Swe1Wee1-Dependent Tyrosine Phosphorylation of Hsp90 Regulates Distinct Facets of Chaperone Function
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Saccharomyces WEE1 (Swe1), the only "true" tyrosine kinase in budding yeast, is an Hsp90 client protein. Here we show that Swe1(Wee1) phosphorylates a conserved tyrosine residue (Y24 in yeast Hsp90 and Y38 in human Hsp90alpha) in the N domain of Hsp90. Phosphorylation is cell-cycle associated and modulates the ability of Hsp90 to chaperone a selected clientele, including v-Src and several other kinases. Nonphosphorylatable mutants have normal ATPase activity, support yeast viability, and productively chaperone the Hsp90 client glucocorticoid receptor. Deletion of SWE1 in yeast increases Hsp90 binding to its inhibitor geldanamycin, and pharmacologic inhibition/silencing of Wee1 sensitizes cancer cells to Hsp90 inhibitor-induced apoptosis. These findings demonstrate that Hsp90 chaperoning of distinct client proteins is differentially regulated by specific posttranslational modification of a unique subcellular pool of the chaperone, and they provide a strategy to increase the cellular potency of Hsp90 inhibitors.
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Several key cell cycle regulators, including Swe1, Cdc28, Cdc50 and Cdc60, have been identified as Hsp90 interactors in S. cerevisiae.
“Several key cell cycle regulators have been identified as Hsp90 interactors in S. cerevisiae, including Swe1, Cdc28, Cdc50 and Cdc6061,92,123.”
From Fungal Hsp90: a biological transistor that tunes cellular outputs to thermal inputs (2012) · cites this paper as [61]
Hsp90 has evolutionarily conserved roles in cell cycle progression.
“Hsp90 also has evolutionarily conserved roles in cell cycle progression.”
From Fungal Hsp90: a biological transistor that tunes cellular outputs to thermal inputs (2012) · cites this paper as [61]
Hsp90 itself is subject to posttranslational modification in a cell cycle-dependent manner.
“Recently it was demonstrated that Hsp90 itself is subject to posttranslational modification in a cell cycle–dependent manner. In S. cerevisiae, during S phase of the cell cycle the tyrosine kinase Swe1 phosphorylates a residue in the N-terminus of Hsp90 that facilitates chaperone interaction with numerous client proteins (Mollapour et al., 2010).”
From Cdc28 provides a molecular link between Hsp90, morphogenesis, and cell cycle progression in<i>Candida albicans</i> (2012) · cites this paper as Mollapour et al., 2010
In S. cerevisiae, the CDK Cdc28 interacts with Hsp90 and with the cochaperone Cdc37.
“In S. cerevisiae, the CDK Cdc28 has been shown to interact with both Hsp90 and one of its cochaperones, Cdc37 (Mort-Bontemps-Soret et al., 2002; Mollapour et al., 2010).”
From Cdc28 provides a molecular link between Hsp90, morphogenesis, and cell cycle progression in<i>Candida albicans</i> (2012) · cites this paper as Mollapour et al., 2010
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References 54 · Cited by 196
- Authors
- Mollapour, M., Tsutsumi, S., Donnelly, A. C., Beebe, K., Tokita, M. J., Lee, M.-J., Lee, S., Morra, G., Bourboulia, D., Scroggins, B. T., Colombo, G., Blagg, B. S., Panaretou, B., Stetler-Stevenson, W. G., Trepel, J. B., Piper, P. W., Prodromou, C., Pearl, L. H., & Neckers, L.
- Affiliations
- National Cancer Institute (US)
- University of Kansas (US)
- National Institutes of Health (US)
- Institute of Chemistry of Molecular Recognition (IT)
- King's College London (GB)
- University of Sheffield (GB)
- Institute of Cancer Research (GB)
- Corresponding author
- Neckers, Len
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2010-02
- Volume
- 37
- Issue
- 3
- Pages
- 333-343
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC2824606
- OpenAlex
- W2084527454
- Cited by
- 196
- References
- 54
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 10 · 2023: 8 · 2022: 10 · 2021: 5 · 2020: 9 · 2019: 10 · 2018: 9 · 2017: 8 · 2016: 8 · 2015: 14 · 2014: 20 · 2013: 21 · 2012: 23
- FWCI
- 8.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Figshare (submittedVersion, cc-by)
- Kent Academic Repository (University of Kent) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- KU ScholarWorks (University of Kansas) (submittedVersion, other-oa)
- Funders
- National Institutes of Health (Z99 CA999999)
- National Cancer Institute (Z01SC010074, Z01BC011032)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- HSP90, tyrosine phosphorylation, Hsp90 client proteins, chaperone activity, cell cycle regulation, v-Src, glucocorticoid receptor, geldanamycin, Hsp90 inhibitors, apoptosis sensitization, post-translational modification, Saccharomyces cerevisiae
- MeSH terms
- Humans, Nuclear Proteins, Phosphorylation, Protein-Tyrosine Kinases, Tyrosine, Cell Cycle Proteins, HSP90 Heat-Shock Proteins, Dimerization, Saccharomyces cerevisiae Proteins, RNA Interference, Cell Line, Tumor, Proteasome Endopeptidase Complex, Ubiquitination
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