Abstract
SummaryDickkopf-1 (Dkk1) is a secreted Wnt antagonist with a well-established role in head induction during development. Numerous studies have emerged implicating Dkk1 in various malignancies and neurodegenerative diseases through an unknown mechanism. Using zebrafish gastrulation as a model for collective cell migration, we unveil such a mechanism, identifying a role for Dkk1 in control of cell connectivity and polarity in vivo, independent of its known function. We find that Dkk1 localizes to adhesion complexes at the plasma membrane and regions of concentrated actomyosin, suggesting a direct involvement in regulation of local cell adhesion. Our results show that Dkk1 represses cell polarization and integrity of cell-cell adhesion, independently of its impact on β-catenin protein degradation. Concurrently, Dkk1 prevents nuclear localization of β-catenin by restricting its distribution to a discrete submembrane pool. We propose that redistribution of cytosolic β-catenin by Dkk1 concomitantly drives repression of cell adhesion and inhibits β-catenin-dependent transcriptional output.
Highlights
Signaling by Wnt proteins occurs through several receptor complexes, which trigger intracellular signaling cascades affecting cell fate, polarity, and proliferation
Activation of the canonical Wnt pathway occurs by formation of a ternary complex between the Wnt ligand, Frizzled receptor, and co-receptor LRP6, which protects cytosolic b-catenin from proteosomal degradation
The accumulated b-catenin translocates to the nucleus where it turns on transcription of target genes by associating with members of the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors
Summary
Signaling by Wnt proteins occurs through several receptor complexes, which trigger intracellular signaling cascades affecting cell fate, polarity, and proliferation. Activation of the canonical Wnt pathway occurs by formation of a ternary complex between the Wnt ligand, Frizzled receptor, and co-receptor LRP6, which protects cytosolic b-catenin from proteosomal degradation. Secreted Dickkopf-1 (Dkk1) is thought to inhibit canonical Wnt signaling through its binding to the LRP6 co-receptor, preventing formation of an active signaling complex, leading to degradation of cytosolic b-catenin and reduction of nuclear b-catenin-dependent gene transcription (Ahn et al, 2011; Cheng et al, 2011; Matoba et al, 2017). B-catenin functions both as a structural component of adhesive complexes and as a regulator of transcription. Intracellular trafficking of b-catenin is seemingly regulated by phosphorylation and localized interaction partners, which themselves shuttle between compartments (Daugherty and Gottardi, 2007; Krieghoff et al, 2006)
Sign-in/Register to view highlights & summary 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.
