| 2008 |
PP1α (PPP1CA) dephosphorylates phospho-Thr186 in the Cdk9 T-loop, thereby releasing P-TEFb from the inactive 7SK snRNP complex. This occurs downstream of Ca2+/PP2B signaling: PP2B first induces a conformational change in 7SK snRNP that enables PP1α access, and PP1α then dephosphorylates Cdk9 Thr186. The released, dephosphorylated P-TEFb is subsequently recruited by Brd4 to the preinitiation complex. |
Co-immunoprecipitation, in vitro phosphatase assays, siRNA knockdown, UV/HMBA stimulation of P-TEFb release |
Genes & development |
High |
18483222
|
| 1999 |
PP1α (PPP1CA) is phosphorylated at Thr-320 by Cdk2 (but not Cdk4) during M-phase and again at the G1/S transition in a pRB-dependent manner. PP1α phosphorylated at Thr-320 co-precipitates with pRB during G1/S but is found in pRB-immunodepleted extracts in M-phase, indicating distinct subpopulations of PP1α regulate different cell cycle transitions. Expression of a T320A phosphorylation-resistant PP1α mutant in pRB-expressing cells causes G1 arrest. |
In vitro kinase assay with Cdk2/Cdk4, phospho-specific antibodies, co-immunoprecipitation with pRB, inhibitor treatments (Cdk2 inhibitor), cell cycle synchronization |
The Journal of biological chemistry |
High |
10506210
|
| 2006 |
PP1α (PPP1CA) associates with caspase-9 in vitro and in vivo in IL-2-proliferating cells. IL-2 deprivation induces PP1α dephosphorylation and activation, leading to dephosphorylation of phospho-Thr125 on caspase-9, thereby activating caspase-9 and subsequent caspase-3 cleavage. PP1α is indispensable for triggering caspase-9 in cell-free systems. Two novel PP1α-binding sites on caspase-9 distinct from the canonical RVxF motif were identified. |
Co-immunoprecipitation in vivo and in vitro, cell-free caspase activation assays, siRNA knockdown of PP1α, IL-2 deprivation model |
Journal of immunology |
High |
16888006
|
| 2010 |
PINCH1 directly binds PP1α and inhibits its phosphatase activity, resulting in increased Akt1 phosphorylation and enhanced cell survival/radioresistance. PP1α acts as an Akt1-dephosphorylating phosphatase that is negatively regulated by PINCH1 at integrin adhesion sites. |
Direct binding assay (PINCH1-PP1α interaction), PP1α activity assays, Akt1 phosphorylation measurements, siRNA knockdown, in vitro and in vivo irradiation survival assays |
The Journal of clinical investigation |
High |
20530873
|
| 2014 |
PP1A (PPP1CA) dephosphorylates TAZ during canonical Wnt3a signaling. Wnt3a-induced dephosphorylation of TAZ by PP1A prevents TAZ from binding 14-3-3 proteins, stabilizes TAZ, and induces its nuclear localization, thereby promoting osteoblastic differentiation. Depletion of PP1A blocks Wnt3a-induced TAZ stabilization. |
siRNA knockdown of PP1A, western blotting for TAZ phosphorylation, co-immunoprecipitation with 14-3-3, nuclear fractionation, osteogenic differentiation assays |
Cell death and differentiation |
High |
24510127
|
| 2011 |
PP1A (PPP1CA) interacts with and dephosphorylates YAP2 at Serine-127 in vitro and in vivo. PP1A-mediated YAP2 dephosphorylation induces nuclear accumulation and transcriptional activation of YAP2. Inhibition of PP1 by okadaic acid increases YAP2 phospho-Ser127 and promotes its cytoplasmic retention. |
Co-immunoprecipitation, in vitro dephosphorylation assay, subcellular fractionation, okadaic acid treatment, YAP2 transcriptional reporter assays, siRNA knockdown |
PloS one |
High |
21909427
|
| 2008 |
PPP1CA (PP1α) contributes to oncogenic Ras-induced senescence. Loss of PPP1CA function (via antisense RNA or shRNA) bypasses ras/p53-induced growth arrest and senescence. PPP1CA is required for p53-dependent induction of p21 after DNA damage and subsequent pRb dephosphorylation. Oncogenic Ras increases intracellular ceramide levels and PPP1CA protein levels; ceramide-induced senescence is blocked by PPP1CA downregulation. |
Retroviral genetic screen, shRNA knockdown of PPP1CA, western blotting for p21 and pRb phosphorylation, ceramide addition experiments, tumor growth assays |
Carcinogenesis |
High |
18204081
|
| 2018 |
PP1α (PPP1CA) acts as a B-Raf activating phosphatase in an S6K/PP1α/B-Raf signaling pathway that leads to MAPK activation. PML sequesters PP1α into PML nuclear bodies, repressing S6K-dependent PP1α phosphorylation, 14-3-3 binding, and cytoplasmic accumulation. PPP1CA gene is genomically amplified in metastatic prostate cancer. |
Co-immunoprecipitation, subcellular fractionation, in vitro phosphatase assays, genomic amplification analysis, PML knockdown/overexpression, B-Raf activity assays |
Nature communications |
High |
29335436
|
| 2019 |
USP11 stabilizes PPP1CA by deubiquitinating it, protecting PPP1CA from proteasome-mediated degradation. The USP11/PPP1CA complex activates the ERK/MAPK signaling pathway to promote colorectal cancer progression. |
LC-MS/MS interactome, co-immunoprecipitation, ubiquitination assays, proteasome inhibitor treatment, siRNA/overexpression experiments, in vitro and in vivo tumor assays |
EBioMedicine |
Medium |
31521612
|
| 2019 |
Cavin-3, upon UV-induced release from caveolae, interacts with and inhibits PP1α. This interaction increases H2AX phosphorylation to stimulate apoptosis, defining a pro-apoptotic signaling pathway from surface caveolae to the nucleus. |
Biotin affinity proteomics, mass spectrometry, cell-free protein binding assays, co-immunoprecipitation, UV stress experiments, H2AX phosphorylation measurement |
Nature communications |
High |
31332168
|
| 2021 |
PP1A (PPP1CA) dephosphorylates SRSF1, and reduced PP1α activity enhances SRSF1 phosphorylation and nucleus translocation, causing a switch in MKNK2 alternative splicing from MKNK2a to MKNK2b in colon adenocarcinoma. PP1α and SRPK1/2 exert opposing functions balancing SRSF1 phosphorylation and localization. |
Western blotting, immunohistochemistry, PP1α activity assays, siRNA knockdown, alternative splicing analysis by PCR, xenograft models |
Journal of experimental & clinical cancer research |
Medium |
33602301
|
| 2021 |
The Smad4-MYO18A-PP1A complex dephosphorylates PAK1 at Thr-423. MYO18A functions as the PP1-interacting protein (regulatory subunit) for PP1A substrate recognition in cholangiocarcinoma, binding PP1A via its RVFFR motif and Smad4 via its CC domain. PP1A-mediated PAK1-T423 dephosphorylation inhibits β-catenin-S675 phosphorylation and its nuclear translocation. |
LC-MS/MS, co-immunoprecipitation, biochemical complex reconstitution, site-directed mutagenesis (RVFFR motif), phosphorylation assays for PAK1 and β-catenin, in vitro and in vivo functional assays |
Cell death and differentiation |
High |
34799729
|
| 2023 |
CARM1 methylates PPP1CA at Arg-23 (R23). This arginine methylation affects PPP1CA-mediated dephosphorylation of AKT-T450 and AMPK-T172, and increases activities of phosphofructokinase-1 and PFKFB3, upregulating glycolytic flux. This mechanism promotes osteogenic differentiation and inhibits osteoclastic differentiation. |
In vitro methylation assays (identifying R23 as methylation site), CRISPR/Cas9 knockout, lentiviral overexpression, transcriptomic and metabolomic assays, western blotting for AKT and AMPK phosphorylation |
Clinical and translational medicine |
Medium |
37649137
|
| 2023 |
SUV39H2 methyltransferase monomethylates PPP1CA at Lys-141 (K141). K141 methylation disrupts PPP1CA's interaction with TFEB and blocks TFEB dephosphorylation and nuclear translocation, leading to autophagy deficiency and nucleus pulposus cell senescence. PPP1R9B (spinophilin) facilitates PPP1CA-TFEB targeting, and K141 methylation also impairs PPP1R9B binding to PPP1CA. |
Proteomic analysis (identifying SUV39H2 as writer), in vitro methylation assays, co-immunoprecipitation, western blotting for TFEB phosphorylation and localization, CRISPR/KO and overexpression, autophagy assays, animal models of IDD |
Cell death and differentiation |
High |
37605006
|
| 2023 |
PP1A (PPP1CA/Ppp1Ca) directly binds to and dephosphorylates the NaCl cotransporter (NCC) in the kidney in a potassium-regulated manner, reducing blood pressure. Dietary potassium upregulates Ppp1Ca expression and suppresses its negative regulator Ppp1r1a (I1), shifting the balance toward PP1A-mediated NCC dephosphorylation. Confirmed using genetically engineered mice with constitutively active SPAK kinase. |
Transcriptomics screen, direct binding assay (PP1A-NCC), in vivo dephosphorylation experiments in SPAK-constitutively active transgenic mice, high-potassium dietary intervention, blood pressure measurements |
The Journal of clinical investigation |
High |
37676724
|
| 2008 |
Drosophila URI binds PP1alpha with much higher affinity than PP1beta, and this isoform-discriminating ability is conserved in humans. URI loss-of-function in Drosophila causes transcriptional defects, reduced cell viability, germline differentiation defects, and nuclear DNA damage accumulation. |
Binding affinity measurements (Drosophila and human URI vs PP1alpha/PP1beta), generation of uri loss-of-function allele, viability assays, transcriptional analysis, DNA damage markers |
BMC molecular biology |
Medium |
18412953
|
| 2017 |
PP1α activity is regulated by oxidative stress via formation of transient intramolecular disulfide bonds (involving Cys39 and Cys127), which protect the enzyme from irreversible over-oxidation. Glutathione (GSH) mediates this protection mechanism, reducing PP1α activity under redox stress. The dimerization of PP1α via these cysteines protects the active surface. |
Mass spectrometry with cross-over-read search for disulfide-linked species, in vitro PP1α activity assays under oxidative conditions, site-specific cysteine analysis |
Scientific reports |
Medium |
30531830
|
| 2013 |
PP1α (PPP1CA), PP1β, and Wip1 phosphatases regulate histone H4 Ser47 phosphorylation (H4S47ph) levels and H3.3 deposition. Depletion of each phosphatase increases H4S47ph. PP1α and PP1β bind H3-H4 in vitro and in vivo and also interact with the Pak2 kinase in vivo, suggesting regulation at the level of both the substrate H4S47 and the kinase Pak2. Depletion of these phosphatases increases H3.3 occupancy and chaperone (HIRA/Daxx) association. |
siRNA knockdown of PP1α, PP1β, and Wip1; co-immunoprecipitation for H3-H4 and Pak2 binding; ChIP for H3.3 occupancy; western blotting for H4S47ph levels |
Nucleic acids research |
Medium |
23828041
|
| 2017 |
The GADD34/PP1α complex dephosphorylates both eIF2α (phosphoserine-51) and SIRT1 (phosphoserine-47) in response to arsenite-induced oxidative stress. A GADD34 mutant unable to bind PP1α fails to restore eIF2α or SIRT1 dephosphorylation in GADD34-/- MEFs. SIRT1 dephosphorylation by the GADD34/PP1α complex increases SIRT1 deacetylase activity, affecting cell fate after oxidative stress. |
Mass spectrometry of GADD34 acetylation, co-immunoprecipitation of GADD34/PP1α/eIF2α/SIRT1 complex, rescue experiments in GADD34-/- MEFs with WT vs PP1α-binding-deficient GADD34 mutant, in vitro and in-cell SIRT1 deacetylase activity assays |
Cell death and differentiation |
High |
28984870
|
| 2005 |
PP1 inhibitor-3 (Inh3) co-localizes with PP1alpha at centrosomes (and with PP1gamma1 at nucleoli) in interphase HEK 293 cells. Inh3 co-immunoprecipitates with PP1alpha and PP1gamma1 but not PP1beta in vitro, demonstrating isoform-specific interactions. The nuclear localization signal and nucleolar targeting signals of Inh3 were mapped by site-directed mutagenesis. |
Immunofluorescence co-localization, co-immunoprecipitation, site-directed mutagenesis of nuclear/nucleolar localization signals, laser scanning cytometry |
Archives of biochemistry and biophysics |
Medium |
16256067
|
| 2014 |
14-3-3ζ binds PP1α within residues 159–279 in a phosphorylation-independent manner. 14-3-3ζ does not affect PP1α catalytic activity in vitro, but causes cytoplasmic retention of PP1α: cells expressing both PP1α and 14-3-3ζ have a significantly higher cytoplasmic/nuclear PP1α ratio. Expression of dominant-negative 14-3-3ζ (K49E) causes nuclear accumulation of PP1α. |
Co-immunoprecipitation from HEK-293 lysates, GST pulldown, PP1α deletion mutant mapping, in vitro phosphatase activity assay, subcellular fractionation, dominant-negative 14-3-3ζ expression |
Archives of biochemistry and biophysics |
Medium |
24956593
|
| 2015 |
HSV-1 γ34.5 protein targets PP1α to reverse translational arrest (dephosphorylation of eIF2α) during viral infection. HSV-1 carrying a PP1α-binding mutation in γ34.5 shows complete absence of disseminated disease in neonatal mice and increased survival in brain infection models. PP1α targeting by HSV-1 is required for later stages of disseminated infection but not for early replication in visceral organs. |
Murine neonatal infection model, HSV-1 PP1α-binding mutant virus, type I IFN-deficient mouse rescue experiments, brain slice culture pharmacologic inhibition of eIF2α dephosphorylation |
Proceedings of the National Academy of Sciences of the United States of America |
High |
26621722
|
| 2019 |
PP1A (PPP1CA) directly dephosphorylates NACA (nascent polypeptide-associated complex and co-regulator α) at Thr-89, Ser-151, and Thr-174. NACA interacts with the PPP1CA catalytic subunit and regulatory subunits PPP1R9B, PPP1R12A, and PPP1R18. NACA dephosphorylation promotes nuclear localization of NACA, recruitment of BTF3/BTF3L4, and cooperatively potentiates cJUN/AP-1 transcriptional activity and osteoblast differentiation. |
Affinity purification-MS (identifying PP1A holoenzyme components), co-immunoprecipitation in HEK293T and MC3T3-E1 cells, phosphosite MS analysis, phosphomimetic and alanine substitution mutants, AP-1 reporter assays, osteogenic differentiation assays |
The Journal of biological chemistry |
High |
30948508
|
| 2011 |
Taperin (C9orf75) preferentially docks the alpha isoform of PP1 over PP1beta via a classic RVxF motif, suppresses the general phosphatase activity of PP1α, and is found complexed to PP1α in both nuclear and cytoplasmic compartments. Taperin shuttles between nucleus and cytoplasm and is recruited to sites of DNA damage, interacting with Ku70, Ku80, PARP and topoisomerases. |
Biochemical binding assays, co-immunoprecipitation, SILAC MS for interactors, PP1 isoform specificity assays, subcellular fractionation, DNA damage recruitment assays |
Biology open |
Medium |
23213405
|
| 2016 |
PP1α is a negative regulator of TRPV1 (transient receptor potential vanilloid 1) channel activity. HSV-based coexpression of PP1α rescued viral replication suppressed by TRPV1 in a cell-based screen. In vivo, HSV vectors expressing PP1α reduced thermal sensitivity in rat footpads, demonstrating functional specificity for thermal but not chemical pain modalities. |
HSV-based cDNA library screen for TRPV1 negative regulators, viral rescue of replication, in vivo rat thermal sensitivity assays |
Molecular therapy. Methods & clinical development |
Medium |
27382601
|
| 2021 |
LACTB directly binds PP1A and attenuates the interaction between PP1A and YAP, reducing YAP dephosphorylation and increasing phospho-YAP (Ser127), which prevents YAP nuclear translocation in a LATS1-independent manner. This constitutes an SOX10/LACTB/PP1A signaling cascade controlling melanoma progression. |
Co-immunoprecipitation (LACTB-PP1A and PP1A-YAP interactions), western blotting for YAP phosphorylation, subcellular fractionation, siRNA/overexpression, in vivo xenograft experiments |
Cancer letters |
Medium |
33675985
|
| 2021 |
SNORD12B interacts with PP1α, disrupts the interaction between 14-3-3ζ and PP1α, and causes PP1α to relocalize from the cytosol to the nucleus. Nuclear sequestration of PP1α leads to enhanced cytosolic AKT phosphorylation and activation of AKT-mTOR-4EBP1 signaling in esophageal squamous cell carcinoma. |
Co-immunoprecipitation (SNORD12B-PP1α and 14-3-3ζ-PP1α interactions), subcellular fractionation, western blotting for AKT phosphorylation, RNA interference and overexpression, in vivo tumor models |
Oncogene |
Medium |
33941854
|
| 2024 |
The peptide PDHK1-241aa (encoded by circPDHK1) interacts with PPP1CA and causes its relocation to the nucleus. This nuclear relocation of PPP1CA inhibits AKT dephosphorylation and activates the AKT-mTOR signaling pathway to promote clear cell renal cell carcinoma progression. |
Immunoprecipitation-mass spectrometry (identifying PPP1CA as PDHK1-241aa interactor), co-immunoprecipitation, immunofluorescence, subcellular fractionation, AKT phosphorylation western blot, functional assays in ccRCC cells and nude mice |
Molecular cancer |
Medium |
38360682
|
| 2019 |
MIIP interacts with PP1α via its C-terminal domain but does not affect PP1α protein level. MIIP interaction with PP1α enhances PP1α-mediated AKT dephosphorylation. Silencing PP1α reverses MIIP's inhibitory effect on AKT phosphorylation and cell growth; MIIPC lacking the PP1α-interacting C-terminus loses MIIP's tumor-suppressive function. |
Co-immunoprecipitation, immunofluorescence co-localization, western blotting for AKT phosphorylation, siRNA knockdown of PP1α, MIIP deletion mutants (MIIP∆C), xenograft assays |
Cell communication and signaling |
Medium |
31092266
|
| 1997 |
PP1α is phosphorylated by PKC at Ser-325 (in its C-terminal region) in response to B-cell receptor (IgM) stimulation. PP1 activity transiently decreases after B-cell stimulation. PP1alpha undergoes isoform-specific modification (altered isoelectric point pattern on 2D gels) upon BCR stimulation or PMA treatment, while PP1delta does not. The C-terminal peptide of PP1alpha is a better PKC substrate than PP1gamma1/2. |
2D electrophoresis + western blot, in vitro phosphorylation of C-terminal peptides by PKC with [gamma-32P]ATP, PP1 activity assays, B-cell stimulation model |
Journal of biochemistry |
Medium |
9399575
|
| 2024 |
In Zika virus infection, NS2B acts as a scaffold protein mediating interaction between PP1α and eIF2α. This NS2B-PP1α complex promotes eIF2α dephosphorylation by PP1α, inhibiting stress granule formation and promoting viral replication. The NS2B-PP1α complex is stabilized against ubiquitin-induced degradation. The NS2BV35A mutant interacts only with eIF2α and fails to inhibit stress granule formation. |
Co-immunoprecipitation of NS2B-PP1α-eIF2α complex, eIF2α dephosphorylation assays, stress granule formation assays, NS2BV35A mutagenesis, ubiquitination resistance assay, viral replication assays, brain organoid experiments |
PLoS pathogens |
High |
38935808
|
| 2025 |
NY-ESO-1 acts as a scaffold protein recruiting the deubiquitinase OTUB1 to PP1α, forming a ternary NY-ESO-1/OTUB1/PP1α complex. OTUB1 deubiquitinase activity (not its E2-suppressing function) prevents PP1α polyubiquitination and promotes its stability. Accumulated PP1α then activates ERK1/2 signaling to promote anoikis resistance and tumor metastasis. |
Co-immunoprecipitation of ternary complex, ubiquitination assays, OTUB1 deubiquitinase activity assay, PP1α knockdown rescue experiments, ERK1/2 activity measurements, in vivo metastasis assays |
Cell death & disease |
Medium |
41053024
|
| 2025 |
PP1A dephosphorylates Keap1 at site Ser104 (site 104), disrupting the Keap1-Nrf2 interaction, enhancing transcription of ferroptosis-related markers and immune checkpoint PD-L1, thereby inhibiting Lenvatinib-induced ferroptosis in hepatocellular carcinoma. |
Transcriptomic analysis, ferroptosis metabolite profiling (ROS, Fe2+, lipid-ROS, GSH), PP1A knockdown, western blotting for Keap1-Nrf2 interaction, PD-L1 expression, single-cell sequencing, co-culture T-cell exhaustion assays, in vivo tumor models |
Advanced science |
Medium |
40344394
|
| 2025 |
PP1α selectively removes activation-loop phosphorylation from AMPK (dephosphorylating the activation-loop sites) while autophosphorylation sites remain protected, establishing asymmetric phosphatase control of AMPK regulatory states. |
Phosphatase competition assay (PP1A treatment of phosphorylated AMPK), integrated bottom-up and top-down mass spectrometry for site-specific kinetics, proteoform characterization |
bioRxivpreprint |
Medium |
bio_10.1101_2025.10.10.681638
|