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VprBP mitigates TGF-? and Activin signaling by promoting Smurf1-mediated type I receptor degradation.


ABSTRACT: The transforming growth factor-? (TGF-?) family controls embryogenesis, stem cell differentiation, and tissue homeostasis. However, how post-translation modifications contribute to fine-tuning of TGF-? family signaling responses is not well understood. Inhibitory (I)-Smads can antagonize TGF-?/Smad signaling by recruiting Smurf E3 ubiquitin ligases to target the active TGF-? 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-? target gene expression. VprBP was found to promote Smad7-Smurf1-T?RI complex formation and induce proteasomal degradation of TGF-? type I receptor (T?RI). Moreover, VprBP appears to stabilize Smurf1 by suppressing Smurf1 poly-ubiquitination. In multiple adult and mouse embryonic stem cells, depletion of VprBP promotes TGF-? 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-? and Activin cascade and identify VprBP as a critical determinant of embryonic mesoderm induction.

SUBMITTER: Li Y 

PROVIDER: S-EPMC7109606 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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VprBP mitigates TGF-β and Activin signaling by promoting Smurf1-mediated type I receptor degradation.

Li Yihao Y   Cui Chao C   Xie Feng F   Kiełbasa Szymon S   Mei Hailiang H   van Dinther Maarten M   van Dam Hans H   Bauer Andreas A   Zhang Long L   Ten Dijke Peter P  

Journal of molecular cell biology 20200201 2


The transforming growth factor-β (TGF-β) family controls embryogenesis, stem cell differentiation, and tissue homeostasis. However, how post-translation modifications contribute to fine-tuning of TGF-β family signaling responses is not well understood. Inhibitory (I)-Smads can antagonize TGF-β/Smad signaling by recruiting Smurf E3 ubiquitin ligases to target the active TGF-β receptor for proteasomal degradation. A proteomic interaction screen identified Vpr binding protein (VprBP) as novel bindi  ...[more]

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