title: Naked1 antagonizes Wnt signaling by preventing nuclear accumulation of β-catenin.
abstract: Cyto-nuclear shuttling of β-catenin is at the epicenter of the canonical Wnt pathway and mutations in genes that result in excessive nuclear accumulation of β-catenin are the driving force behind the initiation of many cancers. Recently, Naked Cuticle homolog 1 (Nkd1) has been identified as a Wnt-induced intracellular negative regulator of canonical Wnt signaling. The current model suggests that Nkd1 acts between Disheveled (Dvl) and β-catenin. Here, we employ the zebrafish embryo to characterize the cellular and biochemical role of Nkd1 in vivo. We demonstrate that Nkd1 binds to β-catenin and prevents its nuclear accumulation. We also show that this interaction is conserved in mammalian cultured cells. Further, we demonstrate that Nkd1 function is dependent on its interaction with the cell membrane. Given the conserved nature of Nkd1, our results shed light on the negative feedback regulation of Wnt signaling through the Nkd1-mediated negative control of nuclear accumulation of β-catenin.
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America. tvanraay@uoguelph.ca
authors.forename: Terence J
authors.initials: TJ
authors.lastname: Van Raay
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Fortino
authors.forename: Bryan W
authors.initials: BW
authors.lastname: Miller
authors.forename: Haiting
authors.initials: H
authors.lastname: Ma
authors.forename: Garnet
authors.initials: G
authors.lastname: Lau
authors.forename: Cunxi
authors.initials: C
authors.lastname: Li
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Franklin
authors.forename: Liliana
authors.initials: L
authors.lastname: Attisano
authors.forename: Lilianna
authors.initials: L
authors.lastname: Solnica-Krezel
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Coffey
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C525385:Nkd1 protein, zebrafish; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin