Transforming growth factor-β (TGFβ) regulates the activation state of the endothelium via two opposing type I receptor/Smad pathways. Activin receptor-like kinase-1 (ALK1) induces Smad1/5 phosphorylation, leading to an increase in endothelial cell proliferation and migration, while ALK5 promotes Smad2/3 activation and inhibits both processes. Here, we report that ALK5 is important for TGFβ/ALK1 signaling; endothelial cells lacking ALK5 are deficient in TGFβ/ALK1-induced responses. More specifically, we show that ALK5 mediates a TGFβ-dependent recruitment of ALK1 into a TGFβ receptor complex and that the ALK5 kinase activity is required for optimal ALK1 activation. TGFβ type II receptor is also required for ALK1 activation by TGFβ. Interestingly, ALK1 not only induces a biological response opposite to that of ALK5 but also directly antagonizes ALK5/Smad signaling.
