ALK5 and ALK1 play antagonistic roles in TGFβ-induced podosome formation in aortic endothelial cells

ABSTRACT

TGFβ and related cytokines play a central role in the vascular system. In vitro, TGFβ induces aortic endothelial cells to assemble subcellular actin-rich structures specialized for matrix degradation called podosomes. To explore further this TGFβ-specific response and determine in which context podosomes form, ALK5 and ALK1 TGFβ receptor signaling pathways were investigated in bovine aortic endothelial cells. We report that TGFβ drives podosome formation through ALK5 and the downstream effectors Smad2 and Smad3. Concurrent TGFβ-induced ALK1 signaling mitigates ALK5 responses through Smad1. ALK1 signaling induced by BMP9 also antagonizes TGFβ-induced podosome formation but this occurs through both Smad1 and Smad5. Whereas ALK1 neutralization brings ALK5 signals to full potency for TGFβ-induced podosome formation, ALK1 depletion leads to cell disturbances not compatible with podosome assembly. Thus, ALK1 possesses passive and active modalities. Altogether, we reveal specific features of ALK1 and ALK5 signaling with potential clinical implications.