Affinage

PPP6C

Serine/threonine-protein phosphatase 6 catalytic subunit · UniProt O00743

Length
305 aa
Mass
35.1 kDa
Annotated
2026-06-10
55 papers in source corpus 34 papers cited in narrative 34 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

PPP6C is the catalytic subunit of the PP6 serine/threonine protein phosphatase, a heterotrimeric enzyme that assembles with SAPS/PPP6R and ANKRD regulatory subunits and dephosphorylates a defined substrate set to govern mitotic fidelity, the DNA damage response, innate immune signaling, and cell-death decisions (PMID:21451261, PMID:26462736, PMID:36897279). In mitosis and the cell cycle, PP6 reverses kinase-driven phosphorylation events: it dephosphorylates the condensin I subunit NCAP-G to oppose CK2 and ensure proper chromosome condensation and segregation (PMID:26462736), controls Aurora A activity (a regulation tuned by a Plk1–PP6 feedback loop and by CK2 phosphorylation of SAPS3) (PMID:29764989, PMID:31904830), and restrains Aurora A–TPX2-mediated phosphorylation of the kinetochore protein NDC80 during spindle formation (PMID:36897279). In the DNA damage response, PP6 dephosphorylates γ-H2AX to enable homology-directed repair and acts through the regulatory subunit R1 as a bidentate anchor that recruits the catalytic subunit to DNA-PK, supporting DNA-PK activation after ionizing radiation (PMID:21451261, PMID:22298787). PP6 is a broad negative regulator of immune and stress signaling, dephosphorylating cGAS and STING to restrain the cGAS–STING–IRF3 axis, activating RIG-I within a mitochondrial WHIP–TRIM14–PPP6C signalosome, inactivating TAK1 and ASK3 kinases, and shaping TCR signaling and Treg stability via Dnmt1 and Akt (PMID:32474700, PMID:32753499, PMID:29053956, PMID:35842423, PMID:29539411, PMID:25609840, PMID:35224167). It is a major MEK phosphatase whose recurrent melanoma-associated mutations cause MEK hyperphosphorylation and altered drug sensitivity (PMID:33789117), and it controls programmed cell death by modulating RIPK1 phosphorylation and ubiquitination within TNF receptor complex I and during PANoptosis (PMID:36071040, PMID:38807188). PP6 additionally regulates ER-to-Golgi trafficking through dephosphorylation of COPII coat subunits and Sec16, and translation elongation through eEF2 [PMID:23864707, PMID:bio_10.1101_2025.06.18.660491, PMID:36384136]. PP6 phosphatase activity is essential for post-implantation mouse embryogenesis (PMID:26868000), and its activity is set by alpha4-mediated allosteric inhibition and by regulated degradation of its ANKRD28 subunit (PMID:16895907, PMID:35512830).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2003 Medium

    Establishing PP6 as a distinct phosphatase required separating its catalytic and regulatory behavior from the related PP2A/PP4 enzymes and demonstrating conservation of the regulatory-subunit interaction.

    Evidence Purification of PP6C from bovine testes with activity assays and GST-alpha4 pulldowns, plus heterologous rescue of yeast sap mutants by human PP6R subunits

    PMID:12963337 PMID:19621075

    Open questions at the time
    • Conflicting alpha4-binding result for PP6C left the regulatory relationship unresolved
    • Did not define mammalian substrates
  2. 2003 High

    Genetic work in fission yeast first linked the PP6 ortholog to chromosome segregation, placing the phosphatase opposite a kinase at the kinetochore.

    Evidence Suppressor screen of mis12, mass spectrometry of Mis12 phosphorylation, chromatin fractionation and gsk3 epistasis in S. pombe

    PMID:12773390

    Open questions at the time
    • Direct dephosphorylation of Mis12 by PP6 not shown in vitro
    • Mammalian kinetochore relevance not established here
  3. 2006 High

    The question of how PP6 activity is tuned was addressed by showing alpha4 acts oppositely on PP6 versus PP2A, defining an allosteric brake specific to PP6.

    Evidence In vitro phosphatase assays with monomeric and alpha4-heterodimeric recombinant PP6/PP2A, inhibitor IC50 measurements, and cell expression

    PMID:16895907

    Open questions at the time
    • Structural basis of differential alpha4 effect not resolved
    • Physiological substrates governed by alpha4 regulation not identified
  4. 2011 High

    PP6 gained its first mammalian molecular substrate when γ-H2AX dephosphorylation was reconstituted, linking the phosphatase to DNA double-strand break repair.

    Evidence In vitro phosphatase assay with bacterially produced PP6 heterotrimers, siRNA, γ-H2AX immunofluorescence, HDR reporter, and ChIP recruitment

    PMID:21451261

    Open questions at the time
    • Which regulatory subunit directs γ-H2AX targeting in vivo not fully defined
    • Recruitment mechanism to DSBs incomplete
  5. 2012 High

    The mechanism of PP6 substrate targeting was clarified by showing the R1 regulatory subunit physically bridges the catalytic subunit to DNA-PK.

    Evidence Deletion-mapping co-IP of R1 with DNA-PK, siRNA knockdown, clonogenic radiosensitivity, and DNA-PK kinase assays

    PMID:22298787

    Open questions at the time
    • Whether DNA-PKcs is a direct PP6 substrate here vs. an activator not fully separated
    • Structure of the R1-bridged complex unknown
  6. 2013 High

    PP6 was extended beyond the nucleus to membrane trafficking by showing it dephosphorylates COPII coat subunits to regulate ER-to-Golgi transport.

    Evidence Yeast phosphatase screen, in vitro dephosphorylation of COPII by Sit4p, COPII localization in sit4Δ, and mammalian PP6 trafficking assay

    PMID:23864707

    Open questions at the time
    • Specific COPII phosphosites in mammals not mapped
    • Regulatory subunit directing COPII targeting not identified here
  7. 2014 Medium

    PP6 was implicated in mitotic DNA-PKcs regulation, integrating it with PLK1 signaling at Ser3205.

    Evidence In vitro PLK1 kinase assay on DNA-PKcs, co-IP, phospho-specific antibodies, PP6 knockdown, and MS phosphosite mapping

    PMID:24844881

    Open questions at the time
    • Direct in vitro PP6 dephosphorylation of Ser3205 not reconstituted
    • Functional consequence of mitotic DNA-PKcs phosphorylation incomplete
  8. 2015 High

    System-wide phosphoproteomics defined the breadth of PP6 mitotic substrates and pinpointed condensin I (NCAP-G) as a CK2-opposed target controlling chromosome architecture.

    Evidence PP6c depletion with quantitative phosphoproteomics, biochemical phosphatase assay, and chromosome condensation/segregation imaging in HeLa

    PMID:26462736

    Open questions at the time
    • Most of the hundreds of altered phosphosites not validated as direct substrates
    • Subunit-substrate assignment for NCAP-G not defined
  9. 2015 High

    Conditional knockout established PP6 as a physiological negative regulator of distal TCR signaling and T cell homeostasis.

    Evidence T cell-specific PP6 KO mice with flow cytometry, signaling western blots, and differentiation assays

    PMID:25609840

    Open questions at the time
    • Direct PP6 substrates within the TCR cascade not identified
    • Which regulatory subunits operate in T cells unclear
  10. 2016 High

    Genetic and biochemical studies defined PP6 regulation by methylation and TOR signaling and demonstrated that its phosphatase activity is indispensable for development.

    Evidence LCMT-1 KO MEFs and BN-PAGE, yeast TORC1/Sit4 epistasis, and an embryonic-lethal Ppp6c phosphatase-domain deletion mouse

    PMID:26868000 PMID:27343235 PMID:27507813

    Open questions at the time
    • Functional role of PP6 C-terminal methylation remains unexplained given no assembly effect
    • Mammalian TOR-PP6 coupling not directly demonstrated
  11. 2017 High

    PP6 was placed in innate immune and stress kinase pathways as an activator of RIG-I and a suppressor of TAK1/JNK signaling.

    Evidence RNAi screen, Y2H, co-IP and RIG-I dephosphorylation for the WHIP-TRIM14-PPP6C signalosome; Drosophila genetic epistasis placing PP6 upstream of dTAK1 in JNK signaling

    PMID:28658615 PMID:29053956

    Open questions at the time
    • RIG-I phosphosites dephosphorylated by PP6 not fully mapped
    • Mammalian TAK1/JNK substrate validation deferred to later work
  12. 2018 High

    PP6 was shown to be embedded in mitotic kinase feedback loops, being inhibited by Plk1 to coordinate Aurora A activity, and to inactivate the stress kinase ASK3 under osmotic stress.

    Evidence Quantitative proteomics with kinase inhibitors and Plk1 phospho-binding mutants, Aurora A and PP6 activity assays; genome-wide siRNA screen with co-IP, kinase assay, and cell-volume readouts for ASK3

    PMID:29539411 PMID:29764989

    Open questions at the time
    • Mechanism of Plk1-dependent PP6 inhibition at the molecular level incomplete
    • ASK3 dephosphorylation site not specified
  13. 2020 High

    Regulatory-subunit phosphorylation and substrate engagement were mechanistically detailed: CK2 phosphorylation of SAPS3 enhances Aurora A dephosphorylation, and PPP6C constitutively restrains cGAS-STING signaling.

    Evidence In vitro CK2 and PP6 activity assays with SAPS3 mutagenesis; co-IP, cGAS/STING phospho-site mutagenesis, in vitro cGAMP synthesis, and PPP6C KO with viral infection

    PMID:31904830 PMID:32474700 PMID:32753499

    Open questions at the time
    • Coordination between cGAS and STING dephosphorylation by PP6 not integrated
    • Selectivity for IRF3 over NF-κB branch unexplained mechanistically
  14. 2021 High

    PP6 was established as a major MEK phosphatase relevant to oncogenic signaling and as a regulator of Treg stability, connecting recurrent melanoma mutations to MEK hyperactivation.

    Evidence PPP6C KO/knockdown with phospho-MEK analysis, regulatory-subunit co-IP, MEK-inhibitor sensitivity, melanoma mutant expression; Treg-specific KO with FoxP3 bisulfite sequencing and Dnmt1/Akt phospho-analysis

    PMID:33789117 PMID:35224167

    Open questions at the time
    • Which regulatory subunit recruits PP6 to MEK not pinned down
    • Direct vs. indirect Dnmt1 dephosphorylation in Tregs needs reconstitution
  15. 2022 High

    PP6 was integrated into cell-death control by acting on TAK1 and RIPK1 within TNF receptor signaling, and additional layers of its own regulation (AMPKγ sequestration, Rab40c/CRL5-mediated ANKRD28 degradation) were defined.

    Evidence CRISPR screens with KO, TAK1 kinase and RIPK1 ubiquitination/phospho assays and gut mouse model; AMPK subunit KO with co-IP and eEF2 phosphoproteomics; Rab40c KO with ubiquitylation and focal-adhesion readouts

    PMID:35512830 PMID:35842423 PMID:36071040 PMID:36384136

    Open questions at the time
    • Direct PP6 dephosphorylation sites on TAK1 and RIPK1 not all mapped
    • How energy state switches PP6 between substrates unresolved
  16. 2023 High

    PP6 was shown to restrain Aurora A-TPX2-driven NDC80 phosphorylation at attached kinetochores, with synthetic lethality to NDC80 defining its mitotic essentiality.

    Evidence PPP6C KO, in vitro Aurora A-TPX2 kinase assay, NDC80-9A phospho-dead rescue, functional genomics, and spindle/nuclear imaging

    PMID:36897279

    Open questions at the time
    • Whether PP6 directly dephosphorylates NDC80 sites not shown in vitro
    • Spatial control of PP6 at kinetochores not defined
  17. 2024 High

    PP6 and its three regulatory subunits were shown to redundantly promote RIPK1-dependent PANoptosis through opposing phosphorylation of pro-death vs. pro-survival RIPK1 sites.

    Evidence Cell-death CRISPR screen, PPP6C and PPP6R1/2/3 KO/knockdown, RIPK1 S166/S321 phospho-analysis, and cell death assays

    PMID:38807188

    Open questions at the time
    • Direct vs. indirect control of RIPK1 S166/S321 not separated
    • Substrate redundancy among the three PPP6R subunits not biochemically mapped
  18. 2025 Medium

    Recent work extended PP6 to secretory regulation (Sec16/ERES via a FAM83A/CK1α feedback loop), to host-pathogen metabolism (Pfkfb1 in Salmonella infection), and to a disease-relevant degradation axis (SMURF2/IL-17C in psoriasis).

    Evidence PPP6R3/PPP6C complex with phospho-Sec16 and secretion assays (preprint); Y2H, conditional KO and NO/Arg-1 readouts for Pfkfb1; co-IP, ubiquitination and rescue with psoriasis mouse model for SMURF2

    PMID:40244332 PMID:41474810 PMID:bio_10.1101_2025.06.18.660491

    Open questions at the time
    • Sec16 work remains a preprint awaiting peer review
    • Direct Pfkfb1 dephosphorylation site not mapped
    • SMURF2-PPP6C degradation single-lab without reciprocal validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single catalytic subunit achieves substrate selectivity across mitosis, DNA repair, immunity, trafficking, and cell death—and how regulatory-subunit/holoenzyme composition and competing post-translational regulation dictate which substrate is engaged in a given context—remains the central open question.
  • No structural model assigning specific SAPS/ANKRD combinations to specific substrates
  • Quantitative rules for substrate competition under different stimuli unknown
  • Most substrate dephosphorylation sites identified in cells lack in vitro reconstitution with defined holoenzymes

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016787 hydrolase activity 4 GO:0098772 molecular function regulator activity 4
Localization
GO:0005634 nucleus 2 GO:0005694 chromosome 2 GO:0005783 endoplasmic reticulum 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-73894 DNA Repair 2
Partners
ANKRD28PLK1PPP6R1PPP6R2PPP6R3SMURF2STING1TRIM14
Complex memberships
PP6 heterotrimer (PPP6C-SAPS/PPP6R-ANKRD)TNF receptor complex IU1 snRNP/spliceosomeWHIP-TRIM14-PPP6C signalosome

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Alpha4 regulatory subunit exerts opposing allosteric effects on PP6 and PP2A: alpha4·PP6 heterodimer has ~100-fold lower Vmax than alpha4·PP2A with MBP substrate, meaning alpha4 activates PP2A but inhibits PP6. Monomeric PP6 and PP2A show identical kinetics with pNPP and MBP, but PP6 is inhibited at 5-fold lower concentrations of toxins (okadaic acid, microcystin-LR, calyculin A, cantharidin) with MBP substrate, suggesting PP6 is a preferred in vivo target. In vitro phosphatase assays with recombinant monomeric and heterodimeric PP6 and PP2A; pNPP and 32P-MBP substrates; IC50 measurements with active-site inhibitors; transient expression of alpha4 in cells The Journal of biological chemistry High 16895907
2003 PP6 catalytic subunit (PP6C) is purified from bovine testes and shows relatively low phosphatase activity toward several substrates compared to PP2A(C) and PP4(C). PP6C does not bind GST-alpha4 in the same pulldown conditions where PP2A(C) binds alpha4. Parallel purification from bovine testes; microcystin-Sepharose affinity resin; GST-alpha4 pulldown; co-immunoprecipitation; in vitro phosphatase activity assays Protein expression and purification Medium 12963337
2003 Fission yeast PP6 ortholog Ppe1 (scSit4/hPP6) and its binding partner Ekc1 (scSAP) negatively regulate kinetochore protein Mis12 localization and are required for faithful chromosome segregation; Gsk3 kinase counteracts Ppe1/PP6 at this step. Mis12 is phosphorylated at ≥2 sites as revealed by mass spectrometry, and Ppe1/Ekc1 co-fractionate with chromatin as non-histone chromatin-associated proteins. Suppressor screen of mis12 mutant in fission yeast; mass spectrometry of Mis12 phosphorylation; chromatin fractionation; genetic epistasis with gsk3; localization recovery assay The EMBO journal High 12773390
2007 The N-terminal domain of human PP6 (first ~53 residues) restricts G1-to-S phase progression in human prostate cancer cells, suppresses cyclin D1 protein levels in G1, and reduces RB1 phosphorylation at Ser807/811, without significantly altering cyclin/cell-cycle gene transcripts. This function is distinct from the PP6 homolog Sit4 in yeast. Transient expression of GFP fusions of PP6 or PP2A N-termini in PC-3 cells; flow cytometry cell cycle analysis; cyclin D1 western blot; RB1 phosphorylation western blot; gene expression microarray Cell cycle (Georgetown, Tex.) Medium 17568194
2009 Human PP6 regulatory subunits PP6R2 and PP6R3 (but not PP6R1) physically interact with yeast Sit4 and rescue growth defects, rapamycin hypersensitivity, cyclin G1 expression, and DNA synthesis of a yeast quadruple sap mutant in a Sit4-dependent manner, demonstrating functional conservation of the PP6 regulatory subunit–phosphatase interaction. Heterologous expression of human PP6R proteins in S. cerevisiae sap mutant; growth assays; rapamycin sensitivity; cyclin expression; DNA synthesis; genetic rescue PloS one Medium 19621075
2011 PP6c-containing heterotrimeric complexes (produced in bacteria) exhibit phosphatase activity against γ-H2AX (phospho-H2AX Ser139) in vitro, establishing γ-H2AX as a substrate of PP6. Depletion of PP6c or its regulatory subunit PP6R2 leads to persistent γ-H2AX after DNA damage and defective homology-directed repair (HDR); PP6c is recruited to DSB sites as shown by ChIP. In vitro phosphatase assay with bacterially-produced PP6 heterotrimers; siRNA knockdown; γ-H2AX immunofluorescence; HDR reporter assay; chromatin immunoprecipitation Cell cycle (Georgetown, Tex.) High 21451261
2012 PP6 regulatory subunit R1 (SAPSR1) acts as a bidentate anchor that bridges DNA-PK and PP6c: two distinct regions of R1 (residues 1–326 and 522–700) each bind DNA-PK, with residues 1–326 as the dominant domain; R1 is necessary to recruit PP6c to DNA-PK. Knockdown of R1 or PP6c prevents DNA-PK activation after ionizing radiation and radiosensitizes glioblastoma cells. R1 deletion mutant co-immunoprecipitation mapping; siRNA knockdown; clonogenic radiosensitivity assay; DNA-PK kinase activity assay The Journal of biological chemistry High 22298787
2013 Yeast PP6 ortholog Sit4p dephosphorylates COPII coat subunits in vitro and in vivo; sit4Δ mutants accumulate hyperphosphorylated COPII coat subunits and show altered COPII distribution. Mammalian PP6 similarly regulates ER-to-Golgi trafficking, establishing PP6 as a regulator of COPII coat recycling. Phosphatase screen in yeast; in vitro dephosphorylation assay with Sit4p and COPII subunits; COPII localization in sit4Δ cells; mammalian PP6 knockdown ER-to-Golgi trafficking assay Molecular biology of the cell High 23864707
2013 PP6 is stably associated with U1 snRNP and is present as part of the spliceosome throughout the splicing reaction, suggesting a role in pre-mRNA splicing regulation. Co-immunoprecipitation of PP6 with U1 snRNP; spliceosome pull-down; biochemical fractionation Biochemical and biophysical research communications Low 24064353
2014 PP6 dephosphorylates DNA-PKcs at Ser3205 in mitosis and after ionizing radiation. PLK1 phosphorylates DNA-PKcs on Ser3205 in vitro and interacts with DNA-PKcs in mitosis; phosphorylation of Thr3950 is DNA-PK-dependent. DNA-PKcs also phosphorylates Chk2 on Thr68 in mitosis in the apparent absence of Ku and DNA damage. In vitro kinase assay (PLK1 on DNA-PKcs); co-immunoprecipitation; phospho-specific antibodies; PP6 knockdown; mass spectrometry identification of phosphosites Bioscience reports Medium 24844881
2015 PP6c depletion in mitotic HeLa cells causes phosphorylation changes in 408 phosphopeptides (272 proteins increased) and 298 phosphopeptides (220 proteins decreased). PP6c directly opposes casein kinase 2 (CK2)-dependent phosphorylation of condensin I subunit NCAP-G; PP6c depletion causes defects in chromosome condensation and segregation in anaphase, consistent with dysregulation of condensin I. Baculovirus-mediated PP6c depletion in HeLa; quantitative mass spectrometry phosphoproteomics; biochemical phosphatase assay; chromosome condensation/segregation imaging Science signaling High 26462736
2015 T cell lineage-specific ablation of PP6 in mice causes hyperactivation of multiple distal TCR signaling molecules including MAPKs, AKT, and NF-κB, enhanced thymic selection, preferential expansion of IL-17-producing Vγ6Vδ1+ T cells, and loss of naive T cell homeostasis. PP6 acts as a critical negative regulator of distal TCR signaling. Conditional PP6 knockout mice (T cell-specific); flow cytometry; western blot of downstream signaling molecules; T cell proliferation and differentiation assays Journal of immunology High 25609840
2016 LCMT-1 is the major carboxyl methyltransferase for PP6 catalytic subunit (as well as PP2A and PP4) in mouse embryonic fibroblasts. PP6 is carboxyl-methylated on its C-terminal leucine. Unlike PP2A and PP4, loss of methylation (LCMT-1 KO) does not significantly affect PP6 holoenzyme assembly. Antibodies specific to unmethylated phosphatases; LCMT-1 knockout MEFs; blue native PAGE; co-immunoprecipitation; western blot The Journal of biological chemistry Medium 27507813
2016 Homozygous deletion of the Ppp6c phosphatase domain in mice is embryonic lethal; mutant embryos degenerate by E7.5 with clear developmental defects at E8.5. Homozygous blastocysts exhibit growth failure of the inner cell mass in vitro, and Ppp6c-deficient MEFs show greatly reduced proliferation, establishing that PP6 phosphatase activity is indispensable for post-implantation embryogenesis. Conditional knockout mouse generation; embryo phenotyping; in vitro blastocyst culture; MEF proliferation assay Mechanisms of development High 26868000
2016 TORC1 signaling suppresses the Tap42-regulated Sit4 (PP6) phosphatase complex; sit4Δ rescues histone acetylation under TORC1-repressive conditions. TORC1 inhibition activates PP6/Sit4, causing nuclear accumulation of sirtuin deacetylase Hst4 (reduced protein turnover), decreased histone H3/H4 acetylation. PP6 thus couples nutrient/TOR signaling to epigenetic regulation via sirtuin nuclear localization. Genetic epistasis (sit4Δ, hst3Δ, hst4Δ, tco89Δ); rapamycin treatment; histone acetylation western blot; Hst4-GFP nuclear localization imaging; protein stability assay Genetics Medium 27343235
2017 TRIM14 provides a mitochondrial docking platform for assembly of the WHIP–TRIM14–PPP6C signalosome required for RIG-I-mediated antiviral signaling. PPP6C dephosphorylates RIG-I within this complex, promoting its activation; WHIP bridges RIG-I with MAVS via polyubiquitin chains at RIG-I K164. Pooled RNAi screen; yeast two-hybrid; co-immunoprecipitation; RIG-I dephosphorylation assay; antiviral reporter assays; viral infection models Molecular cell High 29053956
2017 In Drosophila, the PP6 regulatory subunit Fmt (fiery mountain) negatively regulates JNK signaling upstream of dTAK1; loss of Fmt or PpV (PP6 catalytic subunit) cooperates with oncogenic RasV12 to promote JNK-dependent tumor growth and invasion. Fmt and PpV act synergistically to suppress JNK-dependent tumorigenesis. Genetic screen in Drosophila; genetic epistasis (fmt, ppv, rasV12, dTAK1 alleles); tumor growth and invasion assays; reporter assays for JNK activity Cell reports High 28658615
2018 PP6 directly interacts with and inactivates ASK3 kinase in an osmolality-dependent manner under hyperosmotic stress; PP6-ASK3 interaction promotes regulatory volume increase (RVI) and cell survival. A genome-wide siRNA screen identified PP6 as a direct ASK3 inactivator in the bidirectional osmotic stress response. Genome-wide siRNA screen; co-immunoprecipitation; kinase activity assay; cell volume measurement; cell viability assay; osmotic stress treatments Cell reports High 29539411
2018 Plk1 inhibits the phosphatase PP6 toward Aurora A (Aurora kinase A), generating a Plk1–PP6 feedback loop that coordinates Plk1 and Aurora A activities during mitotic entry. PP6 interaction with Plk1 is phosphorylation-dependent and is terminated by Plk1 degradation during mitotic exit. Quantitative proteomics on HeLa cells with kinase inhibitors or Plk1 phospho-binding mutant; Aurora A activity assays; PP6 activity assays; co-immunoprecipitation Science signaling High 29764989
2020 CK2 phosphorylates SAPS3 (a PP6 regulatory subunit) on multiple acidic motifs; CK2-phosphorylated SAPS3-PP6 complex shows significantly increased phosphatase activity toward pT288-Aurora A kinase substrate. Nine Ala substitutions in SAPS3 CK2 sites block this activation. CK2 inhibitors increase Aurora A phosphorylation in cells, consistent with reduced PP6 activity. SAPS3 knockdown/KO results in hyperactivated Aurora A and abnormal nuclei. In vitro CK2 kinase assay on SAPS3; PP6 phosphatase activity assay with pT288-AurA substrate; mutagenesis of CK2 sites in SAPS3; CK2 inhibitor cell treatment; CRISPR/siRNA depletion of SAPS3; nuclear morphology imaging The Biochemical journal High 31904830
2020 PPP6C is constitutively associated with cGAS in unstimulated cells. DNA virus infection causes rapid dissociation of PPP6C from cGAS, resulting in phosphorylation of human cGAS S435 (mouse cGAS S420) in the catalytic pocket. S420-phosphorylated mcGAS has higher affinity for GTP and higher enzymatic activity. PPP6C dephosphorylation of this site keeps cGAS inactive in the absence of infection to prevent autoimmune response. Co-immunoprecipitation; phospho-specific antibody; site-directed mutagenesis of cGAS S435/S420; in vitro cGAMP synthesis assay; PPP6C knockout cell lines; viral infection experiments Protein & cell High 32474700
2020 PPP6C interacts with STING and negatively regulates the cGAS-STING pathway by dephosphorylating STING. Loss of PPP6C enhances STING phosphorylation, increases IRF3 activation (but not NF-κB activation) in response to dsDNA, restricts HSV-1 and VSV replication, and inhibits KSHV reactivation through increased type I interferon production. Co-immunoprecipitation of PPP6C with STING; PPP6C siRNA depletion; phospho-STING western blot; IRF3/NF-κB reporter assays; viral replication assays mBio Medium 32753499
2021 PPP6C is a major MEK phosphatase in cells with oncogenic ERK pathway activation; PPP6C is recruited to MEK through its associated regulatory subunits. Loss of PPP6C causes hyperphosphorylation of MEK at activating and crosstalk phosphorylation sites, promoting ERK pathway signaling and decreasing sensitivity to MEK inhibitors. Recurrent melanoma-associated PPP6C mutations cause MEK hyperphosphorylation. PPP6C knockdown/knockout; phospho-MEK western blot; co-immunoprecipitation with regulatory subunits; MEK inhibitor sensitivity assays; expression of melanoma-associated PPP6C mutants Cell reports High 33789117
2021 PP6 (Pp6) deficiency in Treg cells increases CpG methylation of the FoxP3 locus by dephosphorylating Dnmt1 and enhances Akt phosphorylation at Ser473/Thr308, leading to impaired FoxP3 expression and Treg cell instability. Conditional Pp6 KO in Treg cells causes spontaneous autoinflammation. Conditional PP6 KO mice (Treg-specific); bisulfite sequencing of FoxP3 locus; Dnmt1 dephosphorylation assay; Akt phosphorylation western blot; flow cytometry; autoimmune model experiments Genes & diseases Medium 35224167
2021 Loss of PP6 C-terminal methylation does not affect PP6 holoenzyme assembly (interaction with ANKRD and SAPS regulatory subunits), in contrast to PP2A and PP4 where methylation is critical for regulatory subunit binding. Mass spectrometry-based proteomics; methylation-ablating mutations; genome editing (CRISPR); BN-PAGE; quantitative interaction proteomics Scientific reports Medium 34845248
2022 PP6 is an identified component of TNF receptor complex I. PP6 loss protects cells from TNFα-mediated cell death in a phosphatase-activity-dependent manner. PP6 modulates LUBAC-mediated M1-ubiquitination of RIPK1 and c-FLIPL, promoting RIPK1 activation and c-FLIPL degradation. Melanoma-associated PP6 inactivating mutations confer resistance to TNFα-mediated cell death. Co-immunoprecipitation identifying PP6 in complex I; PP6 KO/knockdown; cell death assays; RIPK1 and c-FLIPL ubiquitination assays; expression of melanoma PP6 mutants Cell death & disease Medium 36071040
2022 PPP6C acts as a TAK1 phosphatase to inactivate its kinase activity. Deletion of PPP6C leads to hyperactivation of TAK1 and reduced RIPK1 kinase activity upon TNF stimulation, protecting cells from TNF-induced necroptosis. This was identified in a genome-wide CRISPR/Cas9 screen and validated mechanistically. Genome-wide CRISPR/Cas9 screen; PPP6C KO; TAK1 kinase activity assay; RIPK1 phosphorylation analysis; necroptosis/cell death assays; heterozygous Ppp6c mouse gut model Cell death & disease High 35842423
2022 AMPKγ subunit, when bound to AMP under energy starvation, sequesters PPP6C to block dephosphorylation of eukaryotic translation elongation factor 2 (eEF2), thereby inhibiting translation elongation and preserving energy. PPP6C is identified as an AMPKγ-regulated phosphatase of eEF2; this regulation is independent of AMPKα catalytic activity. AMPKγ and AMPKα knockout; co-immunoprecipitation of AMPKγ with PPP6C; eEF2 phosphorylation analysis; phosphoproteomics under energy starvation; cell survival assays Molecular cell High 36384136
2022 Rab40c (SOCS box protein/Cullin5 E3 ligase) binds the PP6 complex and ubiquitylates ANKRD28 (a PP6 regulatory subunit), leading to its lysosomal degradation and decreased PP6 activity. PP6 activity loss via this mechanism decreases FAK and MOB1 phosphorylation, affecting focal adhesion dynamics in migrating cells. Co-immunoprecipitation; ubiquitylation assay; Rab40c KO cells; focal adhesion quantification; phospho-FAK and phospho-MOB1 western blot; lysosome inhibitor experiments Life science alliance Medium 35512830
2023 PP6 (PPP6C) regulates Aurora A-TPX2-mediated phosphorylation of multiple N-terminal sites on NDC80 at checkpoint-silenced, microtubule-attached kinetochores during spindle formation. NDC80 phosphorylation by Aurora A-TPX2 is Aurora B-independent and persists until spindle disassembly in telophase; it is increased in PPP6C KO cells. An Aurora-phosphorylation-deficient NDC80-9A mutant reduces spindle size and suppresses defective nuclear structure in PPP6C KO cells. Synthetic lethality between PPP6C and NDC80 was identified by functional genomics. PPP6C knockout; phospho-specific antibodies; functional genomics screen; Aurora A-TPX2 in vitro kinase assay; NDC80-9A phospho-dead mutant rescue; spindle size measurement; nuclear structure imaging The Journal of cell biology High 36897279
2024 PPP6C and its regulatory subunits PPP6R1, PPP6R2, and PPP6R3 (with redundant roles) promote TAK1 inhibitor-induced, RIPK1-dependent PANoptosis. PPP6C promotes pro-death S166 auto-phosphorylation of RIPK1 and leads to reduction in pro-survival S321 phosphorylation of RIPK1. Loss of PPP6C significantly reduces PANoptosis. Cell death-based CRISPR screen; PPP6C and PPP6R1/2/3 KO/knockdown; RIPK1 phosphorylation (S166, S321) western blot; cell death assays; TAK1 inhibitor treatment BMC biology High 38807188
2025 PPP6C (with regulatory subunit PPP6R3) dephosphorylates Sec16 at ER exit sites (ERES), counteracting FAM83A/CK1α-mediated phosphorylation of Sec16. Excessive dephosphorylation of Sec16 impairs secretion. A phosphorylation-coupled autoregulatory feedback loop involving FAM83A/CK1α and PP6 maintains balanced Sec16 phosphorylation state essential for proper ERES function and secretory activity. Phosphatase complex identification; phospho-Sec16 analysis; FAM83A/CK1α inhibitor/overexpression; ERES imaging; secretory assay; phospho-mutant rescue bioRxivpreprint Medium bio_10.1101_2025.06.18.660491
2025 PP6 promotes intracellular Salmonella proliferation in macrophages by dephosphorylating Pfkfb1 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 1); Pp6 deficiency elevates Pfkfb1 expression, which restricts bacterial growth by promoting NO production while suppressing Arg-1 expression and arginine metabolism. Yeast two-hybrid identified Pfkfb1 as a PP6 substrate. Fluorescence-dilution reporter in Salmonella-infected macrophages; conditional PP6 KO; yeast two-hybrid screening; Pfkfb1 KO; NO production assay; Arg-1 expression analysis PLoS pathogens Medium 41474810
2025 SMURF2 E3 ubiquitin ligase interacts with PPP6C and promotes its ubiquitination and proteasomal/lysosomal degradation in keratinocytes, downstream of IL-17C signaling, leading to psoriasis-like changes. IL-17C upregulates SMURF2, which targets PPP6C for degradation. Co-immunoprecipitation (SMURF2–PPP6C); ubiquitination assay; SMURF2 knockdown/overexpression; PPP6C overexpression rescue; lentiviral/plasmid transfection; imiquimod mouse psoriasis model Cell biology international Medium 40244332

Source papers

Stage 0 corpus · 55 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 The alpha4 regulatory subunit exerts opposing allosteric effects on protein phosphatases PP6 and PP2A. The Journal of biological chemistry 83 16895907
2014 Protein phosphatases PP2A, PP4 and PP6: mediators and regulators in development and responses to environmental cues. Plant, cell & environment 69 24810976
2017 Assembly of the WHIP-TRIM14-PPP6C Mitochondrial Complex Promotes RIG-I-Mediated Antiviral Signaling. Molecular cell 68 29053956
2003 Parallel purification of three catalytic subunits of the protein serine/threonine phosphatase 2A family (PP2A(C), PP4(C), and PP6(C)) and analysis of the interaction of PP2A(C) with alpha4 protein. Protein expression and purification 60 12963337
2015 Quantitative phosphoproteomics reveals new roles for the protein phosphatase PP6 in mitotic cells. Science signaling 52 26462736
2014 Polo-like kinase 1 (PLK1) and protein phosphatase 6 (PP6) regulate DNA-dependent protein kinase catalytic subunit (DNA-PKcs) phosphorylation in mitosis. Bioscience reports 46 24844881
2011 Protein phosphatase PP6 is required for homology-directed repair of DNA double-strand breaks. Cell cycle (Georgetown, Tex.) 46 21451261
2007 Protein phosphatase PP6 N terminal domain restricts G1 to S phase progression in human cancer cells. Cell cycle (Georgetown, Tex.) 45 17568194
2020 Dephosphorylation of cGAS by PPP6C impairs its substrate binding activity and innate antiviral response. Protein & cell 43 32474700
2016 Leucine Carboxyl Methyltransferase 1 (LCMT-1) Methylates Protein Phosphatase 4 (PP4) and Protein Phosphatase 6 (PP6) and Differentially Regulates the Stable Formation of Different PP4 Holoenzymes. The Journal of biological chemistry 43 27507813
2013 Sit4p/PP6 regulates ER-to-Golgi traffic by controlling the dephosphorylation of COPII coat subunits. Molecular biology of the cell 42 23864707
2003 The role of Ppe1/PP6 phosphatase for equal chromosome segregation in fission yeast kinetochore. The EMBO journal 39 12773390
2018 A PP6-ASK3 Module Coordinates the Bidirectional Cell Volume Regulation under Osmotic Stress. Cell reports 38 29539411
2017 PP6 Disruption Synergizes with Oncogenic Ras to Promote JNK-Dependent Tumor Growth and Invasion. Cell reports 36 28658615
2012 PP6 regulatory subunit R1 is bidentate anchor for targeting protein phosphatase-6 to DNA-dependent protein kinase. The Journal of biological chemistry 35 22298787
2020 PPP6C Negatively Regulates STING-Dependent Innate Immune Responses. mBio 33 32753499
2024 The protein phosphatase PP6 promotes RIPK1-dependent PANoptosis. BMC biology 32 38807188
2022 Circular RNA CUL2 regulates the development of colorectal cancer by modulating apoptosis and autophagy via miR-208a-3p/PPP6C. Aging 31 35027503
2018 Global assessment of its network dynamics reveals that the kinase Plk1 inhibits the phosphatase PP6 to promote Aurora A activity. Science signaling 28 29764989
2021 PPP6C negatively regulates oncogenic ERK signaling through dephosphorylation of MEK. Cell reports 25 33789117
2019 MicroRNA-31 Regulates Immunosuppression in Ang II (Angiotensin II)-induced Hypertension by Targeting Ppp6C (Protein Phosphatase 6c). Hypertension (Dallas, Tex. : 1979) 24 30929511
2021 Regulation of PP2A, PP4, and PP6 holoenzyme assembly by carboxyl-terminal methylation. Scientific reports 22 34845248
2016 The protein phosphatase 6 catalytic subunit (Ppp6c) is indispensable for proper post-implantation embryogenesis. Mechanisms of development 22 26868000
2011 Pp6-FEH1 encodes an enzyme for degradation of highly polymerized levan and is transcriptionally induced by defoliation in timothy (Phleum pratense L.). Journal of experimental botany 21 21317211
2021 MiR-20a-5p functions as a potent tumor suppressor by targeting PPP6C in acute myeloid leukemia. PloS one 19 34587164
2016 Saccharomyces cerevisiae TORC1 Controls Histone Acetylation by Signaling Through the Sit4/PP6 Phosphatase to Regulate Sirtuin Deacetylase Nuclear Accumulation. Genetics 18 27343235
2022 PP6 negatively modulates LUBAC-mediated M1-ubiquitination of RIPK1 and c-FLIPL to promote TNFα-mediated cell death. Cell death & disease 17 36071040
2009 Human protein phosphatase PP6 regulatory subunits provide Sit4-dependent and rapamycin-sensitive sap function in Saccharomyces cerevisiae. PloS one 17 19621075
2023 PP6 regulation of Aurora A-TPX2 limits NDC80 phosphorylation and mitotic spindle size. The Journal of cell biology 16 36897279
2015 PP6 controls T cell development and homeostasis by negatively regulating distal TCR signaling. Journal of immunology (Baltimore, Md. : 1950) 16 25609840
2022 Deficiency of PPP6C protects TNF-induced necroptosis through activation of TAK1. Cell death & disease 15 35842423
2022 Energy sensor AMPK gamma regulates translation via phosphatase PPP6C independent of AMPK alpha. Molecular cell 15 36384136
2013 Protein phosphatase 2A family members (PP2A and PP6) associate with U1 snRNP and the spliceosome during pre-mRNA splicing. Biochemical and biophysical research communications 15 24064353
2022 Rab40c regulates focal adhesions and PP6 activity by controlling ANKRD28 ubiquitylation. Life science alliance 13 35512830
2021 Ppp6c deficiency accelerates K-rasG12D -induced tongue carcinogenesis. Cancer medicine 12 34145991
2022 PPP6C, a serine-threonine phosphatase, regulates melanocyte differentiation and contributes to melanoma tumorigenesis through modulation of MITF activity. Scientific reports 10 35368039
2021 Protein phosphatase 6 (Pp6) is crucial for regulatory T cell function and stability in autoimmunity. Genes & diseases 9 35224167
2014 AEG-1 expression correlates with CD133 and PPP6c levels in human glioma tissues. Journal of biomedical research 9 25332711
2020 Protein kinase CK2 phosphorylation of SAPS3 subunit increases PP6 phosphatase activity with Aurora A kinase. The Biochemical journal 8 31904830
1975 [Isolation and characterization of a 19S-alpha1-glycoprotein from human erythrocytes and its identification as placenta protein PP6]. Blut 7 1125435
2022 PP6 deficiency in mice with KRAS mutation and Trp53 loss promotes early death by PDAC with cachexia-like features. Cancer science 5 35247012
2021 Ppp6c haploinsufficiency accelerates UV-induced BRAF(V600E)-initiated melanomagenesis. Cancer science 5 33743547
2024 M6A-induced transcription factor IRF5 contributes to the progression of cervical cancer by upregulating PPP6C. Clinical and experimental pharmacology & physiology 4 38745265
2015 Adaptation of HepG2 cells to a steady-state reduction in the content of protein phosphatase 6 (PP6) catalytic subunit. Experimental cell research 4 25999147
2025 IL-17C-Mediated Upregulation of SMURF2 Induces Psoriatic Changes in Keratinocytes by Facilitating PPP6C Ubiquitination. Cell biology international 2 40244332
2024 Analysis of goat PPP6C mRNA profile, detection of genetic variations, and their associations with litter size. Animal reproduction science 2 38981196
2017 Unexpected Alliance of WHIP-TRIM14-PPP6C to Combat Viruses. Molecular cell 2 29053952
2025 miR-208a-3p Targets PPP6C to Regulate the Progression of Radiation-Induced Pneumonia. Antioxidants & redox signaling 1 40197027
2025 Pp6-Pfkfb1 axis modulates intracellular bacterial proliferation by orchestrating host-pathogen metabolic crosstalk. PLoS pathogens 1 41474810
2024 Oncogenic K-RasG12V cannot overcome proliferation failure caused by loss of Ppp6c in mouse embryonic fibroblasts. FEBS open bio 1 38318686
2023 Neuron-specific loss of Ppp6c induces neonatal death and decreases the number of cortical neurons and interneurons. Biochemical and biophysical research communications 1 38101002
2025 Functional Role of Protein Phosphatase-6 (PPP6c): Regulation of Expression and Modulation of Activity. Current medicinal chemistry 0 40051355
2025 Hypermethylation of miR-129-2-3p inhibits esophageal cancer proliferation and migration by down-regulating PPP6C expression. American journal of translational research 0 40092081
2025 PP6 phosphatase and Elongator contribute to kinesin 5-dependent spindle assembly by controlling microtubule regulators levels. PLoS genetics 0 41056333
2024 Depletion of Ppp6c in hematopoietic and vascular endothelial cells causes embryonic lethality and decreased hematopoietic potential. Experimental hematology 0 38490577

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