{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Lamrani L"],"funding":["Institut National de la Santé et de la Recherche Médicale","Fondation pour la Recherche Médicale"],"pagination":["e12672"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8924993"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["6(2)"],"pubmed_abstract":["<h4>Background</h4>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.<h4>Objectives</h4>The aim of this study was to evaluate the role of filamin A (FLNa) subdomains on the regulation of integrin αIIbβ3 signaling.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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."],"journal":["Research and practice in thrombosis and haemostasis"],"pubmed_title":["New insights into regulation of αIIbβ3 integrin signaling by filamin A."],"pmcid":["PMC8924993"],"funding_grant_id":["LPC20170637458"],"pubmed_authors":["Rosa JP","Raslova H","Lamrani L","Bryckaert M","Denis CV","Adam F","Soukaseum C"],"additional_accession":[]},"is_claimable":false,"name":"New insights into regulation of αIIbβ3 integrin signaling by filamin A.","description":"<h4>Background</h4>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.<h4>Objectives</h4>The aim of this study was to evaluate the role of filamin A (FLNa) subdomains on the regulation of integrin αIIbβ3 signaling.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Feb","modification":"2025-04-04T07:45:31.444Z","creation":"2025-04-04T07:45:31.444Z"},"accession":"S-EPMC8924993","cross_references":{"pubmed":["35316942"],"doi":["10.1002/rth2.12672"]}}