Community Action Needed: Please respond to the NIH RFI
ZFIN ID: ZDB-PUB-100302-1
Myristoylated naked2 antagonizes WNT-{beta}-catenin activity by degrading dishevelled-1 at the plasma membrane
Hu, T., Li, C., Cao, Z., Van Raay, T.J., Smith, J.G., Willert, K., Solnica-Krezel, L., and Coffey, R.J.
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.
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.