PUBLICATION
USP4 inhibits SMAD4 monoubiquitination and promotes activin and BMP signaling
- Authors
- Zhou, F., Xie, F., Jin, K., Zhang, Z., Clerici, M., Gao, R., van Dinther, M., Sixma, T.K., Huang, H., Zhang, L., Ten Dijke, P.
- ID
- ZDB-PUB-170505-9
- Date
- 2017
- Source
- The EMBO journal 36(11): 1623-1639 (Journal)
- Registered Authors
- Keywords
- SMAD4, TGF‐β, USP4, embryonic stem cells, zebrafish
- MeSH Terms
-
- Animals
- Bone Morphogenetic Protein Receptors/metabolism*
- Cell Differentiation
- Cell Movement
- Cells, Cultured
- Humans
- Inhibin-beta Subunits/metabolism*
- Mice
- Mouse Embryonic Stem Cells/physiology
- Protein Processing, Post-Translational*
- Proto-Oncogene Proteins/metabolism*
- Signal Transduction*
- Smad4 Protein/metabolism*
- Ubiquitin Thiolesterase/metabolism*
- Ubiquitin-Protein Ligases/metabolism
- Ubiquitination*
- Zebrafish/embryology
- PubMed
- 28468752 Full text @ EMBO J.
Citation
Zhou, F., Xie, F., Jin, K., Zhang, Z., Clerici, M., Gao, R., van Dinther, M., Sixma, T.K., Huang, H., Zhang, L., Ten Dijke, P. (2017) USP4 inhibits SMAD4 monoubiquitination and promotes activin and BMP signaling. The EMBO journal. 36(11):1623-1639.
Abstract
SMAD4 is a common intracellular effector for TGF-β family cytokines, but the mechanism by which its activity is dynamically regulated is unclear. We demonstrated that ubiquitin-specific protease (USP) 4 strongly induces activin/BMP signaling by removing the inhibitory monoubiquitination from SMAD4. This modification was triggered by the recruitment of the E3 ligase, SMURF2, to SMAD4 following ligand-induced regulatory (R)-SMAD-SMAD4 complex formation. Whereas the interaction of the negative regulator c-SKI inhibits SMAD4 monoubiquitination, the ligand stimulates the recruitment of SMURF2 to the c-SKI-SMAD2 complex and triggers c-SKI ubiquitination and degradation. Thus, SMURF2 has a role in termination and initiation of TGF-β family signaling. An increase in monoubiquitinated SMAD4 in USP4-depleted mouse embryonic stem cells (mESCs) decreased both the BMP- and activin-induced changes in the embryonic stem cell fate. USP4 sustained SMAD4 activity during activin- and BMP-mediated morphogenic events in early zebrafish embryos. Moreover, zebrafish depleted of USP4 exhibited defective cell migration and slower coordinated cell movement known as epiboly, both of which could be rescued by SMAD4. Therefore, USP4 is a critical determinant of SMAD4 activity.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping