The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase
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The c-Jun and c-Myc oncogenic transcription factors are highly unstable proteins due to polyubiquitination. Similar to c-Myc, we report here that phosphorylation of c-Jun by GSK3 creates a high-affinity binding site for the E3 ligase Fbw7, which targets c-Jun for polyubiquitination and proteasomal degradation. In keeping with this, we found that c-Jun levels were inversely related to GSK3 activity in mammalian cells that had entered the cell cycle. Importantly, phosphorylation of c-Jun by GSK3 requires a priming phosphorylation event at Ser-243. Ser-243 is mutated to phenylalanine in v-Jun and allows it to escape recognition by Fbw7. These findings explain the enhanced stability and oncogenicity of v-Jun relative to its cellular counterpart and reveal that GSK3 and Fbw7 coordinately regulate c-Jun and c-Myc.
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PU.1 phosphorylation by GSK creates a high-affinity binding site for FBW7, which targets PU.1 but not interaction-resistant PU.1-S41,S140A for polyubiquitination and proteasomal degradation.
“It appears that like in case of other GSK3 substrates (17), PU.1 phosphorylation by GSK apparently creates highaffinity binding site for FBW7 which eventually targets PU.1 but not the interaction-resistant PU.1-S41, S141A for polyubiquitination and proteasomal degradation.”
From FBW7 Inhibits Myeloid Differentiation in Acute Myeloid Leukemia via GSK3-Dependent Ubiquitination of PU.1 (2021) · cites this paper as [17]
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- Authors
- Wei, W., Jin, J., Schlisio, S., Harper, J. W., & Kaelin, W. G.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Corresponding author
- Kaelin, William G.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2005-07
- Volume
- 8
- Issue
- 1
- Pages
- 25-33
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2034375388
- Cited by
- 403
- References
- 37
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 9 · 2023: 11 · 2022: 26 · 2021: 10 · 2020: 23 · 2019: 12 · 2018: 17 · 2017: 24 · 2016: 13 · 2015: 20 · 2014: 26 · 2013: 27 · 2012: 25
- FWCI
- 8.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG11085, R01AG011085)
- National Cancer Institute (R01CA076120)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- c-Jun, v-Jun, glycogen synthase kinase-3, FBXW7, ubiquitin ligase, protein phosphorylation, polyubiquitination, proteasomal degradation, protein stability, c-Myc, oncogenic transcription factor, cell cycle
- MeSH terms
- F-Box-WD Repeat-Containing Protein 7, Binding Sites, Cell Cycle, Cells, Cultured, Enzyme Inhibitors, Humans, Ligases, Phenylalanine, Phosphorylation, Serine, Proto-Oncogene Proteins c-myc, Proto-Oncogene Proteins c-jun, Oncogene Protein p65(gag-jun), Point Mutation, Cell Cycle Proteins, Ubiquitin, RNA, Small Interfering, Glycogen Synthase Kinase 3, Ubiquitin-Protein Ligases, F-Box Proteins, Proteasome Inhibitors
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