Structural and Functional Characterization of the Wnt Inhibitor APC Membrane Recruitment 1 (Amer1)
Open accessAbstract
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.
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Additional genes of interest that had comutation interactions with KRAS G12D include increased comutation with AMER1.
“These include increased comutation with AMER1, a negative regulator of Wnt signaling53,54.”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [54]
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The origins and genetic interactions of KRAS mutations are allele- and tissue-specific
Cook, J. H., Melloni, G. E. M., Gulhan, D. C., Park, P. J., & Haigis, K. M. (2021) · Nature Communications · doi:10.1038/s41467-021-22125-z · Cited by 208 · see citing works
(2015) · International Journal of Kinesiology and Sports Science · doi:10.7575/aiac.ijkss.v.3n.4p.40 · Cited by 5 · see citing works
- Authors
- Tanneberger, K., Pfister, A. S., Kriz, V., Bryja, V., Schambony, A., & Behrens, J.
- Affiliations
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Corresponding author
- Behrens, Jürgen
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-06
- Volume
- 286
- Issue
- 22
- Pages
- 19204-19214
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3103299
- OpenAlex
- W1978080674
- Cited by
- 62
- References
- 40
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 7 · 2023: 3 · 2022: 3 · 2021: 6 · 2020: 8 · 2019: 1 · 2018: 5 · 2017: 6 · 2016: 2 · 2015: 3 · 2014: 1 · 2013: 4 · 2012: 4
- FWCI
- 1.30
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ASEP (submittedVersion, public-domain)
- Funders
- Deutsche Forschungsgemeinschaft (SCHA965/6-1)
- Grantová Agentura České Republiky
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- AMER1, WTX, Wnt signaling inhibition, β-catenin degradation, β-catenin destruction complex, adenomatous polyposis coli, Axin, armadillo repeats, plasma membrane recruitment, membrane-binding domain, splice variants, cell contact, scaffold proteins, cell density
- MeSH terms
- Prohibitins, Animals, Cell Membrane, Humans, Repressor Proteins, Structure-Activity Relationship, Xenopus laevis, Signal Transduction, Protein Structure, Tertiary, Tumor Suppressor Proteins, Adenomatous Polyposis Coli Protein, Xenopus Proteins, Adaptor Proteins, Signal Transducing, Wnt Proteins, beta Catenin, Mice, Gene Knockdown Techniques, HEK293 Cells, Axin Protein
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