Loss of protein phosphatase 2A regulatory subunit B56δ promotes spontaneous tumorigenesis in vivo
Abstract
Protein Phosphatase 2A (PP2A) enzymes counteract diverse kinase-driven oncogenic pathways and their function is frequently impaired in cancer. PP2A inhibition is indispensable for full transformation of human cells, but whether loss of PP2A is sufficient for tumorigenesis in vivo has remained elusive. Here, we describe spontaneous tumor development in knockout mice for Ppp2r5d, encoding the PP2A regulatory B56δ subunit. Several primary tumors were observed, most commonly, hematologic malignancies and hepatocellular carcinomas (HCCs). Targeted immunoblot and immunohistochemistry analysis of the HCCs revealed heterogeneous activation of diverse oncogenic pathways known to be suppressed by PP2A-B56. RNA sequencing analysis unveiled, however, a common role for oncogenic c-Myc activation in the HCCs, independently underscored by c-Myc Ser62 hyperphosphorylation. Upstream of c-Myc, GSK-3β Ser9 hyperphosphorylation occurred both in the HCCs and non-cancerous B56δ-null livers. Thus, uncontrolled c-Myc activity due to B56δ-driven GSK-3β inactivation is the likely tumor predisposing factor. Our data provide the first compelling mouse genetics evidence sustaining the tumor suppressive activity of a single PP2A holoenzyme, constituting the final missing incentive for full clinical development of PP2A as cancer biomarker and therapy target.
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PP2A trimers with B56 subunits are predominantly human tumour suppressors.
“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 [4]
PP2A-B56α is a human tumour suppressor.
“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 [4]
Ppp2r5d knockout in mice causes frequent spontaneous tumors, including hematologic malignancies and hepatocellular carcinomas.
“Although PPP2R5D alterations are not frequently seen in human cancers, Ppp2r5d knockout in mice results in frequent spontaneous tumor development (Lambrecht et al., 2018).”
From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Lambrecht et al., 2018
Loss of B56δ results in elevated hematologic malignancies, mainly non-Hodgkin small B-cell lymphomas, in aging mice.
“Loss of B56δ resulted in elevated levels of hematologic malignancies, mainly non-Hodgkin small B-cell lymphomas, in aging mice.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [110]
Of the HCCs in B56δ knockout mice, 70% arise in a normal liver context with no signs of inflammation, fibrosis, or necrosis.
“Of these HCCs, 70% arose in a normal liver context, with no signs of inflammation, fibrosis or necrosis.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [110]
Elevated Ser9 phosphorylation of GSK-3β is seen in both non-cancerous and cancerous B56δ knockout liver samples.
“Interestingly, elevated Ser9 phosphorylation of GSK-3β was indeed seen in both non-cancerous and cancerous B56δ KO liver samples”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [110]
Unbiased transcriptome data reveal commonly upregulated c-Myc activity in B56δ knockout HCCs, corroborated by increased c-Myc phosphorylation at Ser62 and enhanced CIP2A expression in all HCCs examined.
“Unbiased transcriptome data revealed a commonly upregulated c-Myc activity in the HCCs, further corroborated by increased c-Myc phosphorylation (Ser62) and enhanced CIP2A expression (a Myc target gene) in all HCCs examined.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [110]
A prominent spontaneous cancer phenotype is observed in total-body constitutive B56δ knockout mice and in homozygous and heterozygous hypomorphic Ptpa mice.
“A very prominent spontaneous cancer phenotype was indeed observed in the total-body, constitutive KO model of the B56δ subunit [110] and in both homozygous and heterozygous mice of a hypomorphic Ptpa allele [43].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [110]
B56δ knockout mice show a high incidence of hepatocellular carcinomas, up to 60% in the oldest age category, while HCC does not occur in aging wild-type mice.
“More surprisingly, a high incidence of hepatocellular carcinomas (HCCs) was observed as well, in up to 60% of mice in the oldest age category, while HCC did not occur at all in aging WT mice.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [110]
Dysregulated GSK-3β activity plays a role in the tumor predisposing mechanism in B56δ knockout mice.
“implying a role for dysregulated GSK-3β activity in the tumor predisposing mechanism [110].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [110]
GSK3β is an established substrate of the PP2A holoenzyme containing B56δ.
“GSK3 b is an established substrate of the PP2A holoenzyme containing B56 d (Lambrecht et al., 2018; Haesen et al., 2016).”
From Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis (2019) · cites this paper as Lambrecht et al., 2018
The B56δ-containing PP2A complex plays important tumor suppressor roles through its established function in the regulation of GSK3β dephosphorylation.
“Particularly, the B56 d -containing PP2A complex plays important tumor suppressor roles through its established function in the regulation of GSK3 b dephosphorylation (Lambrecht et al., 2018; Haesen et al., 2016) and possibly other substrates.”
From Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis (2019) · cites this paper as Lambrecht et al., 2018
In the B56δ knockout model, there was a high incidence of malignant lymphomas, predominantly non-Hodgkin B-cell lymphomas, in aging animals, and up to 60% of the oldest mice developed hepatocellular carcinoma.
“Particularly striking in the B56δ KO model was the high incidence of malignant lymphomas (predominantly non-Hodgkin B-cell lymphomas) in aging animals. Furthermore, up to 60% of the oldest mice developed HCC.”
From Targeting PP2A in cancer: an underrated option (2025) · cites this paper as [169]
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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.”
BackgroundMethodInfluentialSelf-citationTargeting PP2A in cancer: an underrated option
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Self-citation
- Authors
- Lambrecht, C., Libbrecht, L., Sagaert, X., Pauwels, P., Hoorne, Y., Crowther, J., Louis, J. V., Sents, W., Sablina, A., & Janssens, V
- Affiliations
- KU Leuven (BE)
- Ghent University Hospital (BE)
- Antwerp University Hospital (BE)
- Corresponding author
- Janssens, V
- Venue
- Oncogene
- Published
- 2017-10-02
- Volume
- 37
- Issue
- 4
- Pages
- 544-552
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2761478733
- Cited by
- 50
- References
- 64
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 6 · 2023: 6 · 2022: 8 · 2021: 8 · 2020: 6 · 2019: 5 · 2018: 5 · 2017: 2
- FWCI
- 2.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Libraries (submittedVersion)
- Lirias (KU Leuven) (submittedVersion)
- Funders
- KU Leuven
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- 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
- protein phosphatase 2A, spontaneous tumor development, hepatocellular carcinoma, hematologic malignancies, c-myc activation, tumor suppressor function
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Animals, Female, Male, Mice, Inbred C57BL, Neoplasms, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Proto-Oncogene Proteins c-myc, Sequence Analysis, RNA, Mice, Knockout, Mice, Protein Phosphatase 2, Carcinogenesis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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