VprBP mitigates TGF-ß and Activin signaling by promoting Smurf1-mediated type I receptor degradation.
J Mol Cell Biol
; 12(2): 138-151, 2020 02 20.
Article
em En
| MEDLINE
| ID: mdl-31291647
ABSTRACT
The transforming growth factor-ß (TGF-ß) family controls embryogenesis, stem cell differentiation, and tissue homeostasis. However, how post-translation modifications contribute to fine-tuning of TGF-ß family signaling responses is not well understood. Inhibitory (I)-Smads can antagonize TGF-ß/Smad signaling by recruiting Smurf E3 ubiquitin ligases to target the active TGF-ß receptor for proteasomal degradation. A proteomic interaction screen identified Vpr binding protein (VprBP) as novel binding partner of Smad7. Mis-expression studies revealed that VprBP negatively controls Smad2 phosphorylation, Smad2-Smad4 interaction, as well as TGF-ß target gene expression. VprBP was found to promote Smad7-Smurf1-TßRI complex formation and induce proteasomal degradation of TGF-ß type I receptor (TßRI). Moreover, VprBP appears to stabilize Smurf1 by suppressing Smurf1 poly-ubiquitination. In multiple adult and mouse embryonic stem cells, depletion of VprBP promotes TGF-ß or Activin-induced responses. In the mouse embryo VprBP expression negatively correlates with mesoderm marker expression, and VprBP attenuated mesoderm induction during zebrafish embryogenesis. Our findings thereby uncover a novel regulatory mechanism by which Smurf1 controls the TGF-ß and Activin cascade and identify VprBP as a critical determinant of embryonic mesoderm induction.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Fator de Crescimento Transformador beta
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Proteínas Serina-Treonina Quinases
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Ativinas
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Ubiquitina-Proteína Ligases
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Proteólise
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Receptor do Fator de Crescimento Transformador beta Tipo I
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Mol Cell Biol
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Holanda