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Published on: October 6, 2014
Structural and functional characterization of the Wnt inhibitor APC membrane recruitment 1 (Amer1)
Kristina Tanneberger1, Astrid S Pfister, Vitezslav Kriz
1Nikolaus-Fiebiger-Center, Biology Department, University Erlangen-Nuremberg, Erlangen, Germany.
Abstract:
Amer1/WTX binds to the tumor suppressor adenomatous polyposis coli and acts as an inhibitor of Wnt signaling by inducing β-catenin degradation. We show here that Amer1 directly interacts with the armadillo repeats of β-catenin via a domain consisting of repeated arginine-glutamic acid-alanine (REA) motifs, and that Amer1 assembles the β-catenin destruction complex at the plasma membrane by recruiting β-catenin, adenomatous polyposis coli, and Axin/Conductin. Deletion or specific mutations of the membrane binding domain of Amer1 abolish its membrane localization and abrogate negative control of Wnt signaling, which can be restored by artificial targeting of Amer1 to the plasma membrane. In line, a natural splice variant of Amer1 lacking the plasma membrane localization domain is deficient for Wnt inhibition. Knockdown of Amer1 leads to the activation of Wnt target genes, preferentially in dense compared with sparse cell cultures, suggesting that Amer1 function is regulated by cell contacts. Amer1 stabilizes Axin and counteracts Wnt-induced degradation of Axin, which requires membrane localization of Amer1. The data suggest that Amer1 exerts its negative regulatory role in Wnt signaling by acting as a scaffold protein for the β-catenin destruction complex and promoting stabilization of Axin at the plasma membrane.
Insights
Amer1 protein inhibits Wnt signaling by promoting β-catenin degradation at the cell membrane. Its membrane localization is crucial for Wnt pathway regulation and Axin stabilization.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Wnt signaling is a critical pathway in development and disease.
- Adenomatous polyposis coli (APC) is a tumor suppressor involved in Wnt signaling.
- β-catenin is a key effector protein in the Wnt pathway.
Purpose of the Study:
- To elucidate the mechanism by which Amer1 inhibits Wnt signaling.
- To investigate the role of Amer1's membrane localization in Wnt pathway regulation.
- To understand Amer1's interaction with the β-catenin destruction complex.
Main Methods:
- Co-immunoprecipitation to study protein interactions.
- Deletion and mutation analysis of Amer1 domains.
- Cell culture and knockdown experiments.
- Analysis of Wnt target gene expression.
Main Results:
- Amer1 directly binds to β-catenin via REA motifs and recruits the destruction complex to the plasma membrane.
- Amer1's membrane binding domain is essential for Wnt inhibition; its deletion or mutation abrogates this function.
- A splice variant lacking the membrane domain is deficient in Wnt inhibition.
- Amer1 knockdown activates Wnt target genes, particularly in dense cultures, indicating regulation by cell contacts.
- Amer1 stabilizes Axin, counteracting Wnt-induced degradation, which requires membrane localization.
Conclusions:
- Amer1 acts as a scaffold protein for the β-catenin destruction complex at the plasma membrane.
- Membrane localization of Amer1 is critical for its Wnt inhibitory function and Axin stabilization.
- Amer1's activity is regulated by cell contacts, suggesting a role in contact-dependent Wnt signaling inhibition.
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