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Identification of PP2A Complexes and Pathways Involved in Cell Transformation
Open accessPublished version of a preprint
Abstract
The simian virus 40 small t (SV40ST) oncoprotein interacts with protein phosphatase 2A (PP2A), an abundantly expressed family of serine–threonine phosphatases. This interaction is essential for the transformation of human cells by SV40, and several PP2A subunits have been implicated as tumor suppressor genes. However, the pathways controlled by specific PP2A complexes involved in cell transformation remain incompletely understood. Using a comprehensive loss-of-function approach, we identified 4 PP2A regulatory subunits [B56α, B56γ, PR72/PR130, and PTPA (protein phosphatase 2A activator)], which when suppressed replaced the expression of SV40ST in human cell transformation. We found that manipulation of complexes containing PP2A B56α, B56γ, and PR72/PR130 activates the pathways regulated by c-Myc, Wnt, and PI3K (phosphoinositide 3-kinase)/Akt in a manner that depends on their specific phosphatase activity. In contrast, suppression of PTPA disrupts the assembly of PP2A heterotrimeric complexes, which leads to the activation of these same oncogenic pathways. These observations delineate the PP2A family members and pathways perturbed by SV40ST during human cell transformation. Cancer Res; 70(24); 10474–84. ©2010 AACR.
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“Very importantly, among the all PP2A B subunits, B56 a and B56 c are the two subunits with the most convincing functional evidence of tumor suppressor activity [25,37].”
From Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56 (2017) · cites this paper as [25]
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“Among the PP2A complexes, PP2A trimers with B56 subunits are predominantly human tumour suppressors4–7.”
From Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A (2023) · cites this paper as [6]
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“However, fully consistent with the requirement of PP2A-B56 inhibition for anchorage-independent growth6,7, CIP2A K21A targeted clones were almost completely incompetent to grow as spheres on soft agar (Fig. 3F, G).”
From Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A (2023) · cites this paper as [6]
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“negatively regulates Akt kinase phosphorylation [25,29]”
From Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56 (2017) · cites this paper as [25]
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“only a subset of the numerous B subunits are relevant for the tumor suppressor activity of PP2A [25,26]”
From Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56 (2017) · cites this paper as [25]
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“Through loss-of-function studies it has been shown that PP2A-B56α inhibition drives malignant transformation of human cells, as well promotes malignant growth6,8.”
From Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A (2023) · cites this paper as [6]
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“The protein phosphatase 2A (PP2A) heterotrimer PP2A-B56α is a human tumour suppressor.”
From Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A (2023) · cites this paper as [6]
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Cites
1 retracted
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Loss of protein phosphatase 2A regulatory subunit B56δ promotes spontaneous tumorigenesis in vivo
Lambrecht, C., Libbrecht, L., Sagaert, X., Pauwels, P., Hoorne, Y., Crowther, J., Louis, J. V., Sents, W., Sablina, A., & Janssens, V (2018) · Oncogene · doi:10.1038/onc.2017.350 · Cited by 50
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“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.”
BackgroundMethodInfluentialFunctional importance of PP2A regulatory subunit loss in breast cancer
Watt, L. F., Panicker, N., Mannan, A., Copeland, B., Kahl, R. G. S., Dun, M. D., Young, B., Roselli, S., & Verrills, N. M. (2017) · Breast Cancer Research and Treatment · doi:10.1007/s10549-017-4403-5 · Cited by 29
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MacKay, K. B., Tu, Y., Young, S. G., & Clarke, S. G. (2013) · PLoS ONE · doi:10.1371/journal.pone.0065967 · Cited by 14
In vivo pieces of the PP2A onco-puzzle fallen into place
Meeusen, B., & Janssens, V. (2017) · Oncoscience · doi:10.18632/oncoscience.384 · Cited by 2
Metadata
- Authors
- Sablina, A. A., Hector, M., Colpaert, N., & Hahn, W. C.
- Affiliations
- Brigham and Women's Hospital (US)
- Authors' Affiliations: 1Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; 2VIB Institute, Center of Human Genetics, KULeuven, Leuven, Belgium; and 3Broad Institute of Harvard and MIT, Cambridge, Massachusetts
- Broad Institute (US)
- Corresponding author
- Sablina, Anna A.
- Hahn, William C.
- Venue
- Cancer Research
- Published
- 2010-12-14
- Volume
- 70
- Issue
- 24
- Pages
- 10474-10484
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3056544
- OpenAlex
- W2149754768
- Cited by
- 193
- References
- 50
- Citations by year
- 2026: 4 · 2025: 18 · 2024: 8 · 2023: 13 · 2022: 5 · 2021: 8 · 2020: 13 · 2019: 14 · 2018: 10 · 2017: 16 · 2016: 9 · 2015: 12 · 2014: 16 · 2013: 16 · 2012: 22
- FWCI
- 6.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- Funders
- National Institutes of Health (1k99ca125974-01a2)
- National Cancer Institute (1K99 CA125974-01A2, P01CA050661, K99 CA125974)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Health Sciences › Medicine › Oncology › Polyomavirus and related diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- protein phosphatase 2A, PP2A regulatory subunit, cell transformation, PTPA, c-Myc, Wnt signaling, PI3K/Akt signaling, tumor suppressor, phosphatase activity
- MeSH terms
- Cell Transformation, Neoplastic, Humans, Phosphoprotein Phosphatases, Proteins, Proto-Oncogene Proteins c-myc, Phosphatidylinositol 3-Kinases, Protein Subunits, RNA, Small Interfering, Proto-Oncogene Proteins c-akt, Wnt Proteins, beta Catenin, Protein Phosphatase 2
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