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

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