title: ALK5 and ALK1 play antagonistic roles in transforming growth factor β-induced podosome formation in aortic endothelial cells.
abstract: Transforming growth factor β (TGF-β) and related cytokines play a central role in the vascular system. In vitro, TGF-β induces aortic endothelial cells to assemble subcellular actin-rich structures specialized for matrix degradation called podosomes. To explore further this TGF-β-specific response and determine in which context podosomes form, ALK5 and ALK1 TGF-β receptor signaling pathways were investigated in bovine aortic endothelial cells. We report that TGF-β drives podosome formation through ALK5 and the downstream effectors Smad2 and Smad3. Concurrent TGF-β-induced ALK1 signaling mitigates ALK5 responses through Smad1. ALK1 signaling induced by BMP9 also antagonizes TGF-β-induced podosome formation, but this occurs through both Smad1 and Smad5. Whereas ALK1 neutralization brings ALK5 signals to full potency for TGF-β-induced podosome formation, ALK1 depletion leads to cell disturbances not compatible with podosome assembly. Thus, ALK1 possesses passive and active modalities. Altogether, our results reveal specific features of ALK1 and ALK5 signaling with potential clinical implications.
authors.affiliation: IECB and INSERM U1045, University of Bordeaux, Bordeaux, France.
authors.forename: Filipa
authors.initials: F
authors.lastname: Curado
authors.affiliation: IECB and INSERM U1045, University of Bordeaux, Bordeaux, France.
authors.forename: Pirjo
authors.initials: P
authors.lastname: Spuul
authors.affiliation: IECB and INSERM U1045, University of Bordeaux, Bordeaux, France.
authors.forename: Isabel
authors.initials: I
authors.lastname: Egaña
authors.affiliation: IECB and INSERM U1045, University of Bordeaux, Bordeaux, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Rottiers
authors.affiliation: IECB and INSERM U1045, University of Bordeaux, Bordeaux, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Daubon
authors.affiliation: IECB and INSERM U1045, University of Bordeaux, Bordeaux, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Veillat
authors.affiliation: IECB and INSERM U1045, University of Bordeaux, Bordeaux, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Duhamel
authors.affiliation: IECB and INSERM U1045, University of Bordeaux, Bordeaux, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Leclercq
authors.affiliation: Bordeaux Imaging Center, UMS 3420 CNRS/US4 INSERM, University of Bordeaux, Bordeaux, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Gontier
authors.affiliation: IECB and INSERM U1045, University of Bordeaux, Bordeaux, France e.genot@iecb.u-bordeaux.fr.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Génot
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D029404:Activin Receptors / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D002417:Cattle; D042783:Endothelial Cells / Q000378:metabolism; D055427:Growth Differentiation Factor 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D055427:Growth Differentiation Factor 2; D018125:Receptors, Transforming Growth Factor beta; D051896:Smad Proteins, Receptor-Regulated; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D029404:Activin Receptors; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625842:Tgfbr1 protein, mouse