PUBLICATION
Myristoylated naked2 antagonizes WNT-{beta}-catenin activity by degrading dishevelled-1 at the plasma membrane
- Authors
- Hu, T., Li, C., Cao, Z., Van Raay, T.J., Smith, J.G., Willert, K., Solnica-Krezel, L., and Coffey, R.J.
- ID
- ZDB-PUB-100302-1
- Date
- 2010
- Source
- The Journal of biological chemistry 285(18): 13561-13568 (Journal)
- Registered Authors
- Solnica-Krezel, Lilianna
- Keywords
- Colon cancer, Protein degradation, Protein myristoylation, Ubiquitylation, Wnt pathway, Dishevelled, Naked, Wnt signaling, myristoylation, ubiquitylation
- MeSH Terms
-
- Adaptor Proteins, Signal Transducing/genetics
- Adaptor Proteins, Signal Transducing/metabolism*
- Animals
- Caco-2 Cells
- Carrier Proteins/genetics
- Carrier Proteins/metabolism*
- Cell Membrane/genetics
- Cell Membrane/metabolism*
- Cell Polarity/physiology
- Dogs
- Drosophila
- Epithelial Cells/metabolism*
- Humans
- Myristic Acid/metabolism*
- Phosphoproteins/genetics
- Phosphoproteins/metabolism*
- Proteasome Endopeptidase Complex/genetics
- Proteasome Endopeptidase Complex/metabolism
- Protein Modification, Translational/physiology*
- Signal Transduction/physiology
- Ubiquitination/physiology
- Wnt Proteins/genetics
- Wnt Proteins/metabolism*
- beta Catenin/genetics
- beta Catenin/metabolism*
- PubMed
- 20177058 Full text @ J. Biol. Chem.
Citation
Hu, T., Li, C., Cao, Z., Van Raay, T.J., Smith, J.G., Willert, K., Solnica-Krezel, L., and Coffey, R.J. (2010) Myristoylated naked2 antagonizes WNT-{beta}-catenin activity by degrading dishevelled-1 at the plasma membrane. The Journal of biological chemistry. 285(18):13561-13568.
Abstract
In Drosophila, naked cuticle is an inducible antagonist of the Wnt- beta-catenin pathway, likely acting at the level of Dishevelled (Dsh/Dvl), an essential component of this pathway. The mechanism by which naked cuticle and its two vertebrate orthologs, Naked1 (NKD1) and Naked2 (NKD2), inhibit Dvl function is unknown. NKD2 is myristoylated, a co-translational modification that leads to its plasma membrane localization. In contrast, myristoylation-deficient G2A NKD2 is cytoplasmic. Herein we show that the ability of Nkd2/NKD2 to antagonize Wnt- beta-catenin activity during zebrafish embryonic development and in mammalian HEK293 cells is myristoylation-dependent. NKD2 and Dvl-1 interact and co-localize at the lateral membrane of polarized epithelial cells. In reciprocal overexpression and siRNA knockdown experiments, NKD2 and Dvl-1 destabilize each other via enhanced polyubiquitylation; this effect is also dependent upon Naked2 myristoylation. Cell fractionation and ubiquitylation assays indicate that endogenous NKD2 interacts with a slower migrating, ubiquitylated form of Dvl-1 in plasma membrane fractions. These results provide a mechanism by which NKD2 antagonizes Wnt signaling: myristoylated NKD2 interacts with Dvl-1 at the plasma membrane and this interaction leads to their mutual ubiquitin-mediated proteasomal degradation.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping