Suppression of GSK3β by ERK mediates lipopolysaccharide induced cell migration in macrophage through β-catenin signaling
Open accessAbstract
We investigate the role of β-catenin signaling in the response of macrophage to lipopolysaccharide (LPS) using RAW264.7 cells. LPS rapidly stimulated cytosolic β-catenin accumulation. β-catenin-mediated transcription was showed to be required for LPS induced gene expression and cell migration. Mechanically, ERK activation-primed GSK3β inactivation by Akt was demonstrated to mediate the LPS induced β-catenin accumulation. Overall, our findings suggest that suppression of GSK3β by ERK stimulates β-catenin signaling therefore contributes to LPS induced cell migration in macrophage activation.
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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 [47]
The Introduction (page unavailable) says that GSK3β activity promotes β-catenin phosphorylation and degradation, while blocking that activity allows cytosolic β-catenin to accumulate, enter the nucleus, and activate target genes. The transcription-results section identifies c-Myc as a β-catenin-responsive gene, but our copy does not identify Cyclin D1 as a target or say that GSK3β inactivation disrupts the destruction complex’s integrity. (LLM, conf=0.86)
Experimental — accuracy not yet measuredA well-established mechanism for ERK/Wnt crosstalk involves direct regulation of GSK3β, the master kinase of the β-catenin destruction complex.
“A well-established mechanism for this crosstalk involves the direct regulation of Glycogen Synthase Kinase 3β (GSK3β), the master kinase of the β-catenin destruction complex [46–51].”
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 [47]
The section “Activated ERK associates with and primes GSK3β inactivation by AKT in response to LPS” reports ERK–GSK3β association and subsequent GSK3β inactivation in LPS-treated macrophages. The Introduction identifies GSK3β as part of the complex that phosphorylates β-catenin for degradation. The paper supports this route of crosstalk, but describes ERK as facilitating inactivation by AKT rather than establishing direct ERK-mediated inactivation as a general, well-established mechanism. (LLM, conf=0.82)
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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
- Gong, K., Zhou, F., Huang, H., Gong, Y., & Zhang, L.
- Affiliations
- Tsinghua University (CN)
- Leiden University Medical Center (NL)
- Chongqing Medical University (CN)
- Corresponding author
- Zhou, Fangfang
- Zhang, Long
- Venue
- Protein & Cell
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-09-15
- Volume
- 3
- Issue
- 10
- Pages
- 762-768
- ISSN
- 1674-800X (ISSN-L)
- 1674-8018
- PMC
- PMC4875346
- OpenAlex
- W2034261562
- Cited by
- 29
- References
- 30
- Citations by year
- 2026: 2 · 2025: 1 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 1 · 2019: 1 · 2018: 3 · 2017: 3 · 2016: 2 · 2015: 4 · 2014: 2
- FWCI
- 0.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Protein & Cell (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Funders
- National Natural Science Foundation of China
- Chongqing Science and Technology Commission
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- GSK3β, ERK, β-catenin signaling, lipopolysaccharide, macrophage migration, macrophage activation, Akt, RAW 264.7 macrophages
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Animals, Cell Line, Cell Movement, Enzyme Activation, Lipopolysaccharides, Macrophages, Transcription, Genetic, Signal Transduction, Gene Expression Regulation, Enzymologic, Matrix Metalloproteinase 9, Glycogen Synthase Kinase 3, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins c-akt, Wnt Proteins, beta Catenin, Mice
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