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

作　　者：Yihao Li Chao Cui Feng Xie Szymon Kietbasa Hailiang Mei Maarten van Dinther Hans van Dam Andreas Bauer Long Zhang Peterten Dijke 

机构地区：[1]Department of Cell and Chemical Biology and Oncode Institute,Leiden University Medical Center,2300RC Leiden,The Netherlands [2]MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network,Life Sciences Institute,Zhejiang University,Hangzhou 310058,China [3]Department of Human Genetics,Leiden Genome Technology Centre,Leiden University Medical Center,2300RC Leiden,The Netherlands [4]Sequence Analysis Support Core,Leiden University Medical Center,2300RC Leiden,The Netherlands [5]Novartis Institutes for BioMedical Research,Inc.,Novartis Campus,Forum 2.5.01.30,CH-4056,Basel,Switzerland

出　　处：《Journal of Molecular Cell Biology》2020年第2期138-151,共14页分子细胞生物学报（英文版）

基　　金：This research was supported by Cancer Genomics Centre Netherlands and a grant from the National Natural Science Foundation of China(31471315).

摘　　要：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-βfamily 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-βreceptor 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-βtarget gene expression.VprBP was found to promote Smad7–Smurf1–TβRI complex formation and induce proteasomal degradation of TGF-βtype 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-βor 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-βand Activin cascade and identify VprBP as a critical determinant of embryonic mesoderm induction.

关 键 词：Smurfl TGF-βtype I receptor UBIQUITINATION ACTIVIN mesoderm induction 

分 类 号：Q75[生物学—分子生物学]