tyrosine kinase Syk 13 (reviewed by Falet et al 14 ). Filamin A arginylation occurs on three different sites, i.e.…”

confidence: 99%

Post-translational arginylation as a novel regulator of platelet function

Bender

Falet

2014

Haematologica

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A novel interaction between FlnA and Syk regulates platelet ITAM-mediated receptor signaling and function

Cited by 21 publications

References 51 publications

Microtubule and cortical forces determine platelet size during vascular platelet production

Microtubule and cortical forces determine platelet size during vascular platelet production

Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists

Post-translational arginylation as a novel regulator of platelet function

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