Abstract
Wnt signaling components have been shown to control key events in embryogenesis and to maintain tissue homeostasis in the adult. Nkd1/2 and Axin1/2 protein families are required for feedback regulation of Wnt signaling. The mechanisms by which Nkd1 and Nkd2 exhibit significant differences in signal transduction remain incompletely understood. Here we report that Rnf25/AO7, a previously identified E3 ubiquitin ligase for Nkd2, physically interacts with Nkd1 and Axin in an E3 ligase-independent manner to strengthen Wnt signalling. To determine the biological role of Rnf25 in vivo, we found that the renal mesenchymal cell, in which rnf25 was knocked-down, also exhibited more epithelial characters than MOCK control. Meanwhile, the transcriptional level of rnf25 was elevated in three separate tumor tissues more than that in paracarcinomatous tissue. Depletion of Rnf25 in zebrafish embryos attenuated transcriptions of maternal and zygotic Wnt target genes. Our results indicated that Rnf25 might serve as a molecular device, controlling the different antagonizing functions against canonical Wnt signaling between Nkd1 and Nkd2 cooperated with Axin.
Highlights
Wnt/Beta-Catenin orchestrates tissue patterning, embryonic development, adult homeostasis, and is frequently implicated in congenital malformations, cancer, and metabolic syndromes [1,2,3]
Axin plays a pivotal role in Wnt signaling and is an essential factor required for integrating incoming signals by dynamic assembly of protein complexes [16]
Nkd1 and Axin coordinately inhibit endogenous Wnt signaling while Nkd2 and Axin presented a much weaker association, which supported the hypothesis that Nkd1 is the Naked cuticle (Nkd) orthologue and appears more specific for Wnt signaling
Summary
Wnt/Beta-Catenin orchestrates tissue patterning, embryonic development, adult homeostasis, and is frequently implicated in congenital malformations, cancer, and metabolic syndromes [1,2,3]. Tight regulation of Wnt/Beta-Catenin requires signal-inducible regulators to generate reproducible patterns during development, and negative feedback circuits provide efficient limiting of the signaling level and sharpening the boundaries between regions that respond differently [6]. Drosophila Naked cuticle (Nkd) is a Wg/Wnt inducible intracellular protein that antagonizes Wnt signaling in a negative feedback circuit targeting Dvl [7]. Vertebrate Nkd and Nkd both attenuate Wnt signaling but exhibit different expression patterns [8, 9]. The interaction with Axin was shown to be required for the inhibitory effect of Nkd on Wnt signaling, irrespective of mechanism [11, 12]. Nkd is expressed ubiquitously [8] and rarely interacts with Axin (Figure S2)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
