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

Document Type

Article

Abstract

In endothelial cells, two type I receptors of the transforming growth factor β (TGF-β) family, ALK1 and ALK5, coordinate to regulate embryonic angiogenesis in response to BMP9/10 and TGF-β. Whereas TGF-β binds to and activates ALK5, leading to Smad2/3 phosphorylation and inhibition of endothelial cell proliferation and migration, BMP9/10 and TGF-β 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-β/BMP9-dependent biological processes by its ability to both positively and negatively modulate the activities of Smad-dependent pathways.

Keywords

Activin Receptors, Type I, Activin Receptors, Type II, Animals, Apoptosis, Blotting, Western, Cell Movement, Cell Proliferation, Embryo, Mammalian, Endothelium, Vascular, Female, Fibroblasts, Fluorescent Antibody Technique, Humans, Immunoenzyme Techniques, Immunoprecipitation, Mice, Mice, Inbred C57BL, Mice, Knockout, Neovascularization, Physiologic, Phosphorylation, Proto-Oncogene Proteins, Pulmonary Artery, RNA, Messenger, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Smad1 Protein, Smad5 Protein

Medical Subject Headings

Activin Receptors, Type I; Activin Receptors, Type II; Animals; Apoptosis; Blotting, Western; Cell Movement; Cell Proliferation; Embryo, Mammalian; Endothelium, Vascular; Female; Fibroblasts; Fluorescent Antibody Technique; Humans; Immunoenzyme Techniques; Immunoprecipitation; Mice; Mice, Inbred C57BL; Mice, Knockout; Neovascularization, Physiologic; Phosphorylation; Proto-Oncogene Proteins; Pulmonary Artery; RNA, Messenger; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Smad1 Protein; Smad5 Protein

Publication Date

9-16-2013

Publication Title

The Journal of cell biology

ISSN

1540-8140

Volume

202

Issue

6

First Page

937

Last Page

950

PubMed ID

24019535

Digital Object Identifier (DOI)

10.1083/jcb.201208113

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