New insights into regulation of αIIbβ3 integrin signaling by filamin A - Archive ouverte HAL
Journal Articles Research and Practice in Thrombosis and Haemostasis Year : 2022

New insights into regulation of αIIbβ3 integrin signaling by filamin A

Abstract

Background: Filamin (FLN) regulates many cell functions through its scaffolding activity cross-linking cytoskeleton and integrins. FLN was shown to inhibit integrin activity, but the exact mechanism remains unclear. Objectives: The aim of this study was to evaluate the role of filamin A (FLNa) subdomains on the regulation of integrin αIIbβ3 signaling. Methods: Three FLNa deletion mutants were overexpressed in the erythro-megakaryocytic leukemic cell line HEL: Del1, which lacks the N-terminal CH1-CH2 domains mediating the FLNa-actin interaction; Del2, lacking the Ig-like repeat 21, which mediates the FLNa-β3 interaction; and Del3, lacking the C-terminal Ig repeat 24, responsible for FLNa dimerization and interaction with the small Rho guanosine triphosphatase involved in actin cytoskeleton reorganisation. Fibrinogen binding to HEL cells in suspension and talin-β3 proximity in cells adherent to immobilized fibrinogen were assessed before and after αIIbβ3 activation by the protein kinase C agonist phorbol 12-myristate 13-acetate. Results: Our results show that FLNa-actin and FLNa-β3 interactions negatively regulate αIIbβ3 activation. Moreover, FLNa-actin interaction represses Rac activation, contributing to the negative regulation of αIIbβ3 activation. In contrast, the FLNa dimerization domain, which maintains Rho inactive, was found to negatively regulate αIIbβ3 outside-in signaling. Conclusion: We conclude that FLNa negatively controls αIIbβ3 activation by regulating actin polymerization and restraining activation of Rac, as well as outside-in signaling by repressing Rho.
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hal-04471560 , version 1 (25-09-2024)

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Lamia Lamrani, Frédéric Adam, Christelle Soukaseum, Cécile Denis, Hana Raslova, et al.. New insights into regulation of αIIbβ3 integrin signaling by filamin A. Research and Practice in Thrombosis and Haemostasis, 2022, 6 (2), pp.e12672. ⟨10.1002/rth2.12672⟩. ⟨hal-04471560⟩
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