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

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 binding partner of Smad7. Mis-expression studies revealed that VprBP negatively controls Smad2 phosphorylation, Smad2–Smad4 interaction, as well as TGF- β target gene expression. VprBP was found to promote Smad7–Smurf1–T β RI complex formation and induce proteasomal degradation of TGF- β type I receptor (T β 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- β 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- β and Activin cascade and identify VprBP as a critical determinant of embryonic mesoderm induction. [ABSTRACT FROM AUTHOR]