B55α PP2A Holoenzymes Modulate the Phosphorylation Status of the Retinoblastoma-related Protein p107 and Its Activation
Open accessAbstract
Pocket proteins negatively regulate transcription of E2F-dependent genes and progression through the G(0)/G(1) transition and the cell cycle restriction point in G(1). Pocket protein repressor activities are inactivated via phosphorylation at multiple Pro-directed Ser/Thr sites by the coordinated action of G(1) and G(1)/S cyclin-dependent kinases. These phosphorylations are reversed by the action of two families of Ser/Thr phosphatases: PP1, which has been implicated in abrupt dephosphorylation of retinoblastoma protein (pRB) in mitosis, and PP2A, which plays a role in an equilibrium that counteracts cyclin-dependent kinase (CDK) action throughout the cell cycle. However, the identity of the trimeric PP2A holoenzyme(s) functioning in this process is unknown. Here we report the identification of a PP2A trimeric holoenzyme containing B55α, which plays a major role in restricting the phosphorylation state of p107 and inducing its activation in human cells. Our data also suggest targeted selectivity in the interaction of pocket proteins with distinct PP2A holoenzymes, which is likely necessary for simultaneous pocket protein activation.
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Tau and p107 share very little overlap in the residues required for B55α binding.
“It is conceivable that this acidic top may use substrate-specific sequences to discriminate between its various binding partners, as Tau and p107 have been shown to share very little overlap between residues necessary for binding (Jayadeva et al., 2010).”
From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Jayadeva et al., 2010
A single aspartic acid to lysine mutation in the B55α top surface abolishes binding to p107.
“Binding of B55α to one of its other substrates, p107, has also been shown to be abrogated by a single aspartic acid to lysine mutation in the top surface.”
From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Jayadeva et al., 2010
PP2A removes phosphate from pocket proteins throughout the cell cycle; pRB is a target of PP2A/PR70, and p107, p130 and probably pRB are targets of PP2A/B55α.
“As previously mentioned, PP2A can dephosphorylate pocket proteins in all phases in cell cycle, with pRB as a target of PP2A/PR70 and p107, p130 and likely pRB as targets of PP2A/B55α (Jayadeva et al., 2010; Kurimchak et al., 2013; Magenta et al., 2008).”
From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Jayadeva et al., 2010
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PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer
(2019) · Advances in Cancer Research · doi:10.1016/bs.acr.2019.03.009 · Cited by 93 · see citing works
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- Authors
- Jayadeva, G., Kurimchak, A., Garriga, J., Sotillo, E., Davis, A. J., Haines, D. S., Mumby, M., & Graña, X.
- Affiliations
- Temple University (US)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Graña, Xavier
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2010-09
- Volume
- 285
- Issue
- 39
- Pages
- 29863-29873
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2943288
- OpenAlex
- W1998903301
- Cited by
- 37
- References
- 29
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 3 · 2019: 4 · 2017: 1 · 2016: 3 · 2015: 3 · 2014: 4 · 2013: 6 · 2012: 4
- FWCI
- 1.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA095569, P01CA095569)
- National Institute of General Medical Sciences (R01GM086560)
- National Institute of Allergy and Infectious Diseases (K02 AI01823, K02AI001823)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- PP2A holoenzyme, p107, retinoblastoma-related protein, pocket proteins, protein phosphorylation, dephosphorylation, cyclin-dependent kinases, cell cycle regulation, G1/S transition
- MeSH terms
- Cell Cycle, Humans, Phosphorylation, Transcription, Genetic, Cyclin-Dependent Kinases, Holoenzymes, Cell Line, Tumor, E2F Transcription Factors, Retinoblastoma-Like Protein p107, Protein Phosphatase 2, Protein Multimerization
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