PUBLICATION
VprBP mitigates TGF-β and Activin signaling by promoting Smurf1-mediated type I receptor degradation
- Authors
- Li, Y., Cui, C., Xie, F., Kiełbasa, S., Mei, H., van Dinther, M., van Dam, H., Bauer, A., Zhang, L., Ten Dijke, P.
- ID
- ZDB-PUB-190712-9
- Date
- 2019
- Source
- Journal of molecular cell biology 12(2): 138-151 (Journal)
- Registered Authors
- Keywords
- Activin, Smurf1, TGF-β type I receptor, mesoderm induction, ubiquitination
- MeSH Terms
-
- Activins/metabolism*
- Activins/pharmacology
- Animals
- Embryonic Development/drug effects
- Embryonic Development/genetics
- Embryonic Stem Cells/metabolism
- Gene Knockdown Techniques
- HEK293 Cells
- HaCaT Cells
- Hep G2 Cells
- Humans
- Mesoderm/embryology
- Mesoderm/metabolism
- Mice
- Protein Serine-Threonine Kinases/genetics
- Protein Serine-Threonine Kinases/metabolism*
- Proteolysis*
- Receptor, Transforming Growth Factor-beta Type I/metabolism*
- Smad7 Protein/genetics
- Smad7 Protein/metabolism
- Transfection
- Transforming Growth Factor beta/metabolism*
- Transforming Growth Factor beta/pharmacology
- Ubiquitin-Protein Ligases/genetics
- Ubiquitin-Protein Ligases/metabolism*
- Ubiquitination/genetics
- Zebrafish/embryology
- PubMed
- 31291647 Full text @ J. Mol. Cell Biol.
Citation
Li, Y., Cui, C., Xie, F., Kiełbasa, S., Mei, H., van Dinther, M., van Dam, H., Bauer, A., Zhang, L., Ten Dijke, P. (2019) VprBP mitigates TGF-β and Activin signaling by promoting Smurf1-mediated type I receptor degradation. Journal of molecular cell biology. 12(2):138-151.
Abstract
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 I-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-TβRI complex formation and induce proteasomal degradation of TGF-β type I receptor (TβRI). 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping