Site-specific proteasome phosphorylation controls cell proliferation and tumorigenesis.
Open accessAbstract
Despite the fundamental importance of proteasomal degradation in cells, little is known about whether and how the 26S proteasome itself is regulated in coordination with various physiological processes. Here we show that the proteasome is dynamically phosphorylated during the cell cycle at Thr 25 of the 19S subunit Rpt3. CRISPR/Cas9-mediated genome editing, RNA interference and biochemical studies demonstrate that blocking Rpt3-Thr25 phosphorylation markedly impairs proteasome activity and impedes cell proliferation. Through a kinome-wide screen, we have identified dual-specificity tyrosine-regulated kinase 2 (DYRK2) as the primary kinase that phosphorylates Rpt3-Thr25, leading to enhanced substrate translocation and degradation. Importantly, loss of the single phosphorylation of Rpt3-Thr25 or knockout of DYRK2 significantly inhibits tumour formation by proteasome-addicted human breast cancer cells in mice. These findings define an important mechanism for proteasome regulation and demonstrate the biological significance of proteasome phosphorylation in regulating cell proliferation and tumorigenesis.
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Cell cycle-dependent phosphorylation of Rpt3 at Thr25 is important for cell cycle progression and tumorigenesis.
“Recently, the cell cycle-dependent phosphorylation of Rpt3 at Thr25 was shown to be important for cell cycle progression and tumorigenesis (Guo et al., 2016)”
From Altered Phosphorylation of the Proteasome Subunit Rpt6 Has Minimal Impact on Synaptic Plasticity and Learning (2021) · cites this paper as Guo et al., 2016
Phosphorylation of Rpt3 controls cell proliferation and tumorigenesis.
“Furthermore, a previous study has revealed that phosphorylation of Rpt3 controls cell proliferation and tumorigenesis (Guo et al., 2016).”
From Inducible Rpt3, a Proteasome Component, Knockout in Adult Skeletal Muscle Results in Muscle Atrophy (2020) · cites this paper as Guo et al., 2016
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References 70 · Cited by 169
- Authors
- Guo, X., Wang, X., Wang, Z., Banerjee, S., Yang, J., Huang, L., & Dixon, J. E.
- Affiliations
- University of California San Diego (US)
- University of California, Irvine (US)
- Corresponding author
- Guo, Xing
- Dixon, Jack E.
- Venue
- Nature Cell Biology
- Published
- 2015-12-14
- Volume
- 18
- Issue
- 2
- Pages
- 202-212
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC4844191
- OpenAlex
- W2195466096
- Cited by
- 169
- References
- 70
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 15 · 2023: 15 · 2022: 12 · 2021: 22 · 2020: 21 · 2019: 17 · 2018: 22 · 2017: 20 · 2016: 5
- FWCI
- 6.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Cancer Institute (R01CA168689, P30CA023100, R01CA174869)
- National Institute of General Medical Sciences (R01GM074830)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK018024, R01DK018849)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- 19S proteasome, DYRK2, cell cycle regulation, cell proliferation, carcinogenesis, proteasome activity, substrate translocation, breast cancer, 26S proteasome
- MeSH terms
- ATPases Associated with Diverse Cellular Activities, Dyrk Kinases, Animals, Breast Neoplasms, Cell Cycle, Cell Transformation, Neoplastic, Female, Humans, Mice, Nude, Phosphorylation, Protein-Tyrosine Kinases, Threonine, Time Factors, Transfection, Signal Transduction, Gene Expression Regulation, Neoplastic, Protein Serine-Threonine Kinases, RNA Interference, Cell Line, Tumor, Proteasome Endopeptidase Complex, Tumor Burden, Cell Proliferation, Proteolysis, CRISPR-Cas Systems, Heterografts
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