The -Catenin Destruction Complex
Open accessAbstract
The Wnt/β-catenin pathway is highly regulated to insure the correct temporal and spatial activation of its target genes. In the absence of a Wnt stimulus, the transcriptional coactivator β-catenin is degraded by a multiprotein "destruction complex" that includes the tumor suppressors Axin and adenomatous polyposis coli (APC), the Ser/Thr kinases GSK-3 and CK1, protein phosphatase 2A (PP2A), and the E3-ubiquitin ligase β-TrCP. The complex generates a β-TrCP recognition site by phosphorylation of a conserved Ser/Thr-rich sequence near the β-catenin amino terminus, a process that requires scaffolding of the kinases and β-catenin by Axin. Ubiquitinated β-catenin is degraded by the proteasome. The molecular mechanisms that underlie several aspects of destruction complex function are poorly understood, particularly the role of APC. Here we review the molecular mechanisms of destruction complex function and discuss several potential roles of APC in β-catenin destruction.
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Inactivation of GSK3β disrupts the destruction complex, preventing β-catenin phosphorylation, leading to accumulation of unphosphorylated stable β-catenin, nuclear translocation, and activation of target genes including c-Myc and Cyclin D1.
“The inactivation of GSK3β disrupts the integrity and function of the destruction complex, thereby preventing β-catenin phosphorylation. As a result, unphosphorylated, stable β-catenin accumulates in the cytoplasm, translocates to the nucleus, and activates the transcription of its target genes, including c-Myc and Cyclin D1 [35, 46, 47, 52–55].”
From PPP1R18-mediated activation of Wnt/β-catenin and EMT is dependent on ERK signaling in clear cell renal cell carcinoma (2026) · cites this paper as [52]
The ‘Phosphorylation by the Destruction Complex’ section identifies GSK-3 as a kinase that phosphorylates β-catenin, and ‘β-Catenin Destruction Occurs via Proteasomal Degradation’ links loss of the relevant phosphorylation sites to elevated β-catenin and Wnt target-gene activation. But the paper says GSK-3α and GSK-3β act redundantly in β-catenin destruction; it does not establish that inactivating GSK-3β alone disrupts complex integrity or prevents phosphorylation. The cited body passages also do not identify c-Myc or Cyclin D1 as the activated genes. (LLM, conf=0.86)
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“As a result, unphosphorylated, stable β-catenin accumulates in the cytoplasm, translocates to the nucleus, and activates the transcription of its target genes, including c-Myc and Cyclin D1 [35, 46, 47, 52– 55].”
- Authors
- Stamos, J. L., & Weis, W. I.
- Affiliations
- Stanford Medicine (US)
- Venue
- Cold Spring Harbor Perspectives in Biology
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2012-11-20
- Volume
- 5
- Issue
- 1
- Pages
- a007898-a007898
- ISSN
- 1943-0264 (ISSN-L)
- PMC
- PMC3579403
- OpenAlex
- W2096171021
- Cited by
- 1,062
- References
- 9
- Citations by year
- 2026: 62 · 2025: 80 · 2024: 98 · 2023: 87 · 2022: 98 · 2021: 104 · 2020: 118 · 2019: 86 · 2018: 75 · 2017: 78 · 2016: 60 · 2015: 44 · 2014: 46 · 2013: 19 · 2012: 3
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cold Spring Harbor Perspectives in Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (GM56169)
- National Institute on Aging (R01AG039420)
- National Institute of General Medical Sciences (R01GM119156, GM 56169, R01GM056169)
- 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 › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- Wnt/β-catenin signaling, β-catenin destruction complex, Axin, adenomatous polyposis coli, glycogen synthase kinase-3, casein kinase 1, protein phosphatase 2A, β-TrCP, ubiquitination, proteasomal degradation, protein phosphorylation, transcriptional coactivator
- MeSH terms
- Amino Acid Sequence, Binding Sites, Gene Expression Regulation, Models, Biological, Molecular Sequence Data, Phosphorylation, Signal Transduction, Adenomatous Polyposis Coli Protein, Proteasome Endopeptidase Complex, beta Catenin, Ubiquitination, Axin Signaling Complex, Axin Protein
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