SnoN facilitates ALK1-Smad1/5 signaling during embryonic angiogenesis.

ABSTRACT: In endothelial cells, two type I receptors of the transforming growth factor ? (TGF-?) family, ALK1 and ALK5, coordinate to regulate embryonic angiogenesis in response to BMP9/10 and TGF-?. Whereas TGF-? binds to and activates ALK5, leading to Smad2/3 phosphorylation and inhibition of endothelial cell proliferation and migration, BMP9/10 and TGF-? also bind to ALK1, resulting in the activation of Smad1/5. SnoN is a negative regulator of ALK5 signaling through the binding and repression of Smad2/3. Here we uncover a positive role of SnoN in enhancing Smad1/5 activation in endothelial cells to promote angiogenesis. Upon ligand binding, SnoN directly bound to ALK1 on the plasma membrane and facilitated the interaction between ALK1 and Smad1/5, enhancing Smad1/5 phosphorylation. Disruption of this SnoN-Smad interaction impaired Smad1/5 activation and up-regulated Smad2/3 activity. This resulted in defective angiogenesis and arteriovenous malformations, leading to embryonic lethality at E12.5. Thus, SnoN is essential for TGF-?/BMP9-dependent biological processes by its ability to both positively and negatively modulate the activities of Smad-dependent pathways.

SUBMITTER: Zhu Q 

PROVIDER: S-EPMC3776356 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature