Myristoylated Naked2 antagonizes Wnt-beta-catenin activity by degrading Dishevelled-1 at the plasma membrane.

Hu T, Li C, Cao Z, Van Raay TJ, Smith JG, Willert K, Solnica-Krezel L, Coffey RJ
J Biol Chem. 2010 285 (18): 13561-8

PMID: 20177058 · PMCID: PMC2859517 · DOI:10.1074/jbc.M109.075945

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.

MeSH Terms (21)

Adaptor Proteins, Signal Transducing Animals beta Catenin Caco-2 Cells Calcium-Binding Proteins Carrier Proteins Cell Membrane Cell Polarity Dishevelled Proteins Dogs Drosophila Drosophila Proteins Epithelial Cells Humans Myristic Acid Phosphoproteins Proteasome Endopeptidase Complex Protein Modification, Translational Signal Transduction Ubiquitination Wnt Proteins

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