Affinage

PPP1CC

Serine/threonine-protein phosphatase PP1-gamma catalytic subunit · UniProt P36873

Length
323 aa
Mass
37.0 kDa
Annotated
2026-04-28
62 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPP1CC encodes the catalytic subunit PP1γ of protein phosphatase 1, a serine/threonine phosphatase that assembles with a broad repertoire of regulatory subunits to dephosphorylate substrates in diverse cellular processes including TGF-β signaling, RAS-MAPK pathway activation, cell cycle progression, innate immunity, meiotic cohesin removal, Hippo/YAP signaling, and synaptic transmission (PMID:14718519, PMID:35831509, PMID:27760328, PMID:34862394, PMID:36276179, PMID:40626009). Substrate specificity is conferred by regulatory/scaffolding partners—such as SHOC2–MRAS for RAF dephosphorylation, Repo-Man for chromatin dephosphorylation, GADD34–Smad7 for TβRI, PPP1R3G for RIPK1, and iASPP for p53—that direct PP1γ to distinct subcellular compartments and substrates, with structural studies revealing how RVXF and SILK motifs mediate holoenzyme assembly (PMID:35831509, PMID:36175670, PMID:31402222, PMID:32938714, PMID:34862394). PP1γ dynamically relocalizes during mitosis from nucleoli to kinetochores, chromosomes, the cleavage furrow, and midbody, and its recruitment to chromatin is antagonized by Aurora B phosphorylation of Repo-Man (PMID:12529430, PMID:32938714). The alternatively spliced testis-enriched isoform PP1γ2 is essential for spermatid chromatin condensation, acrosome development, and sperm tail morphogenesis, and germ-cell-specific deletion causes male infertility (PMID:17301292, PMID:24089200, PMID:20385779).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1993 High

    Establishing that PPP1CC encodes two alternatively spliced catalytic isoforms (PP1γ1 and PP1γ2) on chromosome 12q24 resolved the gene's identity as distinct from PP1α and set the stage for isoform-specific functional studies.

    Evidence cDNA cloning, somatic cell hybrid analysis, and FISH mapping

    PMID:8394140

    Open questions at the time
    • No functional characterization of either isoform at this stage
    • Tissue-specific expression patterns not yet defined
  2. 1997 High

    Demonstration that both PP1γ1 and PP1γ2 retain phosphatase activity by complementing a fission yeast PP1 mutant confirmed that alternative splicing does not ablate catalytic function, validating both isoforms as active enzymes.

    Evidence Complementation of S. pombe dis2-11 cold-sensitive mutant

    PMID:9339378

    Open questions at the time
    • Mammalian substrate specificity of each isoform unknown
    • Whether isoforms have non-redundant roles in vivo untested
  3. 2003 High

    Live imaging revealed that PP1γ dynamically relocalizes throughout the mammalian cell cycle—from nucleoli in interphase to kinetochores, chromosome arms, cleavage furrow, and midbody during mitosis—establishing that its function is spatiotemporally regulated rather than constitutive.

    Evidence Stable HeLa lines expressing FP-PP1γ, time-lapse microscopy and FRAP

    PMID:12529430

    Open questions at the time
    • Targeting subunits responsible for each localization not identified
    • Whether relocalization is essential for mitotic fidelity not tested
  4. 2004 High

    Identification of the GADD34–Smad7 adaptor complex recruiting PP1γ to dephosphorylate TβRI provided the first concrete substrate-targeting mechanism for PP1γ in a major signaling pathway (TGF-β negative feedback).

    Evidence Co-immunoprecipitation, RNAi of Smad7, phosphorylation assays in cells

    PMID:14718519

    Open questions at the time
    • Whether PP1α or PP1β can substitute in this complex not fully resolved
    • In vivo relevance in TGF-β-dependent tissues not tested
  5. 2007 High

    Studies in Ppp1cc knockout mice established an essential, non-redundant role for PP1γ2 in spermiogenesis: loss causes malformed mitochondrial sheaths, extra outer dense fibers, and chromatin condensation defects, directly linking the testis-enriched isoform to male fertility.

    Evidence Ppp1cc knockout mice, electron microscopy, isoform-specific antibodies; conditional Stra8-Cre deletion later confirmed germ-cell autonomy

    PMID:17301292 PMID:20385779 PMID:24089200

    Open questions at the time
    • Specific spermatid substrates of PP1γ2 not identified
    • Mechanism linking PP1γ2 to chromatin condensation versus structural assembly unclear
  6. 2007 High

    Discovery that URI sequesters PP1γ at mitochondria and that S6K1-mediated phosphorylation of URI releases active PP1γ to dephosphorylate BAD revealed a growth-factor-controlled apoptotic threshold mechanism operating through PP1γ.

    Evidence Co-immunoprecipitation, mitochondrial fractionation, in vitro kinase assay, rapamycin treatment

    PMID:17936702

    Open questions at the time
    • Full spectrum of mitochondrial PP1γ substrates beyond BAD unknown
    • Whether URI-PP1γ regulation operates in non-transformed cells not established
  7. 2009 High

    Transgenic rescue experiments showed that PP1γ2 alone restores spermatid viability but not sperm morphogenesis or motility, demonstrating that PP1γ1 has non-redundant roles in spermatogenesis beyond the anti-apoptotic function of PP1γ2.

    Evidence PP1γ2 transgene expressed in Ppp1cc-null testes; histology, motility, and fertility analysis

    PMID:19420386

    Open questions at the time
    • PP1γ1-specific substrates in spermatogenesis not identified
    • Structural basis of isoform-specific function unknown
  8. 2011 High

    The finding that PP1γ opposes Nek2A kinase within a Nek2A–PP1γ–Mst2 centrosomal complex, regulated by Plk1 phosphorylation of Mst2, established PP1γ as a direct regulator of centrosome disjunction timing.

    Evidence Co-immunoprecipitation, centrosome disjunction assays, Plk1 inhibition

    PMID:21723128

    Open questions at the time
    • Whether PP1α/β contribute to this complex not fully excluded
    • Downstream centrosomal substrates beyond linker proteins not mapped
  9. 2012 High

    PP1γ was shown to interact with Gemin8 and regulate SMN complex phosphorylation and Cajal body localization, revealing a role in snRNP biogenesis beyond its known cell-cycle functions.

    Evidence Direct binding assay, Co-IP, RNAi of PP1γ, 2D gel electrophoresis of SMN phospho-isoforms

    PMID:22454514

    Open questions at the time
    • Specific SMN phosphosites targeted by PP1γ not mapped
    • Functional consequence for snRNP assembly efficiency not quantified
  10. 2013 High

    Identification of hScrib as a scaffold that recruits PP1γ to suppress ERK phosphorylation and oncogenic transformation connected PP1γ to RAS-MAPK tumor suppression upstream of the later-characterized SHOC2 complex.

    Evidence Proteomic pulldown, direct binding assay, ERK phosphorylation and transformation assays

    PMID:23359326

    Open questions at the time
    • Direct ERK dephosphorylation by PP1γ versus indirect mechanism not resolved
    • Relationship to SHOC2-mediated RAF dephosphorylation not clarified
  11. 2016 High

    The NEK1–PP1γ–WAPL axis was identified as a regulator of meiotic cohesin removal: NEK1 phosphorylates PP1γ, which in turn dephosphorylates WAPL to control cohesin dynamics on prophase I chromosomes.

    Evidence Co-immunoprecipitation, phosphorylation assays, Nek1 knockout mouse meiotic spreads

    PMID:27760328

    Open questions at the time
    • Whether PP1γ acts on WAPL directly or through PDS5B not fully resolved
    • Redundancy with PP2A-dependent cohesin regulation not addressed
  12. 2019 High

    The crystal structure of the iASPP–PP1γ complex revealed how SILK, RVxF, and SH3 domain interactions create a modular, dynamically flexible holoenzyme that enhances PP1γ catalytic activity toward p53, providing the first atomic-resolution view of regulatory subunit–PP1γ assembly.

    Evidence X-ray crystallography, SAXS, in vitro phosphatase assays with p53 and pNPP

    PMID:31402222

    Open questions at the time
    • How iASPP directs PP1γ selectivity for p53 over other substrates in cells not determined
    • In vivo relevance for p53-dependent tumor suppression not tested
  13. 2020 High

    Aurora B was shown to phosphorylate Repo-Man to release PP1γ from mitotic chromosomes, explaining how the kinase–phosphatase balance on chromatin is maintained during chromosome condensation and segregation.

    Evidence Co-IP, Aurora B inhibition, phosphomimetic Repo-Man mutants, chromosome condensation assays

    PMID:32938714

    Open questions at the time
    • Full set of chromatin substrates dephosphorylated by Repo-Man–PP1γ not catalogued
    • Whether other PP1 isoforms contribute to this axis unclear
  14. 2021 High

    A genome-wide CRISPR screen identified PPP1R3G as the regulatory subunit that recruits PP1γ to dephosphorylate RIPK1-pSer25 in complex I, activating RIPK1-dependent cell death—connecting PP1γ to innate immune signaling and TNF-induced necroptosis.

    Evidence CRISPR KO screen, Co-IP, PP1γ-binding-deficient mutant, Ppp1r3g knockout mice with TNF-induced SIRS

    PMID:34862394

    Open questions at the time
    • Whether PP1γ dephosphorylates other RIPK1 inhibitory sites beyond Ser25 not tested
    • Cell-type specificity of PPP1R3G–PP1γ complex unclear
  15. 2022 High

    Cryo-EM and crystal structures of the SHOC2–MRAS–PP1C ternary holophosphatase from three independent groups revealed how a leucine-rich-repeat scaffold bridges PP1γ to GTP-loaded RAS to dephosphorylate inhibitory RAF-pSer259, and how RASopathy/cancer mutations at subunit interfaces hyperactivate this complex.

    Evidence Cryo-EM and X-ray crystallography, deep mutational scanning, reconstituted RAF dephosphorylation assays, biophysical binding measurements

    PMID:35830882 PMID:35831509 PMID:36175670

    Open questions at the time
    • Whether the complex dephosphorylates RAF substrates beyond Ser259 not resolved
    • Therapeutic targeting of SHOC2–PP1γ interface not yet validated in animal models
  16. 2022 High

    PP1γ was shown to constitutively associate with HDAC1 and dephosphorylate CREB-pSer133 in dopaminergic neurons, with enhanced CREB–HDAC1/PP1γ complex formation during neurodegeneration contributing to CREB inactivation and neuronal loss.

    Evidence Co-IP, proximity ligation assay in human PD brain, MPTP mouse model, CREB mutant rescue

    PMID:35501151

    Open questions at the time
    • Whether PP1γ or HDAC1 is rate-limiting for CREB dephosphorylation in vivo not determined
    • Broader neuronal substrate spectrum of HDAC1–PP1γ complex unknown
  17. 2025 Medium

    Multiple studies extended PP1γ's substrate repertoire to YAP1 dephosphorylation in trophectoderm specification and esophageal cancer, MLC20 regulation via CEMIP sequestration controlling vascular smooth muscle contractility, JNK-dependent cell competition, and KAP1 dephosphorylation in DNA damage repair, broadening its roles to developmental biology, vascular tone, tumor suppression, and genome integrity.

    Evidence Blastocyst immunofluorescence and GAS5 knockdown; BRET and CEMIP-RVxF mutagenesis with SMC-specific KO mice; Drosophila genetic screen with human cell validation; Co-IP and ubiquitination/radioresistance assays

    PMID:39297166 PMID:40590126 PMID:40626009 PMID:40906558 PMID:41403070

    Open questions at the time
    • Direct phosphatase assay for PP1γ on YAP1 not yet shown in reconstituted system
    • CEMIP–PP1γ interaction specificity versus other PP1 isoforms not tested
    • JNK pathway regulation by PP1γ in human tissues beyond liver cancer not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Despite extensive cataloguing of PP1γ holoenzymes, major gaps remain: a systematic map of isoform-specific substrates distinguishing PP1γ from PP1α/PP1β is lacking, the structural basis for PP1γ2's unique spermatogenic functions is undefined, and whether the numerous regulatory subunit–PP1γ complexes are pharmacologically targetable has not been established.
  • No comprehensive phosphoproteomics comparing PP1γ-specific versus shared PP1 substrates
  • No structural model of PP1γ2 C-terminal domain with testis-specific interactors
  • Therapeutic targeting of specific PP1γ holoenzymes not demonstrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 15 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 3 GO:0005694 chromosome 2 GO:0005730 nucleolus 1 GO:0005739 mitochondrion 1 GO:0005815 microtubule organizing center 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 10 R-HSA-1474165 Reproduction 4 R-HSA-112316 Neuronal System 3 R-HSA-1640170 Cell Cycle 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-168256 Immune System 2 R-HSA-1266738 Developmental Biology 1 R-HSA-73894 DNA Repair 1
Partners
CDCA2GEMIN8HDAC1MRASPPP1R15APPP1R3GSHOC2URI1
Complex memberships
GADD34-Smad7-PP1γRepo-Man-PP1γSHOC2-MRAS-PP1C holophosphataseURI-PP1γ

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 PP1γ (PPP1CC) dynamically relocalizes throughout the mammalian cell cycle: it accumulates in the nucleolus during interphase, localizes to kinetochores at mitotic entry (exchanging rapidly with the cytoplasmic pool), relocalizes to chromosome-containing regions at the early-to-late anaphase transition, and accumulates at the cleavage furrow and midbody by telophase, implicating it in nucleolar function, chromosome segregation, and cytokinesis. Stable HeLa cell lines expressing FP-PP1γ; time-lapse fluorescence microscopy and FRAP Molecular biology of the cell High 12529430
2004 Smad7 acts as an adaptor protein that recruits the GADD34-PP1c (PP1γ) holoenzyme to the TGFβ type I receptor (TβRI), leading to dephosphorylation of TβRI and negative feedback in TGFβ signaling. SARA enhances PP1c recruitment to the Smad7-GADD34 complex by controlling PP1c subcellular localization. Co-immunoprecipitation, RNA interference knockdown of Smad7, cell-based phosphorylation assays The Journal of cell biology High 14718519
2007 URI forms stable complexes with PP1γ at mitochondria in growth factor-deprived cells, inhibiting PP1γ activity. S6K1-mediated phosphorylation of URI at Ser371 upon growth factor stimulation disassembles the URI/PP1γ complex, activating a PP1γ-dependent negative feedback that decreases S6K1 activity and BAD phosphorylation to regulate the apoptotic threshold. Co-immunoprecipitation, in vitro kinase assay, phospho-specific antibodies, rapamycin treatment, mitochondrial fractionation Molecular cell High 17936702
2007 PP1γ2 (encoded by Ppp1cc) is expressed in secondary spermatocytes, round and elongating spermatids, and mature spermatozoa. Targeted disruption of Ppp1cc causes malformed mitochondrial sheaths and extra outer dense fibers in sperm tails, indicating a role for PP1γ2 in sperm tail morphogenesis beyond motility regulation. Ppp1cc knockout mice, immunohistochemistry, electron microscopy, isoform-specific antibodies Biology of reproduction High 17301292
2007 PP1γ2 specifically interacts with endophilin B1t (a testis-specific isoform of endophilin B1) via the unique C-terminal region of PP1γ2, and endophilin B1t inhibits PP1γ2 phosphatase activity toward phosphorylase a. Somatic endophilin B1a does not interact with any PP1 isoform, and PP1α does not interact with endophilin B1t, demonstrating isoform specificity. Yeast two-hybrid, co-immunoprecipitation, sedimentation assay, phosphatase activity assay with recombinant proteins Biochemistry High 17381077
2009 Transgenic expression of PPP1CC2 in Ppp1cc-null mouse testes rescues spermatid viability and spermiation (anti-apoptotic effect) but does not restore normal sperm flagellar morphogenesis, motility, or fertility, indicating that PPP1CC1 is additionally required for normal spermatogenesis. Transgenic rescue experiment in Ppp1cc-/- mice; histology, motility analysis, fertility testing Biology of reproduction High 19420386
2010 Loss of PPP1CC in mice causes chromatin condensation defects and acrosome development abnormalities in spermatids, with germ cell loss concentrated at stages VII-VIII of spermatogenesis and reduced spermatogonial numbers; junctional complexes remain ultrastructurally normal. Light and electron microscopy of Ppp1cc knockout mouse testes Reproduction (Cambridge, England) Medium 20385779
2011 PP1γ counteracts Nek2A kinase activity in a Nek2A-PP1γ-Mst2 complex at centrosomes. Plk1 phosphorylation of Mst2 prevents PP1γ binding to the Mst2-Nek2A complex, allowing Nek2A activity to drive centrosome disjunction; absence of Plk1 phosphorylation promotes assembly of Nek2A-PP1γ-Mst2 complexes that suppress centrosome separation. Co-immunoprecipitation, centrosome disjunction assays, kinase assays, Plk1 inhibition Current biology : CB High 21723128
2012 PP1γ directly interacts with the SMN complex component Gemin8, and this interaction regulates SMN complex formation and localization to Cajal bodies. PP1γ depletion by RNAi leads to SMN hyperphosphorylation and enhanced SMN complex/snRNP localization to Cajal bodies; PP1γ expression restores normal SMN phosphorylation isoforms. Co-immunoprecipitation, in vitro protein binding assay, RNAi knockdown, 2D protein gel electrophoresis, immunofluorescence Journal of cell science High 22454514
2013 hScrib directly interacts with PP1γ through a conserved PP1γ-interaction motif on hScrib, recruits PP1γ to downregulate ERK phosphorylation, controls the subcellular distribution of PP1γ (loss of hScrib enhances nuclear PP1γ translocation), and this hScrib-PP1γ interaction is required for hScrib's tumor-suppressor activity against oncogene-induced transformation. Proteomic pulldown, direct binding assay, co-immunoprecipitation, ERK phosphorylation assays, oncogenic transformation assay PloS one High 23359326
2013 PP1γ, but not PP1α or PP1β, promotes alternative splicing of CaMKIIδ through direct interaction with the splicing factor ASF. PP1γ overexpression or inhibition respectively enhances or suppresses CaMKIIδ splicing and ASF-PP1γ association, and PP1γ exacerbates OGD/R-triggered cardiomyocyte apoptosis through CaMKII activation. Co-immunoprecipitation, splicing assay, PP1γ overexpression/inhibition, cardiomyocyte apoptosis assay American journal of physiology. Cell physiology Medium 24196533
2013 Conditional germ cell-specific deletion of Ppp1cc using Stra8-Cre causes oligo-terato-asthenozoospermia and male infertility, phenocopying global Ppp1cc null mice. PPP1CC2 is the only PP1 isoform expressed in postmeiotic germ cells, and its absence in meiotic and postmeiotic cells underlies spermatogenic defects. Conditional knockout mice (Stra8-Cre), immunohistochemistry, sperm analysis Biology of reproduction High 24089200
2014 Hipk2 facilitates PP1c-mediated dephosphorylation of Dishevelled (Dvl) via its C-terminal domain, preventing ubiquitination and Itch-mediated degradation of Dvl. This Hipk2-PP1c-Dvl axis maintains sufficient Dvl protein levels for Wnt/β-catenin and Wnt/PCP signaling. Wnt-3a under high cell density induces dissociation of the Dvl-Hipk2-PP1c complex as a negative feedback mechanism. Co-immunoprecipitation, ubiquitination assay, PP1c inhibition, zebrafish embryo epistasis, Wnt reporter assays Cell reports High 25159144
2014 PP1γ physically interacts with the E3 ubiquitin ligase TRAF6 and enhances TRAF6 auto-ubiquitination and ubiquitination of IKKγ, promoting NF-κB-mediated innate immune signaling; enzymatically inactive PP1γ represses these events. Gain-of-function genetic screen, co-immunoprecipitation, ubiquitination assay, NF-κB reporter assay, macrophage pathogen challenge PloS one Medium 24586659
2016 NEK1 phosphorylates PP1γ, and PP1γ dephosphorylates WAPL; the NEK1-PP1γ-WAPL axis regulates cohesin removal from chromosome arms during meiotic prophase I via interaction with PDS5B. NEK1 loss causes retention of cohesin on chromosomes at meiotic prophase I. Co-immunoprecipitation, phosphorylation assays, mouse genetics (Nek1 knockout), immunofluorescence on meiotic chromosomes Cell reports High 27760328
2016 TIMAP phosphorylation at Ser331 by PKCα inhibits PP1c activity within the TIMAP-PP1c complex toward phospho-ERM substrates, reducing dephosphorylation of ERM and thereby modulating endothelial barrier function. PKCα was shown to interact with TIMAP and phosphorylate it at Ser331 in vitro and in endothelial cells. In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, electric resistance measurement of endothelial barrier, membrane fractionation Biochimica et biophysica acta. Molecular cell research High 27939168
2019 iASPP (and ASPP2) interact with PP1c via SILK and RVxF motifs on iASPP plus interactions of the PP1c PxxPxR motif with the iASPP SH3 domain. This interaction enhances PP1c catalytic activity toward pNPP and the substrate p53; the modular interface provides dynamic flexibility for dephosphorylation of diverse substrates including p53. Crystal structure of iASPP-PP1c complex, small-angle X-ray scattering, in vitro phosphatase activity assay with p53 and pNPP substrates Structure (London, England : 1993) High 31402222
2020 Aurora B regulates PP1γ-Repo-Man interactions on mitotic chromosomes: PP1γ is recruited to chromosomes by Repo-Man when Aurora B is inactive; Aurora B phosphorylates Repo-Man to disrupt PP1γ-Repo-Man interactions, releasing PP1γ from chromatin to maintain chromosome phosphorylation and condensation. Immunofluorescence, co-immunoprecipitation, Aurora B inhibition, phosphomimetic/phosphonull Repo-Man mutants, ectopic PP1γ targeting The Journal of biological chemistry High 32938714
2021 PPP1R3G recruits its catalytic subunit PP1γ to complex I to dephosphorylate inhibitory phosphorylations on RIPK1 (including Ser25), activating RIPK1 kinase activity and enabling RIPK1-dependent apoptosis and necroptosis. A PPP1R3G mutant that cannot bind PP1γ fails to rescue RIPK1 activation and cell death. CRISPR whole-genome knockout screen, co-immunoprecipitation, PP1γ-binding mutant, phospho-RIPK1 analysis, Ppp1r3g-/- mice with TNF-induced SIRS Nature communications High 34862394
2022 HDAC1 constitutively associates with PP1γ and promotes dephosphorylation of CREB at Ser133; during dopaminergic neurodegeneration CREB interacts with the HDAC1/PP1γ complex leading to CREB inactivation. Disrupting CREB/HDAC1 interaction restores p-CREB (Ser133) and NURR1 levels and protects nigral dopaminergic neurons in MPTP-treated mice. Co-immunoprecipitation, proximity ligation assay in human PD brain tissue, MPTP mouse model, overexpression of CREB mutant, TSA treatment The Journal of neuroscience High 35501151
2022 The SHOC2-MRAS-PP1C ternary holophosphatase complex dephosphorylates RAF at an inhibitory phosphoserine to potentiate MAPK signaling. Cryo-EM structure reveals SHOC2 binds PP1C and MRAS through the concave leucine-rich repeat surface and via an N-terminal cryptic RVXF motif; complex formation is initiated by SHOC2-PP1C interaction and stabilized by GTP-loaded MRAS. RASopathy/cancer mutations in SHOC2 stabilize complex interactions to enhance holophosphatase activity. Cryo-electron microscopy structure, deep mutational scanning of SHOC2, biophysical binding assays, RAF dephosphorylation assay Nature High 35831509
2022 Crystal structure of the SHOC2-MRAS-PP1C complex reveals all three proteins synergistically interact; SHOC2 acts as a scaffolding protein bridging PP1C and MRAS. Dephosphorylation of RAF by PP1C is enhanced upon interaction with SHOC2 and MRAS. Complex formation requires MRAS in its GTP-bound active state and is further stabilized by SHOC2. RASopathy mutations reside at protein-protein interfaces and enhance complex formation and activity. X-ray crystallography, apo-SHOC2 structure, in vitro RAF dephosphorylation assay, biophysical characterization of complex assembly Nature structural & molecular biology High 36175670
2022 X-ray crystal structure of MRAS-SHOC2-PP1C complex shows SHOC2 bridges PP1C and MRAS through its concave surface with reciprocal interactions among all three subunits. GTP-bound MRAS drives cooperative assembly. Rasopathy and cancer mutations at protein-protein interfaces enhance affinities and function. MRAS can be substituted by canonical RAS isoforms. X-ray crystallography, biophysical characterization (SPR/ITC), in vitro RAF dephosphorylation assay Nature High 35830882
2022 I-2 (inhibitor-2) and PP1γ, but not PP1α, positively regulate synaptic transmission in hippocampal neurons. I-2 enhances PP1γ interaction with its synaptic scaffold neurabin (demonstrated by FRET/FLIM), and this positive regulatory effect depends on I-2 Thr72 phosphorylation. Hippocampal neuron electrophysiology, FRET/FLIM imaging, co-immunoprecipitation, Thr72 phosphorylation analysis Frontiers in synaptic neuroscience Medium 36276179
2023 PP1γ (but not PP1α) dephosphorylates AKT2 and regulates neuronal insulin signaling via the AKT2-AS160-GLUT4 axis, and separately regulates GSK3β via AKT2 and GSK3α via MLK3. Imbalance in PP1γ-dependent phosphatase activity promotes an Alzheimer's disease-like phenotype in neuronal cells. siRNA knockdown of PP1α vs PP1γ, western blot of AKT isoforms/AS160/GSK3 isoforms, GLUT4 translocation by confocal microscopy, fluorescence-based glucose uptake assay, high-fat-diet mouse model Cell communication and signaling : CCS Medium 37085815
2004 CaMKII bound to sarcoplasmic reticulum (SR) phosphorylates GM (glycogen- and PP1c-targeting subunit) at Ser48, and PP1c dephosphorylates GM; the GM-GS-PP1c complex selectively localizes to nonjunctional SR, and CaMKII-mediated phosphorylation of GM regulates glycogen synthase activity through this complex. Recombinant fragment pulldown, site-directed mutagenesis, in vitro kinase assay, co-immunoprecipitation, immunofluorescence co-localization The Journal of biological chemistry High 15591318
2025 PPP1CC exhibits uniform distribution before blastocyst formation but becomes localized specifically to the trophectoderm (TE) during blastocyst stage via interaction with lncRNA GAS5. PPP1CC-mediated YAP dephosphorylation in outer cells promotes YAP nuclear translocation and TE lineage specification. Knockdown of GAS5 phenocopies PPP1CC deficiency (developmental arrest at morula with impaired YAP dephosphorylation). Immunofluorescence, knockdown experiments, YAP dephosphorylation assay, GAS5 overexpression in single blastomere of 2-cell stage embryo Cell proliferation Medium 41403070
2025 PPP1CC (PP1γ) dephosphorylates YAP1, and silencing of PPP1CC increases p-YAP1 levels, inhibits YAP1 activity, and reduces SOX2 expression in esophageal squamous cell carcinoma cells, suppressing proliferation, migration, and invasion. PPP1CC siRNA knockdown, western blot (YAP1, p-YAP1, SOX2), CCK-8 proliferation assay, Transwell invasion/migration assay Frontiers in oncology Medium 40626009
2025 CEMIP interacts directly with PP1c (PPP1CC) via three RVxF motifs and sequesters MLC20 from PP1c without affecting MLCK. Mutations in CEMIP RVxF motifs restore PP1c-MLC20 interaction. CEMIP-deficient smooth muscle cells show reduced MLC20 phosphorylation and reduced contractility; SMC-specific Cemip knockout mice have reduced blood pressure. Co-immunoprecipitation, molecular docking, bioluminescence resonance energy transfer (BRET), RVxF motif mutagenesis, SMC-specific conditional knockout mice, ex vivo contractility Circulation research High 40590126
2025 Drosophila Pp1-87B (ortholog of PPP1CC) is an essential regulator of JNK signaling in tumor-suppressive cell competition; its loss activates JNK via the Moe-Rho1 axis, integrating apoptosis and ferroptosis-like cell death through Hippo signaling. The human ortholog PPP1CC functions similarly to drive apoptosis and ferroptosis in human liver tumor cells through JNK activation. Drosophila genetic screen, epistasis analysis, human liver cancer cell experiments, cell death assays Cell reports Medium 40906558
1993 Human PPP1CC encodes two alternatively spliced isoforms, PP1γ1 and PP1γ2, differing only at their C-termini. Both isoforms are ~94% identical to PP1α but are encoded by a distinct gene mapped to chromosome 12q24.1-q24.2, separate from the PP1α gene on chromosome 11. cDNA cloning, somatic cell hybrid analysis, in situ hybridization (FISH), sequence analysis Biochimica et biophysica acta High 8394140
1997 Both PP1γ1 and PP1γ2 isoforms encoded by Ppp1cc retain phosphatase function, as they complement the cold-sensitive PP1 defect in Schizosaccharomyces pombe dis2-11 mutants. The two isoforms arise from alternative splicing with retention of the last intron for PP1γ2. Yeast complementation assay (dis2-11 fission yeast), genomic organization analysis, FISH mapping Genomics High 9339378
2024 gp78 promotes ubiquitination-dependent degradation of PPP1CC (and PPP2CA), leading to elevated KAP1 phosphorylation and enhanced DNA damage repair and radioresistance in breast cancer cells. PPP1CC is a crucial regulator of KAP1 dephosphorylation in response to ionizing radiation. Co-immunoprecipitation, ubiquitination assay, western blot for p-KAP1, radioresistance assays iScience Medium 39297166

Source papers

Stage 0 corpus · 62 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor. The Journal of cell biology 208 14718519
2003 Time-lapse imaging reveals dynamic relocalization of PP1gamma throughout the mammalian cell cycle. Molecular biology of the cell 125 12529430
2016 A Phytophthora infestans RXLR effector targets plant PP1c isoforms that promote late blight disease. Nature communications 113 26822079
2011 Plk1 controls the Nek2A-PP1γ antagonism in centrosome disjunction. Current biology : CB 112 21723128
2007 S6K1-mediated disassembly of mitochondrial URI/PP1gamma complexes activates a negative feedback program that counters S6K1 survival signaling. Molecular cell 96 17936702
1993 Sequence of human protein serine/threonine phosphatase 1 gamma and localization of the gene (PPP1CC) encoding it to chromosome bands 12q24.1-q24.2. Biochimica et biophysica acta 64 8394140
2022 Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex. Nature 62 35831509
2007 Analysis of Ppp1cc-null mice suggests a role for PP1gamma2 in sperm morphogenesis. Biology of reproduction 54 17301292
2022 Structure of the SHOC2-MRAS-PP1C complex provides insights into RAF activation and Noonan syndrome. Nature structural & molecular biology 40 36175670
2022 Structure of the MRAS-SHOC2-PP1C phosphatase complex. Nature 38 35830882
2013 Selective ablation of Ppp1cc gene in testicular germ cells causes oligo-teratozoospermia and infertility in mice. Biology of reproduction 36 24089200
2021 RIPK1 dephosphorylation and kinase activation by PPP1R3G/PP1γ promote apoptosis and necroptosis. Nature communications 31 34862394
2016 Cohesin Removal along the Chromosome Arms during the First Meiotic Division Depends on a NEK1-PP1γ-WAPL Axis in the Mouse. Cell reports 29 27760328
2021 Circular RNA PPP1CC promotes Porphyromonas gingivalis-lipopolysaccharide-induced pyroptosis of vascular smooth muscle cells by activating the HMGB1/TLR9/AIM2 pathway. The Journal of international medical research 28 33769113
1999 Microcystin affinity purification of plant protein phosphatases: PP1C, PP5 and a regulatory A-subunit of PP2A. FEBS letters 27 10471836
2022 CREB Inactivation by HDAC1/PP1γ Contributes to Dopaminergic Neurodegeneration in Parkinson's Disease. The Journal of neuroscience : the official journal of the Society for Neuroscience 23 35501151
2019 Flexible Tethering of ASPP Proteins Facilitates PP-1c Catalysis. Structure (London, England : 1993) 23 31402222
2013 A novel interaction between hScrib and PP1γ downregulates ERK signaling and suppresses oncogene-induced cell transformation. PloS one 23 23359326
2012 A protein phosphatase 1 gamma (PP1γ) of the human protozoan parasite Trichomonas vaginalis is involved in proliferation and cell attachment to the host cell. International journal for parasitology 23 22713760
2014 Hipk2 and PP1c cooperate to maintain Dvl protein levels required for Wnt signal transduction. Cell reports 22 25159144
2012 A role for protein phosphatase PP1γ in SMN complex formation and subnuclear localization to Cajal bodies. Journal of cell science 22 22454514
2007 A testis specific isoform of endophilin B1, endophilin B1t, interacts specifically with protein phosphatase-1c gamma2 in mouse testis and is abnormally expressed in PP1c gamma null mice. Biochemistry 21 17381077
2014 The effect of hypoxia preconditioning on DNA methyltransferase and PP1γ in hippocampus of hypoxia preconditioned mice. High altitude medicine & biology 19 25531462
2010 Loss of protein phosphatase 1c{gamma} (PPP1CC) leads to impaired spermatogenesis associated with defects in chromatin condensation and acrosome development: an ultrastructural analysis. Reproduction (Cambridge, England) 19 20385779
1997 Genomic organization and functional analysis of the murine protein phosphatase 1c gamma (Ppp1cc) gene. Genomics 19 9339378
2018 Guanabenz inhibits TLR9 signaling through a pathway that is independent of eIF2α dephosphorylation by the GADD34/PP1c complex. Science signaling 18 29363586
2004 Glycogen- and PP1c-targeting subunit GM is phosphorylated at Ser48 by sarcoplasmic reticulum-bound Ca2+-calmodulin protein kinase in rabbit fast twitch skeletal muscle. The Journal of biological chemistry 18 15591318
2018 α7nAChR-mediated recruitment of PP1γ promotes TRAF6/NF-κB cascade to facilitate the progression of Hepatocellular Carcinoma. Molecular carcinogenesis 17 30074282
2016 PKC mediated phosphorylation of TIMAP regulates PP1c activity and endothelial barrier function. Biochimica et biophysica acta. Molecular cell research 16 27939168
2016 Effects of 5-Aza-2'-deoxycytidine on expression of PP1γ in learning and memory. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 15 27665473
2021 The role of LR-TIMAP/PP1c complex in the occurrence and development of no-reflow. EBioMedicine 14 33639401
2014 Positive regulation of TRAF6-dependent innate immune responses by protein phosphatase PP1-γ. PloS one 14 24586659
2013 PP1γ functionally augments the alternative splicing of CaMKIIδ through interaction with ASF. American journal of physiology. Cell physiology 14 24196533
2009 Expression of transgenic PPP1CC2 in the testis of Ppp1cc-null mice rescues spermatid viability and spermiation but does not restore normal sperm tail ultrastructure, sperm motility, or fertility. Biology of reproduction 13 19420386
2020 PP1C and PP2A are p70S6K Phosphatases Whose Inhibition Ameliorates HLD12-Associated Inhibition of Oligodendroglial Cell Morphological Differentiation. Biomedicines 11 32316234
2011 Identification and prioritization of NUAK1 and PPP1CC as positional candidate loci for skeletal muscle strength phenotypes. Physiological genomics 11 21750233
2018 The dominant protein phosphatase PP1c isoform in smooth muscle cells, PP1cβ, is essential for smooth muscle contraction. The Journal of biological chemistry 9 30185619
2017 PPP1CC is associated with astrocyte and microglia proliferation after traumatic spinal cord injury in rats. Pathology, research and practice 9 29033188
2016 An Ultra-High-Throughput Screen for Catalytic Inhibitors of Serine/Threonine Protein Phosphatases Types 1 and 5 (PP1C and PP5C). SLAS discovery : advancing life sciences R & D 8 27628691
2008 Molecular modeling of human BAD and its interaction with PKAc or PP1c. Journal of theoretical biology 8 19103207
2015 Micro(mi) RNA-34a targets protein phosphatase (PP)1γ to regulate DNA damage tolerance. Cell cycle (Georgetown, Tex.) 7 26111201
2023 Structural insights into the role of SHOC2-MRAS-PP1C complex in RAF activation. The FEBS journal 6 37074066
2020 Aurora B regulates PP1γ-Repo-Man interactions to maintain the chromosome condensation state. The Journal of biological chemistry 6 32938714
2023 PP1γ regulates neuronal insulin signaling and aggravates insulin resistance leading to AD-like phenotypes. Cell communication and signaling : CCS 5 37085815
2021 miR-140-5p Aggravates Insulin Resistance via Directly Targeting GYS1 and PPP1CC in Insulin-Resistant HepG2 Cells. Diabetes, metabolic syndrome and obesity : targets and therapy 5 34113143
2001 Biochemical characterization of recombinant Drosophila type 1 serine/threonine protein phosphatase (PP1c) produced in Pichia pastoris. Archives of biochemistry and biophysics 5 11747299
2000 Mutation of the toxin binding site of PP-1c: comparison with PP-2B. Biochemical and biophysical research communications 5 10753661
2024 gp78-regulated KAP1 phosphorylation induces radioresistance in breast cancer by facilitating PPP1CC/PPP2CA ubiquitination. iScience 4 39297166
2022 Protein phosphatase-1 inhibitor-2 promotes PP1γ positive regulation of synaptic transmission. Frontiers in synaptic neuroscience 4 36276179
2024 CAVPENET Peptide Inhibits Prostate Cancer Cells Proliferation and Migration through PP1γ-Dependent Inhibition of AKT Signaling. Pharmaceutics 3 39339236
2022 Mapping PP1c and Its Inhibitor 2 Interactomes Reveals Conserved and Specific Networks in Asexual and Sexual Stages of Plasmodium. International journal of molecular sciences 3 35162991
2024 Target silencing of porcine SPAG6 and PPP1CC by shRNA attenuated sperm motility. Theriogenology 2 38430798
2023 Identification of PP1c-PPP1R12A Substrates Using Kinase-Catalyzed Biotinylation to Identify Phosphatase Substrates. ACS omega 2 37810667
2013 PP-1α and PP-1γ display antagonism and differential roles in tumorigenicity of lung cancer cells. Current molecular medicine 2 23176181
1996 Assignment of the gene encoding type 1 gamma protein phosphatase catalytic subunit (PPP1CC) on human, rat, and mouse chromosomes. The Japanese journal of human genetics 2 8914631
2025 PP1γ promotes esophageal squamous cell carcinoma progression through the PP1γ/YAP1/SOX2 axis. Frontiers in oncology 1 40626009
2025 Pp1-87B/PPP1CC-JNK axis integrates apoptosis and ferroptosis-like cell death to regulate cell competition and tumorigenesis. Cell reports 1 40906558
2016 STIP Regulates ERK1/2 Signaling Pathway Involved in Interaction with PP1γ in Lymphoblastic Leukemia. Current molecular medicine 1 27758712
2026 Multiple Roles of Protamine Kinase SRPK1 and Phosphatase PP1γ in Sperm Development. Proteomics 0 41913519
2026 Asiaticoside Alleviates Alzheimer's Disease by Regulating PPP1CC Expression to Suppress Inflammation and Mitochondrial Dysfunction. Annals of clinical and laboratory science 0 41927108
2025 CEMIP Maintains Vascular Contractility by Controlling PP1c-MLC20 Cascade in SMCs. Circulation research 0 40590126
2025 Phosphatase PPP1CC Regulates the First Lineage Segregation by GAS5 in Mouse Preimplantation Embryos. Cell proliferation 0 41403070