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Published on: October 27, 2014
Wnt ligand-dependent activation of the negative feedback regulator Nkd1
Jahdiel Larraguibel1, Alexander R E Weiss1, Daniel J Pasula1
1Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, Canada.
Abstract:
Misregulation of Wnt signaling is at the root of many diseases, most notably colorectal cancer, and although we understand the activation of the pathway, we have a very poor understanding of the circumstances under which Wnt signaling turns itself off. There are numerous negative feedback regulators of Wnt signaling, but two stand out as constitutive and obligate Wnt-induced regulators: Axin2 and Nkd1. Whereas Axin2 behaves similarly to Axin in the destruction complex, Nkd1 is more enigmatic. Here we use zebrafish blastula cells that are responsive Wnt signaling to demonstrate that Nkd1 activity is specifically dependent on Wnt ligand activation of the receptor. Furthermore, our results support the hypothesis that Nkd1 is recruited to the Wnt signalosome with Dvl2, where it becomes activated to move into the cytoplasm to interact with β-catenin, inhibiting its nuclear accumulation. Comparison of these results with Nkd function in Drosophila generates a unified and conserved model for the role of this negative feedback regulator in the modulation of Wnt signaling.
Insights
Wnt signaling
Area of Science:
- Molecular Biology
- Developmental Biology
- Cell Signaling
Background:
- Wnt signaling pathway dysregulation is implicated in diseases like colorectal cancer.
- Understanding Wnt pathway deactivation is crucial but poorly understood.
- Axin2 and Nkd1 are key Wnt-induced negative feedback regulators.
Purpose of the Study:
- To elucidate the regulatory mechanism of Nkd1 in Wnt signaling.
- To investigate the specific conditions under which Nkd1 functions.
- To establish a conserved model for Nkd1's role in Wnt pathway modulation.
Main Methods:
- Utilized zebrafish blastula cells for Wnt signaling studies.
- Investigated Nkd1 activity in response to Wnt ligand activation.
- Examined Nkd1 recruitment to the Wnt signalosome with Dvl2.
Main Results:
- Nkd1 activity is strictly dependent on Wnt ligand receptor activation.
- Nkd1 is recruited to the Wnt signalosome, associating with Dvl2.
- Activated Nkd1 inhibits nuclear accumulation of β-catenin in the cytoplasm.
Conclusions:
- Nkd1 acts as a crucial negative feedback regulator in Wnt signaling.
- A conserved mechanism for Nkd1 function in Wnt pathway modulation exists between zebrafish and Drosophila.
- This study provides insights into controlling Wnt signaling to combat associated diseases.
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