Formation of stable attachments between kinetochores and microtubules depends on the B56-PP2A phosphatase
Open accessAbstract
Error-free chromosome segregation depends on the precise regulation of phosphorylation to stabilize kinetochore-microtubule attachments (K-fibres) on sister chromatids that have attached to opposite spindle poles (bi-oriented). In many instances, phosphorylation correlates with K-fibre destabilization. Consistent with this, multiple kinases, including Aurora B and Plk1, are enriched at kinetochores of mal-oriented chromosomes when compared with bi-oriented chromosomes, which have stable attachments. Paradoxically, however, these kinases also target to prometaphase chromosomes that have not yet established spindle attachments and it is therefore unclear how kinetochore-microtubule interactions can be stabilized when kinase levels are high. Here we show that the generation of stable K-fibres depends on the B56-PP2A phosphatase, which is enriched at centromeres/kinetochores of unattached chromosomes. When B56-PP2A is depleted, K-fibres are destabilized and chromosomes fail to align at the spindle equator. Strikingly, B56-PP2A depletion increases the level of phosphorylation of Aurora B and Plk1 kinetochore substrates as well as Plk1 recruitment to kinetochores. Consistent with increased substrate phosphorylation, we find that chemical inhibition of Aurora or Plk1 restores K-fibres in B56-PP2A-depleted cells. Our findings reveal that PP2A, an essential tumour suppressor, tunes the balance of phosphorylation to promote chromosome-spindle interactions during cell division.
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Some kinases and phosphatases simultaneously target the same kinesins to tune the balance between phosphorylation and dephosphorylation to modulate activity or spindle targeting.
“In addition, some kinases and phosphatases simultaneously hit the same kinesins to tune the balance between phosphorylation and dephosphorylation to modulate activity or spindle targeting [56, 57].”
From Regulatory mechanisms that control mitotic kinesins (2015) · cites this paper as [57]
The discussion of chromosome-spindle attachments (page unavailable) says B56-PP2A counteracts kinases and reduces phosphorylation to stabilize kinetochore–microtubule binding. It does not show that the kinases and phosphatase target the same kinesins or that this balance regulates kinesin activity or spindle targeting. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAurora B/PP2A controls the phosphorylation levels of multiple substrates at the kinetochore.
“The importance of the kinase/phosphatase balance at the kinetochore has also been shown for Aurora B/PP2A, which controls the phosphorylation levels of multiple substrates at the kinetochore [57].”
From Regulatory mechanisms that control mitotic kinesins (2015) · cites this paper as [57]
PP2A/B56 is needed to remove phosphate from Aurora B substrates so that kinetochore-microtubule attachments become stable.
“For a stable kinetochore-microtubule attachment, PP2A/B56 is required to dephosphorylate Aurora B substrates (Foley et al., 2011).”
From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Foley et al., 2011
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- Authors
- Foley, E. A., Maldonado, M., & Kapoor, T. M.
- Affiliations
- Rockefeller University (US)
- Corresponding author
- Kapoor, Tarun M.
- Venue
- Nature Cell Biology
- Published
- 2011-08-28
- Volume
- 13
- Issue
- 10
- Pages
- 1265-1271
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC3186838
- OpenAlex
- W1973519323
- Cited by
- 267
- References
- 43
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 7 · 2023: 4 · 2022: 17 · 2021: 22 · 2020: 24 · 2019: 21 · 2018: 10 · 2017: 29 · 2016: 25 · 2015: 17 · 2014: 24 · 2013: 24 · 2012: 22
- FWCI
- 10.72
- 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)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM065933, GM65933)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- kinetochore-microtubule attachment, Aurora B kinase, PLK1, chromosome segregation, prometaphase, centromere, spindle attachment, chromosome biorientation
- MeSH terms
- Polo-Like Kinase 1, Benzamides, HeLa Cells, Humans, Indoles, Leupeptins, Microscopy, Fluorescence, Microtubules, Phosphorylation, Proto-Oncogene Proteins, Pteridines, Quinazolines, Recombinant Fusion Proteins, Sulfonamides, Time Factors, Transfection, Nocodazole, Protein Serine-Threonine Kinases, Kinetochores, Cell Cycle Proteins, Chromosome Segregation, Tumor Suppressor Proteins, RNA Interference, Protein Kinase Inhibitors, Protein Phosphatase 2, Aurora Kinase B, Aurora Kinases
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