Evidence map›Paper›PMID 34845248›Full record

ArticleScientific reports2021

Regulation of PP2A, PP4, and PP6 holoenzyme assembly by carboxyl-terminal methylation.

Scott P Lyons, Elora C Greiner, Lauren E Cressey, Mark E Adamo, Arminja N Kettenbach

Open access · goldAbstract read
In one paragraph

Article in Scientific reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.

0numbers the graph read from it
0cells of the map it votes in
16citing papers in PubMed
1.2field-weighted citation impact, top 21% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

16 citing papers in PubMed, 24 citations in OpenAlex.

  1. Article
  2. Article
  3. Article
  4. Article
  5. Targeting PP2A in cancer: an underrated option.Journal of experimental & clinical cancer research : CR · 2025
    Review
  6. Article
  7. Article
  8. Functional Role of Protein Phosphatase-6 (Current medicinal chemistry · 2025
    Review
  9. Article
  10. Article
  11. Article
  12. Article
  13. Article
  14. Article
  15. Review
  16. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

5 authors at 3 institutions in 1 country.

Scott P LyonsDepartment of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
Elora C GreinerNorris Cotton Cancer Center, Lebanon, NH, USA.
Lauren E CresseyNorris Cotton Cancer Center, Lebanon, NH, USA.
Mark E AdamoNorris Cotton Cancer Center, Lebanon, NH, USA.
Arminja N KettenbachDepartment of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. Arminja.N.Kettenbach@dartmouth.edu.
USC Norris Comprehensive Cancer Center · USCotton (United States) · USDartmouth College · US

Funding

Translational Engineering in Cancer (TEC)P30CA023108 · NCI · DARTMOUTH COLLEGE · PI Fred W Kolling IV · 1985 to 2026
$91.3M
Understanding the role of RNA-binding protein mutations in cancerP20GM113132 · NIGMS · DARTMOUTH COLLEGE · PI MADDEN, DEAN R · 2016 to 2025
$25.9M
Phosphorylation Signaling by Phosphoprotein PhosphatasesR35GM119455 · NIGMS · DARTMOUTH COLLEGE · PI Arminja Nadine Kettenbach · 2016 to 2026
$5.1M
Activity based profiling of Phosphoprotein phosphatases in cancer using mass spectrometry-based proteomicsR33CA225458 · NCI · DARTMOUTH COLLEGE · PI GERBER, SCOTT A., KETTENBACH, ARMINJA NADINE · 2019 to 2021
$1.2M
NCI NIH HHS P30 CA023108NCI NIH HHS R33 CA225458NIGMS NIH HHS P20 GM113132NIGMS NIH HHS R35 GM119455
6 · The paper itself

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.

Indexed as

Gene Expression Regulation, EnzymologicAnimalsCell Line, TumorHEK293 CellsHeLa CellsHumansMass SpectrometryMCF-7 CellsMethylationMiceNeoplasmsNeurodegenerative DiseasesPhosphoprotein PhosphatasesPhosphorylationProtein DomainsProtein Interaction MappingPhosphoprotein PhosphatasesProtein Phosphatase 2protein phosphatase 4

Identifiers

PMID34845248
PMCPMC8630191
OpenAlexW3215461432

What Socratic holds

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LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.