PP1 and PP2A Use Opposite Phospho-dependencies to Control Distinct Processes at the Kinetochore
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Abstract
PP1 and PP2A-B56 are major serine/threonine phosphatase families that achieve specificity by colocalizing with substrates. At the kinetochore, however, both phosphatases localize to an almost identical molecular space and yet they still manage to regulate unique pathways and processes. By switching or modulating the positions of PP1/PP2A-B56 at kinetochores, we show that their unique downstream effects are not due to either the identity of the phosphatase or its precise location. Instead, these phosphatases signal differently because their kinetochore recruitment can be either inhibited (PP1) or enhanced (PP2A) by phosphorylation inputs. Mathematical modeling explains how these inverse phospho-dependencies elicit unique forms of cross-regulation and feedback, which allows otherwise indistinguishable phosphatases to produce distinct network behaviors and control different mitotic processes. Furthermore, our genome-wide analysis suggests that these major phosphatase families may have evolved to respond to phosphorylation inputs in opposite ways because many other PP1 and PP2A-B56-binding motifs are also phospho-regulated.
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An additional 15% of proteins identified in the screen are interactors of proteins with validated or predicted LxxIxE docking motifs.
“an additional 15% of proteins identified in our screen are interactors of proteins with validated or predicted LxxIxE docking motifs46,48 (Fig. 6D and Supplementary Data 4).”
From Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A (2023) · cites this paper as [48]
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Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A
Pavic, K., Gupta, N., Omella, J. D., Derua, R., Aakula, A., Huhtaniemi, R., Määttä, J. A., Höfflin, N., Okkeri, J., Wang, Z., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36693-9 · Cited by 36 · see citing works
“The data show that the CIP2A(1-560) residues cross-linked to B56α are located primarily in the N-terminal head domain (K18, K21, E23, E34, K40) with an additional residue at the C-terminus (K490) (Fig.”
BackgroundMethodInfluential
- Authors
- Smith, R. J., Cordeiro, M. H., Davey, N. E., Vallardi, G., Ciliberto, A., Gross, F., & Saurin, A. T.
- Affiliations
- University of Dundee (GB)
- University College Dublin (IE)
- IFOM (IT)
- Corresponding author
- Saurin, Adrian T.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2019-08
- Volume
- 28
- Issue
- 8
- Pages
- 2206-2219.e8
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6715587
- OpenAlex
- W2969810690
- Cited by
- 61
- References
- 69
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 6 · 2023: 9 · 2022: 3 · 2021: 10 · 2020: 10 · 2019: 2
- FWCI
- 3.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Science Foundation Ireland
- Tenovus
- Cancer Research UK
- Associazione Italiana per la Ricerca sul Cancro
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- PP1 phosphatase, kinetochore, serine/threonine phosphatase, mitosis, mathematical modeling, feedback regulation, cross-regulation
- MeSH terms
- Amino Acid Sequence, HeLa Cells, Humans, Microtubule-Associated Proteins, Models, Biological, Phenotype, Phosphorylation, Signal Transduction, Receptors, Neuropeptide Y, Kinetochores, Amino Acid Motifs, Protein Phosphatase 2
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