Regulation of PP2A, PP4, and PP6 holoenzyme assembly by carboxyl-terminal methylation
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Abstract
The family of Phosphoprotein Phosphatases (PPPs) is responsible for most cellular serine and threonine dephosphorylation. PPPs achieve substrate specificity and selectivity by forming multimeric holoenzymes. PPP holoenzyme assembly is tightly controlled, and changes in the cellular repertoire of PPPs are linked to human disease, including cancer and neurodegeneration. For PP2A, PP4, and PP6, holoenzyme formation is in part regulated by carboxyl (C)-terminal methyl-esterification (often referred to as “methylation”). Here, we use mass spectrometry-based proteomics, methylation-ablating mutations, and genome editing to elucidate the role of C-terminal methylation on PP2A, PP4, and PP6 holoenzyme assembly. We find that the catalytic subunits of PP2A, PP4, and PP6 are frequently methylated in cancer cells and that deletion of the C-terminal leucine faithfully recapitulates loss of methylation. We observe that loss of PP2A methylation consistently reduced B55, B56, and B72 regulatory subunit binding in cancer and non-transformed cell lines. However, Striatin subunit binding is only affected in non-transformed cells. For PP4, we find that PP4R1 and PP4R3β bind in a methylation-dependent manner. Intriguingly, loss of methylation does not affect PP6 holoenzymes. Our analyses demonstrate in an unbiased, comprehensive, and isoform-specific manner the crucial regulatory function of endogenous PPP methylation in transformed and non-transformed cell lines.
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Global quantification of mammalian gene expression control
Schwanhäusser, B., Busse, D., Li, N., Dittmar, G., Schuchhardt, J., Wolf, J., Chen, W., & Selbach, M. (2011) · Nature · doi:10.1038/nature10098 · Cited by 6,566 · cited 1× · see citing works
“Quantification of LC-MS/MS spectra was performed using BasicQuan or MassChroQ and the iBAQ method [61,62].”
MethodMS3 eliminates ratio distortion in isobaric multiplexed quantitative proteomics
Ting, L., Rad, R., Gygi, S. P., & Haas, W. (2011) · Nature Methods · doi:10.1038/nmeth.1714 · Cited by 1,009 · see citing works
Structure of the Protein Phosphatase 2A Holoenzyme
Xu, Y., Xing, Y., Chen, Y., Chao, Y., Lin, Z., Fan, E., Yu, J. W., Strack, S., Jeffrey, P. D., & Shi, Y. (2006) · Cell · doi:10.1016/j.cell.2006.11.033 · Cited by 450 · see citing works
PP2A holoenzyme assembly: In cauda venenum (the sting is in the tail)
Janssens, V., Longin, S., & Goris, J. (2008) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2007.12.004 · Cited by 390 · see citing works
Structural mechanism of demethylation and inactivation of protein phosphatase 2A
Xing, Y., Li, Z., Chen, Y., Stock, J. B., Jeffrey, P. D., & Shi, Y. (2008) · Cell · doi:10.1016/j.cell.2008.02.041 · Cited by 206 · see citing works
A PP2A-B55 recognition signal controls substrate dephosphorylation kinetics during mitotic exit
Cundell, M. J., Hutter, L. H., Nunes Bastos, R., Poser, E., Holder, J., Mohammed, S., Novak, B., & Barr, F. A. (2016) · Journal of Cell Biology · doi:10.1083/jcb.201606033 · Cited by 193 · see citing works
Ogris, E., Du, X., Nelson, K. C., Mak, E. K., Yu, X. X., Lane, W. S., & Pallas, D. C. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.20.14382 · Cited by 191 · see citing works
Longin, S., Zwaenepoel, K., Louis, J. V., Dilworth, S., Goris, J., & Janssens, V. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m704059200 · Cited by 184 · see citing works
Merrick, S. E., Trojanowski, J. Q., & Lee, V. M.-Y. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-15-05726.1997 · Cited by 143 · see citing works
Ogris, E., Gibson, D. M., & Pallas, D. C. (1997) · Oncogene · doi:10.1038/sj.onc.1201259 · Cited by 134 · see citing works
Lee, J. A., & Pallas, D. C. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m704861200 · Cited by 69 · see citing works
Jackson, J. B., & Pallas, D. C. (2012) · Neoplasia · doi:10.1593/neo.12768 · Cited by 60 · see citing works
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Targeting PP2A in cancer: an underrated option
Sarais, F., Krempien, F., Koehn, C., Brewing, L., Classen, C. F., Walter, M., & Shokraie, O. (2025) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-025-03560-y · Cited by 8 · see citing works
- Authors
- Lyons, S. P., Greiner, E. C., Cressey, L. E., Adamo, M. E., & Kettenbach, A. N.
- Affiliations
- Dartmouth College (US)
- Dartmouth Cancer Center (US)
- Corresponding author
- Kettenbach, Arminja N.
- Venue
- Scientific Reports
- Published
- 2021-11-29
- Volume
- 11
- Issue
- 1
- Pages
- 23031-23031
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC8630191
- OpenAlex
- W3215461432
- Cited by
- 27
- References
- 12
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 4 · 2023: 5 · 2022: 5
- FWCI
- 1.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- NIGMS (R35GM119455)
- NCI (R33CA225458)
- 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 › PI3K/AKT/mTOR signaling in cancer
- Keywords
- protein phosphatase 2A, protein phosphatase 4, protein phosphatase, holoenzyme assembly, protein methylation, catalytic subunit, striatin, cancer cells
- MeSH terms
- Protein Domains, Animals, HeLa Cells, Humans, Methylation, Neoplasms, Phosphoprotein Phosphatases, Phosphorylation, Protein Processing, Post-Translational, Mass Spectrometry, Gene Expression Regulation, Enzymologic, Neurodegenerative Diseases, Protein Interaction Mapping, Proteomics, Cell Line, Tumor, Mice, Protein Phosphatase 2, HEK293 Cells, MCF-7 Cells
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