Affinage

PPP2R2C

Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B gamma isoform · UniProt Q9Y2T4

Length
447 aa
Mass
51.5 kDa
Annotated
2026-06-10
16 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPP2R2C encodes the brain-enriched B55gamma regulatory subunit of the PP2A serine/threonine phosphatase, directing the catalytic core toward specific substrates to control mitotic, growth-signaling, and genome-stability programs (PMID:10945473, PMID:32591484). As part of the PPP2CA–B55gamma–PPP2R1B trimeric holoenzyme, it dephosphorylates NuMA at threonine 2055 to counteract Cdk1, promoting cortical NuMA localization and proper mitotic spindle orientation; this activity was reconstituted in vitro and depends on NuMA polybasic residues (PMID:32591484). In growth-signaling contexts, B55gamma assembles with the PP2A-C subunit and the kinase SIK2, which it binds and stabilizes, to enhance dephosphorylation of S6K and suppress mTOR-pathway activity, glucose uptake, and proliferation in glioma cells (PMID:24126060, PMID:25792973). Subunit function and localization are tuned by phosphorylation: PAK6 phosphorylates B55gamma at serine 381 without altering holoenzyme assembly, instead licensing its recruitment to LRRK2 and redistributing it within the cell (PMID:38169846). At chromatin, PPP2R2C is transcriptionally activated by TRF2 through an intronic interstitial telomeric sequence and is recruited to telomeres and pericentromeres during S phase and replicative stress, where it stimulates PP2A activity to attenuate the DNA damage response, an axis required for normal zebrafish neurodevelopment (PMID:41701876). PPP2R2C also physically interacts with and stabilizes RPS27L against proteasomal degradation, suppressing radiation-induced ferroptosis (PMID:42115626), and is induced by glucocorticoid receptor signaling to gate osteoblast lineage commitment in mesenchymal stem cells (PMID:28805158). Consistent with a growth-suppressive role, PPP2R2C is silenced by miR-572 and miR-1301 across ovarian, prostate, and nasopharyngeal cancers (PMID:26796271, PMID:28525724).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2000 Medium

    Established the existence and identity of PPP2R2C as the third B55-family PP2A regulatory subunit, defining the molecular entity and its brain-selective expression.

    Evidence cDNA cloning, sequence/identity analysis, northern blot, and radiation hybrid mapping of the human gene

    PMID:10945473

    Open questions at the time
    • No substrate or holoenzyme function assigned
    • Tissue-restricted role not mechanistically explored
  2. 2013 Medium

    Linked B55gamma to growth suppression by showing it promotes PP2A-C engagement of S6K, connecting the subunit to mTOR-pathway control and tumor phenotypes.

    Evidence Overexpression/knockdown, Co-IP, and in vitro plus xenograft proliferation assays in glioma cells; parallel RNAi screen in prostate cancer

    PMID:23493267 PMID:24126060

    Open questions at the time
    • Whether S6K is a direct PP2A-B55gamma dephosphorylation substrate not resolved
    • AR-independent prostate growth mechanism undefined
  3. 2015 Medium

    Identified SIK2 as a B55gamma-binding partner whose stabilization is required for S6K suppression, providing a molecular intermediary for the growth-suppressive effect.

    Evidence Proteomic identification, reciprocal Co-IP, and siRNA rescue restoring S6K phosphorylation in glioma cells

    PMID:25792973

    Open questions at the time
    • Direct dephosphorylation target within the B55gamma-SIK2-S6K axis unclear
    • Mechanism of SIK2 stabilization not defined
  4. 2015 Medium

    Demonstrated post-transcriptional silencing of PPP2R2C by miR-572, establishing a route to its downregulation in cancer.

    Evidence 3'UTR luciferase reporter validation plus siRNA rescue in ovarian cancer cells; extended to nasopharyngeal carcinoma in 2017

    PMID:26796271 PMID:28525724

    Open questions at the time
    • Downstream phosphatase substrates mediating growth effects not identified
  5. 2016 Low

    Extended the miRNA-mediated silencing model to prostate cancer via miR-1301, linking PPP2R2C loss to cell-cycle progression.

    Evidence Reporter and functional miRNA gain/loss assays with p27/Cyclin D1 readouts in prostate cancer cells

    PMID:27261573

    Open questions at the time
    • Direct 3'UTR luciferase confirmation for PPP2R2C not explicitly shown
    • Single lab, single method set
  6. 2017 Medium

    Placed B55gamma downstream of glucocorticoid receptor signaling as a lineage gatekeeper, expanding its role beyond cancer into stem-cell differentiation.

    Evidence siRNA knockdown with osteogenic/adipogenic differentiation, morphology, and mineralization readouts in primary human BM-MSCs

    PMID:28805158

    Open questions at the time
    • PP2A substrates governing the osteoblast-vs-adipocyte decision unknown
    • Direct GR-PPP2R2C transcriptional link not defined
  7. 2020 High

    Defined the first reconstituted PP2A-B55gamma holoenzyme substrate, NuMA-T2055, mechanistically explaining a role in spindle orientation.

    Evidence In vitro reconstitution of dephosphorylation, NuMA mutagenesis, live imaging, and immunofluorescence

    PMID:32591484

    Open questions at the time
    • How B55gamma is targeted to mitotic NuMA not established
    • Relationship to brain-specific functions unexplored
  8. 2020 Low

    Connected PPP2R2C to tau dephosphorylation and Alzheimer's pathology, implicating it in neurodegeneration.

    Evidence PP2A activity and tau phosphorylation assays in cultured cells plus expression profiling in AD transgenic mouse brain

    PMID:32291379

    Open questions at the time
    • Limited mechanistic detail; tau as direct holoenzyme substrate not demonstrated
    • Causality between PPP2R2C loss and AD pathology not established
  9. 2023 High

    Showed that PAK6 phosphorylation of B55gamma at S381 acts as a switch controlling LRRK2 recruitment and subcellular localization rather than holoenzyme assembly.

    Evidence In vitro kinase assay with purified proteins, S381A mutagenesis, Co-IP, and subcellular fractionation

    PMID:38169846

    Open questions at the time
    • Whether LRRK2 is a B55gamma-PP2A substrate not shown
    • Functional consequence of LRRK2 recruitment undefined
  10. 2026 Medium

    Established a TRF2-driven transcriptional and chromatin-recruitment axis placing PPP2R2C at telomeres/pericentromeres to dampen the replication-stress DNA damage response.

    Evidence TRF2-ITS binding, chromatin recruitment, PP2A activity assays, and zebrafish neurodevelopment model

    PMID:41701876

    Open questions at the time
    • Chromatin-associated PP2A substrates not identified
    • Mechanism of S-phase recruitment to chromatin unresolved
  11. 2026 Medium

    Identified RPS27L as a physical partner stabilized by PPP2R2C, defining a ferroptosis-suppressing, radioresistance-conferring axis.

    Evidence IP-MS, reciprocal Co-IP, cycloheximide chase, proteasome inhibition, and lipid ROS/GPX4/SLC7A11 readouts in NPC cells

    PMID:42115626

    Open questions at the time
    • Whether stabilization requires PP2A catalytic activity not resolved
    • Mechanism by which PPP2R2C blocks RPS27L proteasomal degradation undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PPP2R2C's diverse substrate-targeting roles—mitotic spindle, mTOR signaling, chromatin stress response, and protein stabilization—are coordinated within its restricted expression domains and selected among competing partners remains unresolved.
  • No unifying model linking the distinct holoenzyme substrate sets
  • Tissue- and context-specific partner selection mechanism unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0000228 nuclear chromosome 1 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1640170 Cell Cycle 1 R-HSA-5357801 Programmed Cell Death 1 R-HSA-73894 DNA Repair 1
Partners
LRRK2NUMAPAK6PPP2CAPPP2R1BRPS27LSIK2TRF2
Complex memberships
PP2A trimeric holoenzyme (PPP2CA-PPP2R2C-PPP2R1B)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 PPP2R2C (B1gamma/B55gamma) was cloned from a human brain cDNA library and identified as the third member of the B55 subfamily of PP2A regulatory subunits, encoding a 447 amino acid protein sharing 81% and 85% identity with PPP2R2A and PPP2R2B respectively; the gene is highly and selectively expressed in brain and maps to chromosome 4p16. cDNA library cloning, sequence analysis, northern blot, radiation hybrid panel mapping Genomics Medium 10945473
2013 Overexpression of PPP2R2C in glioma cells inhibits cancer cell proliferation in vitro and in vivo by suppressing S6K activity in the mTOR pathway, and exogenous PPP2R2C promotes formation of a complex with the PP2A-C subunit that enhances PP2A-C binding to S6K. Cell proliferation assays (in vitro and xenograft in vivo), western blot, co-immunoprecipitation, overexpression/knockdown FEBS letters Medium 24126060
2013 Loss of PPP2R2C (a PP2A substrate-binding regulatory subunit) promotes androgen ligand-independent prostate cancer cell proliferation without altering AR expression or canonical AR-regulated gene expression, and this growth is not inhibited by AR antagonist MDV3100, indicating PPP2R2C loss drives growth independently of known AR-mediated transcriptional programs. High-throughput RNAi screen, cell proliferation assays in androgen-depleted conditions, gene expression analysis Molecular cancer research : MCR Medium 23493267
2015 B55gamma (PPP2R2C) binds to and stabilizes SIK2 protein (identified by proteomic analysis), and the resulting B55gamma-SIK2 association is required for B55gamma-mediated suppression of S6K phosphorylation; knockdown of SIK2 in B55gamma-overexpressing cells recovers S6K phosphorylation. B55gamma also suppresses glucose uptake and lactate production in glioma cells. Co-immunoprecipitation, western blot, proteomic/mass spectrometry analysis, siRNA knockdown, cell viability assay Cancer cell international Medium 25792973
2015 miR-572 directly targets the 3' UTR of PPP2R2C mRNA (confirmed by luciferase reporter assay), suppressing PPP2R2C expression to promote ovarian cancer cell proliferation; siRNA-mediated silencing of PPP2R2C counteracted the growth arrest caused by miR-572 inhibition. Luciferase reporter assay, siRNA knockdown, gain-of-function/loss-of-function miRNA experiments, cell proliferation assay Biomedicine & pharmacotherapy Medium 26796271
2016 miR-1301 directly targets PPP2R2C and promotes prostate cancer cell proliferation; simultaneous downregulation of both PPP2R2C and miR-1301 promoted growth, suggesting miR-1301 acts through PPP2R2C inhibition to drive G1/S transition (inhibiting p27, promoting Cyclin D1). Luciferase reporter assay (implied target validation), MTT assay, colony formation, soft agar growth, western blot, miRNA overexpression/knockdown Biomedicine & pharmacotherapy Low 27261573
2017 miR-572 binds to the 3' UTR of PPP2R2C and decreases its expression in nasopharyngeal carcinoma (NPC) cells; overexpressed miR-572 and decreased PPP2R2C both inhibit NPC cell proliferation and invasion and induce apoptosis, indicating miR-572 promotes NPC progression by downregulating PPP2R2C. Dual luciferase reporter gene assay, qPCR, western blot, MTT assay, flow cytometry, Transwell and wound healing assays Biochemistry and cell biology Medium 28525724
2017 PP2A regulatory subunit B55gamma (PPP2R2C) is induced by glucocorticoid receptor (GR) activation in human primary bone marrow mesenchymal stem cells (BM-MSCs) during osteoblast differentiation (but not adipocyte differentiation); B55gamma knockdown under osteogenic conditions impairs osteoblast morphogenesis and mineralization and causes accumulation of lipid droplets, establishing B55gamma as an essential gatekeeper of osteoblast lineage downstream of GR. siRNA knockdown, differentiation assays (osteogenic/adipogenic), western blot, qPCR, morphological analysis, GR ligand treatment Stem cells and development Medium 28805158
2020 The PPP2CA-B55gamma(PPP2R2C)-PPP2R1B trimeric PP2A complex dephosphorylates NuMA at threonine 2055 (T2055) to counteract Cdk1, thereby promoting cortical NuMA localization and proper mitotic spindle orientation; in vitro reconstitution demonstrated this complex is sufficient for T2055 dephosphorylation, and polybasic residues in NuMA were identified as critical for dephosphorylation and cortical localization. In vitro reconstitution of dephosphorylation, site-directed mutagenesis (NuMA polybasic residues, T2055), live cell imaging, siRNA knockdown, immunofluorescence Journal of cell science High 32591484
2020 PPP2R2C expression in cultured cells regulates PP2A activity and tau dephosphorylation; PPP2R2C is downregulated in the brains of aged Alzheimer's transgenic mice compared to wild-type, suggesting dysregulation of PPP2R2C contributes to altered tau phosphorylation in AD. PP2A activity assay, tau phosphorylation western blot, spatiotemporal expression analysis in transgenic AD mouse brain Aging Low 32291379
2023 PAK6 kinase phosphorylates PPP2R2C at serine 381 (S381); S381 phosphorylation does not affect PP2A holoenzyme assembly but is required for PPP2R2C binding to LRRK2 (phosphodead S381A shows impaired LRRK2 binding), and PAK6 kinase activity changes PPP2R2C subcellular localization in a S381 phosphorylation-dependent manner. PhosTag gel electrophoresis with purified proteins (in vitro kinase assay), co-immunoprecipitation, site-directed mutagenesis (S381A phosphodead), subcellular fractionation/localization Frontiers in molecular neuroscience High 38169846
2026 PPP2R2C physically interacts with RPS27L (confirmed by IP-MS and Co-IP) and stabilizes RPS27L protein by blocking its proteasomal degradation; this PPP2R2C-RPS27L axis suppresses radiation-induced ferroptosis (evidenced by reduced lipid ROS, MDA, and maintained GPX4/SLC7A11 levels) and thereby confers radioresistance in nasopharyngeal carcinoma cells. IP-mass spectrometry, co-immunoprecipitation, immunofluorescence, cycloheximide chase assay, proteasome inhibition, lipid ROS/MDA assays, western blot (GPX4, SLC7A11), TEM, siRNA knockdown, overexpression Cell death & disease Medium 42115626
2026 TRF2 transcriptionally activates PPP2R2C by binding to an intronic interstitial telomeric sequence (ITS) with transactivation activity; PPP2R2C is recruited to telomeres and pericentromeres during S phase and replicative stress, where it attenuates the DNA damage response by stimulating PP2A activity; this TRF2-PPP2R2C axis is required for normal neurodevelopment in zebrafish. ChIP/TRF2-ITS binding assay, luciferase transactivation assay (implied), chromatin recruitment (immunofluorescence/ChIP), PP2A activity assay, zebrafish developmental model, western blot Aging and disease Medium 41701876

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Over expression of PPP2R2C inhibits human glioma cells growth through the suppression of mTOR pathway. FEBS letters 41 24126060
2013 PPP2R2C loss promotes castration-resistance and is associated with increased prostate cancer-specific mortality. Molecular cancer research : MCR 40 23493267
2010 PPP2R2C, a gene disrupted in autosomal dominant intellectual disability. European journal of medical genetics 33 20601260
2015 MiR-572 prompted cell proliferation of human ovarian cancer cells by suppressing PPP2R2C expression. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 30 26796271
2016 miR-1301 promotes prostate cancer proliferation through directly targeting PPP2R2C. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 26 27261573
2000 Molecular cloning and mapping of the brain-abundant B1gamma subunit of protein phosphatase 2A, PPP2R2C, to human chromosome 4p16. Genomics 22 10945473
2018 High genetic risk scores of SLIT3, PLEKHA5 and PPP2R2C variants increased insulin resistance and interacted with coffee and caffeine consumption in middle-aged adults. Nutrition, metabolism, and cardiovascular diseases : NMCD 18 30454882
2020 PP2A subunit PPP2R2C is downregulated in the brains of Alzheimer's transgenic mice. Aging 14 32291379
2015 The association between Salt-inducible kinase 2 (SIK2) and gamma isoform of the regulatory subunit B55 of PP2A (B55gamma) contributes to the survival of glioma cells under glucose depletion through inhibiting the phosphorylation of S6K. Cancer cell international 14 25792973
2020 PP2A--B55γ counteracts Cdk1 and regulates proper spindle orientation through the cortical dynein adaptor NuMA. Journal of cell science 13 32591484
2017 Interaction between miR-572 and PPP2R2C, and their effects on the proliferation, migration, and invasion of nasopharyngeal carcinoma (NPC) cells. Biochemistry and cell biology = Biochimie et biologie cellulaire 12 28525724
2012 PPP2R2C as a candidate gene of a temperament and character trait-based endophenotype of ADHD. Attention deficit and hyperactivity disorders 10 22664926
2017 PP2A Regulatory Subunit B55γ is a Gatekeeper of Osteoblast Maturation and Lineage Maintenance. Stem cells and development 9 28805158
2023 PAK6-mediated phosphorylation of PPP2R2C regulates LRRK2-PP2A complex formation. Frontiers in molecular neuroscience 4 38169846
2026 TRF2 Upregulates Protein Phosphatase 2A Subunit PPP2R2C to Attenuate DNA Damage Response at Telomeres and Pericentromeres Upon Replicative Stress. Aging and disease 0 41701876
2026 PPP2R2C confers radioresistance in nasopharyngeal carcinoma by suppressing ferroptosis via RPS27L stabilization. Cell death & disease 0 42115626

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