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

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.

Authors+Show Affiliations

Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands.Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands.Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China.Department of Human Genetics, Leiden Genome Technology Centre.Sequence Analysis Support Core, Leiden University Medical Center, The Netherlands.Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands.Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands.Novartis Institutes for BioMedical Research, Inc, Basel, Switzerland.Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands. Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China.Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands. Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31291647

Citation

Li, Yihao, et al. "VprBP Mitigates TGF-β and Activin Signaling By Promoting Smurf1-mediated Type I Receptor Degradation." Journal of Molecular Cell Biology, 2019.
Li Y, Cui C, Xie F, et al. VprBP mitigates TGF-β and Activin signaling by promoting Smurf1-mediated type I receptor degradation. J Mol Cell Biol. 2019.
Li, Y., Cui, C., Xie, F., Kiełbasa, S., Mei, H., van Dinther, M., ... Ten Dijke, P. (2019). VprBP mitigates TGF-β and Activin signaling by promoting Smurf1-mediated type I receptor degradation. Journal of Molecular Cell Biology, doi:10.1093/jmcb/mjz057.
Li Y, et al. VprBP Mitigates TGF-β and Activin Signaling By Promoting Smurf1-mediated Type I Receptor Degradation. J Mol Cell Biol. 2019 Jul 10; PubMed PMID: 31291647.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - VprBP mitigates TGF-β and Activin signaling by promoting Smurf1-mediated type I receptor degradation. AU - Li,Yihao, AU - Cui,Chao, AU - Xie,Feng, AU - Kiełbasa,Szymon, AU - Mei,Hailiang, AU - van Dinther,Maarten, AU - van Dam,Hans, AU - Bauer,Andreas, AU - Zhang,Long, AU - Ten Dijke,Peter, Y1 - 2019/07/10/ PY - 2019/02/04/received PY - 2019/05/13/revised PY - 2019/06/06/accepted PY - 2019/7/11/entrez KW - Activin KW - Smurf1 KW - TGF-β type I receptor KW - mesoderm induction KW - ubiquitination JF - Journal of molecular cell biology JO - J Mol Cell Biol N2 - 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. SN - 1759-4685 UR - https://www.unboundmedicine.com/medline/citation/31291647/VprBP_mitigates_TGF-β_and_Activin_signaling_by_promoting_Smurf1-mediated_type_I_receptor_degradation L2 - https://academic.oup.com/jmcb/article-lookup/doi/10.1093/jmcb/mjz057 DB - PRIME DP - Unbound Medicine ER -