Activin Receptor-like Kinase (ALK)1 Is an Antagonistic Mediator of Lateral TGFβ/ALK5 Signaling

Abstract

Transforming growth factor-beta (TGFbeta) 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 TGFbeta/ALK1 signaling; endothelial cells lacking ALK5 are deficient in TGFbeta/ALK1-induced responses. More specifically, we show that ALK5 mediates a TGFbeta-dependent recruitment of ALK1 into a TGFbeta receptor complex and that the ALK5 kinase activity is required for optimal ALK1 activation. TGFbeta type II receptor is also required for ALK1 activation by TGFbeta. Interestingly, ALK1 not only induces a biological response opposite to that of ALK5 but also directly antagonizes ALK5/Smad signaling.

Transforming growth factor‐β stimulates epithelial–mesenchymal transformation in the proepicardium

“…As the TGF␤ concentration is increased, TGF␤ activates only ALK5-mediated pathways to inhibit endothelial cell proliferation and migration. Therefore, by activating ALK1 and ALK5, or ALK5 alone, TGF␤ can both stimulate and inhibit endothelial cell proliferation and migration to balance angiogenesis (Goumans et al, 2002(Goumans et al, , 2003.…”

The role of bone morphogenetic proteins in myeloma cell survival

“…Thus, TGF-β can activate heteromeric receptor complexes consisting of both ALK5 and ALK1, thereby activating both SMAD2/3 and SMAD1/5/8. [8,9] Also, BMP-9 has been shown to induce phosphorylation of SMAD2 by signaling through ActRIIa in pulmonary endothelial cells. [10] More recently, it was shown that BMP-2 also could signal through heteromeric complexes consisting of TGFBR2/ALK5/ALK3, leading to SMAD2 phosphorylation, and BMPR2/ALK5/ALK3 or BMPRII/ALK7/ALK6 leading to Smad3 phosphorylation.…”

Smad1 pathway is activated in systemic sclerosis fibroblasts and is targeted by imatinib mesylate

“…TGF␤-dependent activation of the Smad1 pathway was first described in endothelial cells (27). In these cells, TGF␤ signals through a heteromeric receptor complex that includes TGF␤RII, ALK-5, and ALK-1 (28). While the specific interactions between ALK-5 and ALK-1 are still not fully elucidated, there is evidence that the relative ratio of these 2 receptor subtypes regulates the switch between proliferation and differentiation of endothelial cells (15).…”