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Altered microtubule equilibrium and impaired thrombus stability in mice lacking RanBP10

Item Type:Article
Title:Altered microtubule equilibrium and impaired thrombus stability in mice lacking RanBP10
Creators Name:Meyer, I. and Kunert, S. and Schwiebert, S. and Hagedorn, I. and Italiano, J.E. and Duetting, S. and Nieswandt, B. and Bachmann, S. and Schulze, H.
Abstract:The crucial function of blood platelets in hemostasis is to prevent blood loss by stable thrombus formation. This process is driven by orchestrated mechanisms including several signal transduction cascades and morphologic transformations. The cytoplasmic microtubule modulator RanBP10 is a Ran and beta1-tubulin binding protein that is essential for platelet granule release and mice lacking RanBP10 harbor a severe bleeding phenotype. In this study, we demonstrate that RanBP10-nullizygous platelets show normal adhesion on collagen and von Willebrand factor under flow conditions. However, using a ferric chloride-induced arterial thrombosis model, the formation of stable thrombi was significantly impaired, preventing vessel occlusion or leading to recanalization and thromboembolization. Delta-granule secretion was normal in mutant mice, whereas platelet shape change in aggregometry was attenuated. Lack of RanBP10 leads to increased beta1-tubulin protein, which drives alpha-monomers into polymerized microtubules. In mutant platelets agonists failed to contract the peripheral marginal band or centralize granules. Pretreatment of wild-type platelets with taxol caused microtubule stabilization and phenocopied the attenuated shape change in response to collagen, suggesting that RanBP10 inhibits premature microtubule polymerization of beta1-tubulin and plays a pivotal role in thrombus stabilization.
Keywords:Arteries, Blood Platelets, Chlorides, Collagen, Cytoplasmic Granules, Ferric Compounds, Gene Expression, Guanine Nucleotide Exchange Factors, Hemorheology, Knockout Mice, Microtubule-Associated Proteins, Microtubules, Paclitaxel, Platelet Activation, Platelet Adhesiveness, Platelet Aggregation, Polymerization, Protein Isoforms, Signal Transduction, Thrombosis, Tubulin, von Willebrand Factor, Animals, Mice
Publisher:American Society of Hematology
Page Range:3594-602
Date:25 October 2012
Official Publication:https://doi.org/10.1182/blood-2012-01-401737
PubMed:View item in PubMed

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