PUBLICATION
SCF(FBXL15) regulates BMP signalling by directing the degradation of HECT‐type ubiquitin ligase Smurf1
- Authors
- Cui, Y., He, S., Xing, C., Lu, K., Wang, J., Xing, G., Meng, A., Jia, S., He, F., and Zhang, L.
- ID
- ZDB-PUB-110524-36
- Date
- 2011
- Source
- The EMBO journal 30(13): 2675-89 (Journal)
- Registered Authors
- Jia, Shunji, Meng, Anming, Wang, Jian, Xing, Cencan
- Keywords
- bone remodelling, E3 ubiquitin ligase, embryonic development, SCF complex, smad ubiquitination regulatory factor 1
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Bone Development/genetics
- Bone Development/physiology
- Bone Morphogenetic Proteins/metabolism*
- Bone Morphogenetic Proteins/physiology
- Cells, Cultured
- Computer Simulation
- Embryo, Nonmammalian
- F-Box Proteins/genetics
- F-Box Proteins/metabolism
- F-Box Proteins/physiology*
- Gene Expression Regulation, Developmental
- Humans
- Models, Biological
- Protein Processing, Post-Translational/genetics
- Protein Processing, Post-Translational/physiology
- Protein Structure, Tertiary
- Rats
- SKP Cullin F-Box Protein Ligases/genetics
- SKP Cullin F-Box Protein Ligases/metabolism
- SKP Cullin F-Box Protein Ligases/physiology
- Signal Transduction/genetics
- Signal Transduction/physiology
- Ubiquitin-Protein Ligases/chemistry
- Ubiquitin-Protein Ligases/metabolism*
- Zebrafish/embryology
- Zebrafish/genetics
- PubMed
- 21572392 Full text @ EMBO J.
Citation
Cui, Y., He, S., Xing, C., Lu, K., Wang, J., Xing, G., Meng, A., Jia, S., He, F., and Zhang, L. (2011) SCF(FBXL15) regulates BMP signalling by directing the degradation of HECT‐type ubiquitin ligase Smurf1. The EMBO journal. 30(13):2675-89.
Abstract
Smad ubiquitination regulatory factor 1 (Smurf1), an homologous to E6AP C-terminus (HECT)-type E3 ubiquitin ligase, performs a crucial role in the regulation of the bone morphogenetic protein (BMP) signalling pathway in both embryonic development and bone remodelling. How the stability and activity of Smurf1 are negatively regulated remains largely unclear. Here, we report that F-box and LRR domain-containing protein 15 (FBXL15), an F-box protein of the FBXL family, forms an Skp1-Cullin1-F-box protein-Roc1 (SCF)(FBXL15) ubiquitin ligase complex and targets Smurf1 for ubiquitination and proteasomal degradation. FBXL15, through its leucine-rich repeat domain, specifically recognizes the large subdomain within the N-lobe of the Smurf1 HECT domain and promotes the ubiquitination of Smurf1 on K355 and K357 within the WW-HECT linker region. In this way, FBXL15 positively regulates BMP signalling in mammalian cells. Knockdown of fbxl15 expression in zebrafish embryos by specific antisense morpholinos causes embryonic dorsalization phenocoping BMP-deficient mutants. Injection of FBXL15 siRNAs into rat bone tissues leads to a significant loss of bone mass and decrease in bone mineral density. Collectively, our results demonstrate that Smurf1 stability is suppressed by SCF(FBXL15)-mediated ubiquitination and that FBXL15 is a key regulator of BMP signalling during embryonic development and adult bone formation.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping