Disrupted filamin A/αIIbβ3 interaction induces macrothrombocytopenia by increasing RhoA activity - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Blood Année : 2019

Disrupted filamin A/αIIbβ3 interaction induces macrothrombocytopenia by increasing RhoA activity

Cyril Goizet
  • Fonction : Auteur
Rémi Favier
Lucie Tosca
Gérard Tachdjian
Cecile Denis
Jean-Philippe Rosa
Marijke Bryckaert
Hana Raslova

Résumé

Abstract Filamin A (FLNa) links the cell membrane with the cytoskeleton and is central in several cellular processes. Heterozygous mutations in the X-linked FLNA gene are associated with a large spectrum of conditions, including macrothrombocytopenia, called filaminopathies. Using an isogenic pluripotent stem cell model derived from patients, we show that the absence of the FLNa protein in megakaryocytes (MKs) leads to their incomplete maturation, particularly the inability to produce proplatelets. Reduction in proplatelet formation potential is associated with a defect in actomyosin contractility, which results from inappropriate RhoA activation. This dysregulated RhoA activation was observed when MKs were plated on fibrinogen but not on other matrices (fibronectin, vitronectin, collagen 1, and von Willebrand factor), strongly suggesting a role for FLNa/αIIbβ3 interaction in the downregulation of RhoA activity. This was confirmed by experiments based on the overexpression of FLNa mutants deleted in the αIIbβ3-binding domain and the RhoA-interacting domain, respectively. Finally, pharmacological inhibition of the RhoA-associated kinase ROCK1/2 restored a normal phenotype and proplatelet formation. Overall, this work suggests a new etiology for macrothrombocytopenia, in which increased RhoA activity is associated with disrupted FLNa/αIIbβ3 interaction.

Dates et versions

hal-04441275 , version 1 (06-02-2024)

Identifiants

Citer

Alessandro Donada, Nathalie Balayn, Dominika Sliwa, Larissa Lordier, Valentina Ceglia, et al.. Disrupted filamin A/αIIbβ3 interaction induces macrothrombocytopenia by increasing RhoA activity. Blood, 2019, 133 (16), pp.1778-1788. ⟨10.1182/blood-2018-07-861427⟩. ⟨hal-04441275⟩
31 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More