The tumor suppressor phosphatase PP2A-B56α regulates stemness and promotes the initiation of malignancies in a novel murine model
Open accessAbstract
Protein phosphatase 2A (PP2A) is a ubiquitously expressed Serine-Threonine phosphatase mediating 30-50% of protein phosphatase activity. PP2A functions as a heterotrimeric complex, with the B subunits directing target specificity to regulate the activity of many key pathways that control cellular phenotypes. PP2A-B56α has been shown to play a tumor suppressor role and to negatively control c-MYC stability and activity. Loss of B56α promotes cellular transformation, likely at least in part through its regulation of c-MYC. Here we report generation of a B56α hypomorph mouse with very low B56α expression that we used to study the physiologic activity of the PP2A-B56α phosphatase. The predominant phenotype we observed in mice with B56α deficiency in the whole body was spontaneous skin lesion formation with hyperproliferation of the epidermis, hair follicles and sebaceous glands. Increased levels of c-MYC phosphorylation on Serine62 and c-MYC activity were observed in the skin lesions of the B56αhm/hm mice. B56α deficiency was found to increase the number of skin stem cells, and consistent with this, papilloma initiation was accelerated in a carcinogenesis model. Further analysis of additional tissues revealed increased inflammation in spleen, liver, lung, and intestinal lymph nodes as well as in the skin lesions, resembling elevated extramedullary hematopoiesis phenotypes in the B56αhm/hm mice. We also observed an increase in the clonogenicity of bone marrow stem cells in B56αhm/hm mice. Overall, this model suggests that B56α is important for stem cells to maintain homeostasis and that B56α loss leading to increased activity of important oncogenes, including c-MYC, can result in aberrant cell growth and increased stem cells that can contribute to the initiation of malignancy.
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The skin lesions in B56α knockout mice are associated with increased expression of phosphorylated c-Myc at Ser62 and CDK4.
“This was associated with increased expression of phosphorylated c-Myc (Ser62) and CDK4 (a Myc target gene).”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [90]
In the B56α knockout model, mRNA expression of other PP2A subunits is not additionally affected.
“No additional effects on mRNA expression of all other PP2A subunits were apparent”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [90]
B56α knockout mice spontaneously develop skin lesions characterized by hyperproliferation of the epidermis, hair follicles, and sebaceous glands.
“B56α KO mice spontaneously developed skin lesions, characterized by hyperproliferation of the epidermis, hair follicles and sebaceous glands.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [90]
B56α knockout mice are more susceptible to carcinogen-induced skin carcinogenesis.
“Accordingly, the mice appeared more susceptible to carcinogen-induced skin carcinogenesis as well”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [90]
B56α knockout mice have increased numbers of skin and bone marrow stem cells.
“Notably, an increased number of skin (and bone marrow) stem cells was found”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [90]
PP2A-B56α has a role in suppressing stemness.
“suggestive for a role of PP2A-B56α in suppressing stemness.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [90]
In the B56α knockout model, overall PP2A activity measured on PP2A-C immunoprecipitates is not affected.
“no effects on overall PP2A activity, as measured on PP2A-C IPs, could be found.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [90]
In a constitutive total-body Ppp2r5a knockout mouse model, B56α expression is significantly reduced but not completely absent, with 0.01-0.2% of control levels remaining in all tissues tested.
“In these mice, B56α expression was significantly decreased but not entirely null, with 0.01-0.2% of control levels remaining in all tissues tested.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [90]
In B56α knockout mice, DMBA/TPA treatment accelerates skin papilloma formation, although endpoint levels are similar to wild-type.
“In this model, accelerated skin papilloma formation was observed upon DMBA/TPA treatment of the skin, although endpoint levels were similar to those in WT mice.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [90]
The inability of B56α-depleted skin cells to counteract c-Myc activity in the presence of an oncogenic event might promote tumor initiation.
“The inability of the B56α-depleted skin cells to counteract c-Myc activity in the presence of an oncogenic event, might therefore promote tumor initiation [90].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [90]
The B56α knockout skin phenotype is likely connected to induced stemness potential of skin cells, which may relate to increased phosphorylated c-Myc at Ser62.
“This phenotype is likely connectable to the induced stemness potential of skin cells in these mice, which on its turn could be related to increased expression of phosphorylated c-Myc (Ser62).”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [90]
Loss of B56α increases initiation of carcinogenesis without affecting progression.
“indicating that loss of B56α increases the initiation of carcinogenesis, without affecting progression.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [90]
Loss of B56α does not affect progression of papillomas into squamous cell carcinomas.
“No differences were seen in progression of the papillomas into squamous cell carcinomas”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [90]
In B56α knockout mice, DMBA/TPA treatment resulted in accelerated appearance of skin papillomas, and loss of B56α did not affect progression to squamous cell carcinoma, suggesting that B56α primarily inhibits tumor initiation.
“In B56α KO mice, DMBA/TPA treatment resulted in an accelerated appearance of skin papillomas. The loss of B56α did not affect the progression to squamous cell carcinoma, suggesting that B56α primarily inhibits tumor initiation [ 164 ].”
From Targeting PP2A in cancer: an underrated option (2025) · cites this paper as [164]
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Heil, B. N., Baral, G., Pfeffer, C. M., Bahler, M. B., Gulavani, S., Smith, E., Gartenhaus, L. E., Darling, A. K., Clifford, S. J., Smith-Kinnaman, W., et al. (2026) · Oncogene · doi:10.1038/s41388-026-03772-2 · Cited by 1 · see citing works
Activation of PP2A-B56α leads to aberrant EGFR signaling and proliferative phenotypes in PDACPreprint
Pfeffer, C. M., Clifford, S. J., Karim, S. A., Chianis, E. R. D., Heil, B. N., Gartenhaus, L. E., Kay, E. F., Baral, G., Hoffman, E. G., Utturkar, S. M., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.07.18.665598 · Cited by 1 · see citing works
- Authors
- Janghorban, M., Langer, E. M., Wang, X., Zachman, D., Daniel, C. J., Hooper, J., Fleming, W. H., Agarwal, A., & Sears, R. C.
- Affiliations
- Oregon Health & Science University (US)
- Johns Hopkins University (US)
- Corresponding author
- Sears, Rosalie C.
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2017-11-30
- Volume
- 12
- Issue
- 11
- Pages
- e0188910
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC5708644
- OpenAlex
- W2772300025
- Cited by
- 19
- References
- 58
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2021: 7 · 2020: 3 · 2019: 1 · 2018: 4
- FWCI
- 0.89
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institutes of Health (RO1 5R01CA129040, R01 CA100855, R01 CA100855-05S3)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- protein phosphatase 2A, tumor suppressor, c-Myc phosphorylation, skin carcinogenesis, skin stem cells, stem cell homeostasis, extramedullary hematopoiesis, inflammation, bone marrow-derived stem cells
- MeSH terms
- Animals, Mice, Transgenic, Neoplasms, Experimental, Neoplastic Stem Cells, Mice, Protein Phosphatase 2
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