Affinage

PPM1A

Protein phosphatase 1A · UniProt P35813

Length
382 aa
Mass
42.4 kDa
Annotated
2026-06-10
77 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPM1A (PP2Cα) is a metal-dependent serine/threonine phosphatase that functions as a broad negative regulator of phosphorylation-driven signaling cascades, terminating responses initiated by TGF-β/BMP, Hippo, NF-κB, and innate antiviral pathways (PMID:16751101, PMID:33630828, PMID:18930133, PMID:27419230). Its best-defined role is to dephosphorylate the C-terminal pSXS motif of TGF-β-activated Smad2/3 and BMP-activated Smad1, driving their nuclear export and shutting down the corresponding transcriptional programs (PMID:16751101, PMID:16931515); it reinforces TGF-β termination by also dephosphorylating the nuclear export factor RanBP3 at Ser58 (PMID:21960005). Genetic epistasis in mice places PPM1A directly upstream of Smad2 in cutaneous wound re-epithelialization and upstream of SMAD2 in cartilage homeostasis, where loss of PPM1A sustains pSmad2/3 (PMID:21990361, PMID:36752205). The same active site terminates additional pathways: it dephosphorylates YAP/TAZ at the LATS1 site (YAP Ser127) to restrain Hippo-controlled proliferation and tissue regeneration (PMID:33630828), IKKβ (Ser177/Ser181) and RelA (Ser536/Ser276) to attenuate NF-κB signaling (PMID:18930133, PMID:23812431), the Cdk9 T-loop (Thr186) to limit P-TEFb activity (PMID:18829461), MAVS, STING and TBK1 to silence cytosolic and DNA antiviral sensing (PMID:27419230, PMID:25815785), and PPARγ at Ser273 in metabolic regulation (PMID:32024237). Substrate engagement in cells requires N-myristoylation, which directs membrane association and physiological substrate recognition (PMID:23088624); catalysis proceeds through a three-metal active site engaging the substrate phosphate, with active-site arginines Arg33 and Arg186 contributing to substrate recognition in a random-order bi-substrate mechanism (PMID:29602904, PMID:34637963). Substrate access is gated by cofactor and scaffold interactions—PTEN, the inner nuclear membrane protein MAN1, NDRG2, and the CSIG/NMT1 myristoylation machinery (PMID:18482992, PMID:23779087, PMID:36179025, PMID:30201805)—and PPM1A abundance is set by ubiquitin-mediated proteasomal degradation through multiple TRIM-family E3 ligases (TRIM52, TRIM59, TRIM47) opposed by the deubiquitinase USP33, a balance frequently subverted in fibrosis and cancer to amplify TGF-β signaling (PMID:29898761, PMID:32348176, PMID:39160244, PMID:30308513).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2006 High

    Establishing that a specific phosphatase terminates TGF-β/BMP signaling answered how activated R-Smads are inactivated, identifying PPM1A as the Smad C-terminal phosphatase.

    Evidence Functional genomic screen, in vitro phosphatase assays, RNAi/overexpression, and zebrafish Nodal epistasis for Smad2/3, with reciprocal Co-IP for Smad1/BMP

    PMID:16751101 PMID:16931515

    Open questions at the time
    • Did not define how PPM1A is recruited to nuclear Smads
    • Did not address regulation of PPM1A activity or abundance
  2. 2008 High

    Identifying PPM1A as a phosphatase for IKKβ and the Cdk9 T-loop extended its role beyond TGF-β, showing it attenuates NF-κB and transcriptional elongation machinery.

    Evidence Phosphatase library screens, reciprocal Co-IP, in vitro dephosphorylation with phospho-specific readouts, and RNAi with reporter assays

    PMID:18829461 PMID:18930133

    Open questions at the time
    • Did not establish in vivo physiological relevance of these dephosphorylation events
    • Did not clarify how substrate selectivity among many targets is achieved
  3. 2008 Medium

    Showing that nuclear PTEN forms a complex with PPM1A revealed that cofactor binding can both protect PPM1A from degradation and enhance its Smad-directed activity.

    Evidence Co-IP, phospho-mutant analysis, and fractionation in mammalian cells

    PMID:18482992

    Open questions at the time
    • Co-IP/overexpression-based; structural basis of the complex not defined
    • Generality beyond Smad2/3 substrates not tested
  4. 2011 High

    Demonstrating that N-myristoylation is required for activity toward physiological substrates explained why an in vitro-competent phosphatase needs lipid modification for cellular function.

    Evidence G2A mutagenesis, cell fractionation, and in vitro/cellular phosphatase assays including AMPKα

    PMID:23088624

    Open questions at the time
    • Did not identify the enzymes setting myristoylation in vivo
    • Did not map which substrates strictly require membrane targeting
  5. 2011 High

    Adding RanBP3 dephosphorylation and genetic null MEFs strengthened the model that PPM1A controls Smad nuclear export, while in vivo knockout linked PPM1A loss to enhanced Smad2/3 phosphorylation and a wound-healing phenotype.

    Evidence In vitro phosphatase assay, PPM1A-null MEFs, nuclear export assays, and Ppm1a/Smad2 double-mutant epistasis in mice

    PMID:21960005 PMID:21990361

    Open questions at the time
    • Did not resolve relative contributions of direct Smad versus RanBP3 dephosphorylation
    • Tissue-specific substrate repertoire beyond keratinocytes unexamined
  6. 2013 Medium

    Direct dephosphorylation of RelA and recruitment by the inner nuclear membrane protein MAN1 extended PPM1A's NF-κB role and showed scaffold-directed delivery to nuclear-envelope Smads.

    Evidence In vitro phosphatase assays with site-specific RelA readout; NMR/SAXS structure and in vitro binding for MAN1 recruitment

    PMID:23779087 PMID:23812431

    Open questions at the time
    • MAN1-dependent recruitment not validated in a genetic in vivo model
    • Whether RelA and Smad dephosphorylation occur at distinct subcellular sites unresolved
  7. 2015 High

    Identifying STING, TBK1, MAVS, and IKKε as substrates established PPM1A as a brake on innate antiviral signaling, with whole-organism knockouts confirming enhanced antiviral resistance.

    Evidence In vitro phosphatase assays, Co-IP, STING aggregation assays, PPM1A knockout cells/mice, and viral infection models

    PMID:25815785 PMID:27419230

    Open questions at the time
    • Mechanism dissociating the TBK1/PPM1A complex at high MAVS levels only partly defined
    • Crosstalk between antiviral and TGF-β substrate pools not addressed
  8. 2018 High

    The crystal structure of PPM1Acat with a cyclic phosphopeptide defined the catalytic chemistry, revealing a three-metal active site and a substrate-engaging labile third metal.

    Evidence X-ray crystallography of an enzyme-substrate complex, enzyme kinetics, SAXS, docking, and D146E trapping mutant

    PMID:29602904

    Open questions at the time
    • Structure used a model p38 activation-loop peptide rather than a physiological substrate complex
    • Did not explain selectivity across the diverse substrate set
  9. 2018 Medium

    Discovering that TRIM52 ubiquitinates PPM1A, that CSIG promotes NMT1-dependent myristoylation, and that HCV NS3 drives PPM1A degradation showed that PPM1A levels and modification state are actively controlled to set TGF-β pathway output.

    Evidence Co-IP, ubiquitination assays, myristoylation assays, and overexpression/RNAi with functional readouts in HCC and signaling models

    PMID:27121309 PMID:28283039 PMID:29898761 PMID:30201805

    Open questions at the time
    • Largely single-lab Co-IP/ubiquitination evidence per regulator
    • Substrate specificity of each degradation event not dissected beyond Smad signaling
  10. 2021 High

    Defining active-site arginines and identifying PPM1A as the physiological YAP/TAZ phosphatase clarified both the catalytic determinants and a new tissue-regeneration role through the Hippo pathway.

    Evidence Site-directed mutagenesis with docking; phosphatome screen, in vitro phosphatase assay, Co-IP, PPM1A KO mice/organoids, and LATS1-deficiency epistasis rescue

    PMID:33630828 PMID:34637963

    Open questions at the time
    • How a single active site discriminates YAP versus Smad versus NF-κB substrates remains unresolved
    • Arg-residue study relied partly on computational docking
  11. 2024 Medium

    Mapping additional E3 ligases and deubiquitinases (TRIM47, TRIM59, USP33) and identifying small-molecule activators/inhibitors consolidated PPM1A abundance control as a druggable node in fibrosis and cancer.

    Evidence Co-IP, ubiquitination assays, PPM1A-specific knockdown rescue in vivo, and enzymatic activation assays (otilonium bromide; SMIP-30)

    PMID:30308513 PMID:32348176 PMID:35320734 PMID:39160244

    Open questions at the time
    • Pharmacological tools characterized in single-lab settings
    • Selectivity of activators/inhibitors across PPM1A substrate pathways not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single shallow PP2C active site achieves selectivity across its many substrates, and how the competing scaffolds, cofactors, and degradation machinery are integrated to direct PPM1A toward a specific pathway in a given cell, remains unresolved.
  • No structure of PPM1A bound to a physiological full-length substrate
  • No systematic comparison of substrate flux under competing cofactor conditions
  • Spatial partitioning of distinct substrate pools not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0098772 molecular function regulator activity 4 GO:0016787 hydrolase activity 2
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 2 GO:0005635 nuclear envelope 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 3 R-HSA-9612973 Autophagy 1
Partners
IKBKBMAN1PTENRANBP3SMAD1SMAD2SMAD3YAP1

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 PPM1A (PP2Cα) directly dephosphorylates the C-terminal pSXS motif of TGF-β-activated Smad2 and Smad3, promoting their nuclear export and terminating TGF-β transcriptional responses. Ectopic expression abolishes TGF-β-induced antiproliferative and transcriptional responses; depletion enhances TGF-β signaling. Functional genomic screen, in vitro phosphatase assay, overexpression/RNAi in mammalian cells, zebrafish Nodal signaling epistasis Cell High 16751101
2006 PPM1A physically interacts with and dephosphorylates Smad1 (BMP-activated R-Smad) both in vitro and in vivo, terminating BMP signaling. Overexpression abolishes BMP-induced transcriptional responses; RNAi knockdown enhances BMP signaling. Co-immunoprecipitation, in vitro phosphatase assay, overexpression and RNAi in mammalian cells The Journal of biological chemistry High 16931515
2008 PPM1A (and PPM1B) act as IKKβ phosphatases, dephosphorylating IKKβ at Ser177 and Ser181 to terminate TNFα-induced NF-κB activation. PPM1A associates with the phosphorylated form of IKKβ in a TNFα-induced, transient manner; knockdown of PPM1A enhances IKKβ phosphorylation, NF-κB nuclear translocation, and NF-κB-dependent gene expression. Functional genomic screen, overexpression, Co-immunoprecipitation, RNAi knockdown, NF-κB reporter assay Cellular signalling High 18930133
2008 PPM1A dephosphorylates Thr-186 in the T-loop of Cdk9 (the catalytic subunit of P-TEFb), negatively regulating P-TEFb kinase activity. PPM1A co-immunoprecipitates with Cdk9 in vivo; in vitro, purified PPM1A dephosphorylates Thr-186 in the presence or absence of 7SK RNA. Phosphatase expression library screen, co-immunoprecipitation, in vitro phosphatase assay, shRNA knockdown, phospho-specific antiserum The Journal of biological chemistry High 18829461
2008 Nuclear PTEN acts as a co-factor of PPM1A by forming a complex with it (requiring phosphorylation of PTEN's C-terminal serine/threonine residues but not PTEN's lipid phosphatase activity). Complex formation protects PPM1A from TGF-β-induced degradation and enhances Smad2/3 dephosphorylation. dhS1P stimulates this pathway through PTEN nuclear translocation. Co-immunoprecipitation, overexpression, phospho-mutant analysis, fractionation The Journal of biological chemistry Medium 18482992
2011 PPM1A directly interacts with and dephosphorylates the nuclear export factor RanBP3 at Ser58 in vitro and in vivo, promoting RanBP3-mediated nuclear export of Smad2/3 and efficient termination of TGF-β signaling. RanBP3 phosphorylation is elevated in PPM1A-null mouse embryonic fibroblasts. In vitro phosphatase assay, co-immunoprecipitation, RNAi, PPM1A-null MEFs, nuclear export assays EMBO reports High 21960005
2011 PPM1A and PPM1B are N-myristoylated, and this modification is essential for their ability to dephosphorylate physiological substrates (including AMPKα) in cells. A non-myristoylated G2A mutant prevents membrane association and shows reduced activity toward AMPKα in cells and in vitro, despite higher activity toward the artificial substrate PNPP. Mutagenesis (G2A), in vitro phosphatase assay, cell fractionation, AMPKα dephosphorylation assay The Biochemical journal High 23088624
2011 PPM1A knockout or keratinocyte-specific deletion in mice causes delayed re-epithelialization during cutaneous wound healing due to enhanced Smad2/3 phosphorylation in keratinocytes. Genetic rescue by Smad2 deficiency in PPM1A/Smad2 double-mutant mice restores normal re-epithelialization, placing PPM1A upstream of Smad2 in this pathway. Ppm1a knockout mice, keratinocyte-specific conditional knockout, Smad2/PPM1A double-mutant epistasis, wound healing assay The Journal of biological chemistry High 21990361
2013 PPM1A directly dephosphorylates RelA (NF-κB subunit) at Ser536 and Ser276, selectively inhibiting NF-κB transcriptional activity and reducing expression of MCP-1/CCL2 and IL-6. PPM1A depletion enhances NF-κB-dependent cell invasion. In vitro phosphatase assay, overexpression, RNAi, NF-κB reporter assay, invasion assay Oncogene Medium 23812431
2013 MAN1 (inner nuclear membrane protein) directly binds PPM1A in vitro and recruits it to Smad2/3 at the nuclear envelope, facilitating Smad dephosphorylation and inhibition of TGF-β signaling. MAN1 overexpression promotes Smad2/3 dephosphorylation in a PPM1A-dependent manner. NMR structure, SAXS, in vitro binding assay (pulldown), in vitro dephosphorylation, cell-based overexpression Science signaling High 23779087
2015 PPM1A negatively regulates antiviral DNA sensing by dephosphorylating both STING and TBK1 in vitro in a phosphatase-activity-dependent manner, antagonizing TBK1-mediated STING phosphorylation and aggregation to dampen innate immune signaling. In vitro phosphatase assay, overexpression, RNAi, STING aggregation assay PLoS pathogens Medium 25815785
2016 PPM1A silences cytosolic RNA sensing (RLR-IRF3 axis) by directly dephosphorylating both MAVS and TBK1/IKKε. PPM1A is an inherent partner of the TBK1/IKKε complex; high MAVS levels can dissociate the TBK1/PPM1A complex to override inhibition. PPM1A knockout in HEK293 cells and primary macrophages enhances antiviral responses; Ppm1a-/- mice resist RNA virus attack. In vitro phosphatase assay, Co-immunoprecipitation, PPM1A gene knockout (HEK293 and mouse), primary macrophage assay, transgenic zebrafish, viral infection model Science advances High 27419230
2017 Mycobacterium tuberculosis exploits PPM1A to suppress host macrophage apoptosis by inactivating JNK. Overproduction of PPM1A suppresses JNK activation in Mtb-infected macrophages; PPM1A depletion (shRNA) or inhibition (sanguinarine) restores JNK activation and apoptosis. shRNA knockdown, pharmacological inhibition (sanguinarine), JNK activation assay, apoptosis assay in Mtb-infected macrophages Scientific reports Medium 28176854
2018 Crystal structure of human PPM1Acat complexed with a cyclic phosphopeptide (c(MpSIpYVA), a cyclized activation loop of p38 MAPK) reveals three metal ions in the active site. The Flap subdomain shows reduced conformational flexibility upon substrate binding. Enzyme kinetics support a random-order bi-substrate mechanism with substantial interaction between bound substrate and the labile third metal ion. X-ray crystallography, enzyme kinetics, biophysical methods (SAXS, computational docking), active-site mutagenesis (D146E trapping mutant) The Journal of biological chemistry High 29602904
2018 TRIM52 E3 ubiquitin ligase interacts with PPM1A via Co-IP and promotes its ubiquitination and proteasomal degradation, thereby activating TGF-β/Smad2/3 signaling and promoting HCC cell proliferation, migration, and invasion. Co-immunoprecipitation, ubiquitination assay in vitro, overexpression/RNAi, western blot Journal of experimental & clinical cancer research Medium 29898761
2018 CSIG (cellular senescence-inhibited gene) facilitates the interaction between NMT1 and PPM1A, promoting PPM1A N-myristoylation. CSIG knockdown disturbs PPM1A myristoylation and reduces PPM1A-mediated dephosphorylation of Smad2, thereby modulating TGF-β signaling. Co-immunoprecipitation, myristoylation assay, RNAi knockdown, Smad2 phosphorylation readout Molecular and cellular biology Medium 30201805
2018 HCV NS3 protein directly interacts with PPM1A (via its protease domain) and promotes PPM1A ubiquitination and proteasomal degradation, thereby enhancing HCC cell migration and invasion. Restoration of PPM1A abrogates NS3-mediated promotion in a phosphatase-activity-dependent manner. Co-immunoprecipitation, ubiquitination assay, overexpression/RNAi, invasion/migration assay Journal of experimental & clinical cancer research Medium 28283039
2018 PPM1A controls monocyte-to-macrophage differentiation: overexpression of PPM1A attenuates the macrophage differentiation program (impairs adherence, reduces M1 markers, inhibits inflammatory cytokines), while knockdown accelerates differentiation. TLR agonists imiquimod and Pam3CSK4 induce PPM1A expression. Overexpression/knockdown genetic manipulation, flow cytometry, cytokine measurement, differentiation assays Scientific reports Medium 29343725
2020 PPM1A directly dephosphorylates PPARγ at Ser273, a site phosphorylated by CDK5/ERK that drives diabetic gene reprogramming. PPM1A expression decreases in diet-induced obese and db/db mice, negatively correlating with PPARγ pSer273 levels. In vitro phosphatase assay, overexpression, western blot with phospho-specific antibody, mouse metabolic models Cells Medium 32024237
2021 PPM1A is the physiological phosphatase for YAP/TAZ, directly eliminating phosphorylation at YAP Ser127 (LATS1 site). PPM1A associates with YAP/TAZ in both cytoplasm and nucleus. Genetic ablation of PPM1A in cells, organoids, and mice causes enhanced YAP/TAZ cytoplasmic retention, diminished proliferation, severe gut regeneration defects in colitis, and impeded liver regeneration; these defects are rescued by LATS1 deficiency or Hippo pathway inhibition. Phosphatome screen, Co-IP, in vitro phosphatase assay, PPM1A KO mice/organoids, genetic epistasis (LATS1 KO rescue), pharmacological Hippo inhibition PLoS biology High 33630828
2022 Cytoplasmic NDRG2 binds PPM1A in astrocytes and restricts the dephosphorylation of Smad2/3. After subarachnoid hemorrhage, NDRG2 upregulation sequesters PPM1A, sustaining pSmad2/3 and driving MMP-9 transcription. A blocking peptide (TAT-QFNP12) disrupting NDRG2-PPM1A binding restores Smad2/3 dephosphorylation and reduces MMP-9. Co-immunoprecipitation, Ndrg2 conditional knockout, peptide competition assay, pSmad2/3 readout, MMP-9 expression/BBB assay Science advances Medium 36179025
2021 Active-site arginines Arg33 and Arg186 of PPM1A are critical for enzymatic dephosphorylation activity. Docking-model analysis suggests Arg186 interacts directly with the substrate phosphate group. The relative importance of each Arg residue depends on the substrate. Site-directed mutagenesis, in vitro phosphatase assay, docking model analysis Biochemical and biophysical research communications Medium 34637963
2022 PPM1A inhibition (genetic KO or pharmacological with sanguinarine/BC-21) activates autophagy through a mechanism dependent on phosphorylation of p62-SQSTM1, restricting intracellular Mycobacterium tuberculosis survival in macrophages and mouse lungs. A selective small-molecule PPM1A inhibitor (SMIP-30) was identified. PPM1A gene knockout (ΔPPM1A), small-molecule inhibitor (SMIP-30), autophagy assay (p62 phosphorylation, LC3B), Mtb survival assay in macrophages and mice Cell chemical biology Medium 35320734
2023 PPM1A interacts with phospho-SMAD2 in chondrocytes and its knockout protects mice from cartilage degeneration in the DMM osteoarthritis model by maintaining elevated pSMAD2. The protective phenotype in PPM1A KO mice is abolished by TGF-β/SMAD2 signaling inhibition (SD-208), demonstrating epistasis. Co-immunoprecipitation, PPM1A KO mice with DMM surgery, genetic epistasis (SD-208 inhibitor rescue), PPM1A inhibitors (sanguinarine, BC-21) in vivo JCI insight High 36752205
2012 Maxacalcitol (vitamin D analog) promotes assembly of a PPM1A/VDR complex that is recruited to phospho-Smad3 (pSmad3), facilitating pSmad3 dephosphorylation and attenuating TGF-β1 autoinduction in kidney fibrosis. Without maxacalcitol, the PPM1A/pSmad3 interaction is insufficient for dephosphorylation. Co-immunoprecipitation, chromatin immunoprecipitation, nuclear fractionation, in vivo rat model (UUO) Laboratory investigation Medium 22926646
2013 PPM1A is involved in nerve cell survival and differentiation: overexpression in PC6-3 cells causes G2/M cell cycle arrest and apoptosis in naive but not fully differentiated cells, and modulates NGF signaling and neurite outgrowth. Overexpression, PPM1A knockdown, cell cycle analysis, neurite outgrowth assay in PC6-3 cells PloS one Low 22384250
2016 HBx (Hepatitis B virus X protein) dose-dependently downregulates PPM1A protein (but not mRNA) in the presence of TGF-β by increasing PPM1A ubiquitination and accelerating proteasomal degradation, thereby amplifying TGF-β/pSmad2/3 signaling and HCC cell motility. Western blot, ubiquitination assay, overexpression/RNAi, migration/invasion assay Oncotarget Medium 27121309
2022 Myoneurin (Mynn) interacts with Smad proteins in the nucleus and competes with Ppm1a for Smad binding, preventing Smad dephosphorylation and sustaining BMP signaling. Loss of mynn reduces BMP signal activity in zebrafish and mammalian cells. Co-immunoprecipitation, competitive binding assay, zebrafish mynn mutant, mammalian cell knockdown, BMP signaling readout iScience Medium 35712083
2020 MALAT1 lncRNA regulates TGF-β/Smad signaling by forming a lncRNA-protein complex containing Smads, SETD2, and PPM1A in hepatic cells. This complex facilitates pSmad2/3 dephosphorylation by providing an interaction niche for pSmad2/3 and PPM1A. RNA immunoprecipitation, Co-IP, RNAi depletion of MALAT1, pSmad2/3 readout, iPS cell differentiation assay PloS one Medium 31995604
2018 TRIM52 promotes PPM1A ubiquitination in hepatic stellate cells (LX-2), leading to PPM1A protein degradation and activation of TGF-β/Smad2/3 pathway. Overexpression of PPM1A reverses TRIM52-mediated fibrogenic effects. Co-immunoprecipitation, ubiquitination assay, overexpression, siRNA knockdown, fibrosis markers Cell biology international Medium 31329338
2019 USP33 deubiquitinates PPM1A, stabilizing it; miR-3591-5p suppresses USP33, leading to PPM1A degradation, sustained Smad2/3 phosphorylation, and radiation-induced EMT in lung cancer cells. Ectopic USP33 or PPM1A expression partially abolishes these effects. 3'UTR luciferase reporter assay, western blot, overexpression rescue, RNAi Cellular physiology and biochemistry Medium 30308513
2024 TRIM47 acts as an E3 ubiquitin ligase that promotes PPM1A ubiquitination and proteasomal degradation in pulmonary fibrosis. TRIM47 knockdown stabilizes PPM1A, suppressing TGF-β/SMAD3 and NF-κB/NLRP3 signaling. Otilonium bromide (OB) activates PPM1A enzymatically (EC50 = 4.23 μM) and ameliorates bleomycin-induced pulmonary fibrosis in mice in a PPM1A-dependent manner. Co-immunoprecipitation, ubiquitination assay, PPM1A knockdown mice, in vitro enzymatic activation assay, bleomycin mouse model Acta pharmacologica Sinica Medium 39160244
2025 SLC7A11-AS1 lncRNA interacts with scaffold protein RSL1D1, disrupting the recruitment of PPM1A and NMT1 to RSL1D1, thereby suppressing PPM1A N-myristoylation and prolonging activin A/Smad2/3 signaling in pancreatic cancer cells. RNA pulldown + LC-MS/MS, co-immunoprecipitation, myristoylation assay, overexpression/knockdown British journal of cancer Medium 40926062
2020 TRIM59 promotes ubiquitination and proteasomal degradation of PPM1A (at the post-translational level, without altering PPM1A mRNA) in ectopic endometrial stromal cells, activating TGF-β/Smad2/3 signaling and promoting invasion in endometriosis. Co-immunoprecipitation, ubiquitination assay, overexpression/siRNA, western blot American journal of physiology. Cell physiology Medium 32348176
2022 TRIM65 acts as an E3 ubiquitin ligase targeting PPM1A for ubiquitin-mediated degradation; TRIM65 knockdown increases PPM1A levels and decreases pTBK1 in gastric cancer cells, inhibiting proliferation and invasion. Co-immunoprecipitation, ubiquitination assay, shRNA knockdown, western blot Experimental cell research Low 35421368
2019 PPM1A inhibits triple negative breast cancer cell growth by blocking cell cycle progression and reducing CDK and Rb phosphorylation when expressed in TNBC cells. Induced overexpression, cell cycle analysis, CDK/Rb phosphorylation western blot, in vitro and in vivo tumor growth assay NPJ breast cancer Low 31372497
2023 Extracellular PPM1A promotes osteoblast differentiation in ankylosing spondylitis by inducing dephosphorylation of FOXO1A at Ser256, enabling FOXO1A nuclear translocation and upregulation of RUNX2. Exogenous PPM1A treatment, phospho-FOXO1A western blot, RUNX2 promoter luciferase assay, nuclear fractionation Journal of cellular and molecular medicine Low 36756789

Source papers

Stage 0 corpus · 77 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling. Cell 407 16751101
2016 Ubiquitin Ligases RGLG1 and RGLG5 Regulate Abscisic Acid Signaling by Controlling the Turnover of Phosphatase PP2CA. The Plant cell 117 27577789
2015 PPM1A regulates antiviral signaling by antagonizing TBK1-mediated STING phosphorylation and aggregation. PLoS pathogens 114 25815785
2011 Mechanistic analysis of AKT1 regulation by the CBL-CIPK-PP2CA interactions. Molecular plant 111 21596690
2008 PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation. Cellular signalling 94 18930133
2006 Protein serine/threonine phosphatase PPM1A dephosphorylates Smad1 in the bone morphogenetic protein signaling pathway. The Journal of biological chemistry 83 16931515
2022 Astrocytic NDRG2-PPM1A interaction exacerbates blood-brain barrier disruption after subarachnoid hemorrhage. Science advances 76 36179025
2008 Opposite effects of dihydrosphingosine 1-phosphate and sphingosine 1-phosphate on transforming growth factor-beta/Smad signaling are mediated through the PTEN/PPM1A-dependent pathway. The Journal of biological chemistry 68 18482992
2016 PPM1A silences cytosolic RNA sensing and antiviral defense through direct dephosphorylation of MAVS and TBK1. Science advances 64 27419230
2019 The MATH-BTB BPM3 and BPM5 subunits of Cullin3-RING E3 ubiquitin ligases target PP2CA and other clade A PP2Cs for degradation. Proceedings of the National Academy of Sciences of the United States of America 63 31308219
2019 ABA inhibits myristoylation and induces shuttling of the RGLG1 E3 ligase to promote nuclear degradation of PP2CA. The Plant journal : for cell and molecular biology 59 30730075
2008 Phosphatase PPM1A regulates phosphorylation of Thr-186 in the Cdk9 T-loop. The Journal of biological chemistry 58 18829461
2014 Loss of PPM1A expression enhances invasion and the epithelial-to-mesenchymal transition in bladder cancer by activating the TGF-β/Smad signaling pathway. Oncotarget 51 25026293
2013 Inhibition of TGF-β signaling at the nuclear envelope: characterization of interactions between MAN1, Smad2 and Smad3, and PPM1A. Science signaling 45 23779087
2018 TRIM52 up-regulation in hepatocellular carcinoma cells promotes proliferation, migration and invasion through the ubiquitination of PPM1A. Journal of experimental & clinical cancer research : CR 44 29898761
2013 N-Myristoylation is essential for protein phosphatases PPM1A and PPM1B to dephosphorylate their physiological substrates in cells. The Biochemical journal 43 23088624
2013 PPM1A is a RelA phosphatase with tumor suppressor-like activity. Oncogene 43 23812431
2017 Mycobacterium tuberculosis exploits the PPM1A signaling pathway to block host macrophage apoptosis. Scientific reports 39 28176854
2016 Protein phosphatase type 2C PP2CA together with ABI1 inhibits SnRK2.4 activity and regulates plant responses to salinity. Plant signaling & behavior 39 27901636
2012 Maxacalcitol ameliorates tubulointerstitial fibrosis in obstructed kidneys by recruiting PPM1A/VDR complex to pSmad3. Laboratory investigation; a journal of technical methods and pathology 37 22926646
2018 A DEAD-box RNA helicase, RH8, is critical for regulation of ABA signalling and the drought stress response via inhibition of PP2CA activity. Plant, cell & environment 33 29574779
2018 Radiation Enhances the Epithelial- Mesenchymal Transition of A549 Cells via miR3591-5p/USP33/PPM1A. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 33 30308513
2010 Convergent animal and human evidence suggests a role of PPM1A gene in response to antidepressants. Biological psychiatry 31 20970119
2007 Expression of PTEN, PPM1A and P-Smad2 in hepatocellular carcinomas and adjacent liver tissues. World journal of gastroenterology 31 17729405
2018 The phosphatase PPM1A controls monocyte-to-macrophage differentiation. Scientific reports 30 29343725
2016 Hepatitis B virus X protein amplifies TGF-β promotion on HCC motility through down-regulating PPM1a. Oncotarget 30 27121309
2017 Hepatitis C virus NS3 protein enhances hepatocellular carcinoma cell invasion by promoting PPM1A ubiquitination and degradation. Journal of experimental & clinical cancer research : CR 29 28283039
2023 Protein phosphatase PPM1A inhibition attenuates osteoarthritis via regulating TGF-β/Smad2 signaling in chondrocytes. JCI insight 28 36752205
2020 The long-noncoding RNA MALAT1 regulates TGF-β/Smad signaling through formation of a lncRNA-protein complex with Smads, SETD2 and PPM1A in hepatic cells. PloS one 28 31995604
2011 PPM1A dephosphorylates RanBP3 to enable efficient nuclear export of Smad2 and Smad3. EMBO reports 28 21960005
2021 The protein phosphatase PPM1A dephosphorylates and activates YAP to govern mammalian intestinal and liver regeneration. PLoS biology 26 33630828
2012 Protein phosphatase magnesium dependent 1A (PPM1A) plays a role in the differentiation and survival processes of nerve cells. PloS one 24 22384250
2011 Delayed re-epithelialization in Ppm1a gene-deficient mice is mediated by enhanced activation of Smad2. The Journal of biological chemistry 24 21990361
2022 A selective PPM1A inhibitor activates autophagy to restrict the survival of Mycobacterium tuberculosis. Cell chemical biology 23 35320734
2021 MicroRNA-487a-3p inhibits the growth and invasiveness of oral squamous cell carcinoma by targeting PPM1A. Bioengineered 23 33724144
2019 Chemokine (C-X-C motif) ligand 14 contributes to lipopolysaccharide-induced fibrogenesis in mouse L929 fibroblasts via modulating PPM1A. Journal of cellular biochemistry 23 30920024
2019 The phosphatase PPM1A inhibits triple negative breast cancer growth by blocking cell cycle progression. NPJ breast cancer 22 31372497
2021 CircMAPK9 promotes the progression of fibroblast-like synoviocytes in rheumatoid arthritis via the miR-140-3p/PPM1A axis. Journal of orthopaedic surgery and research 21 34154607
2020 TRIM59 inhibits PPM1A through ubiquitination and activates TGF-β/Smad signaling to promote the invasion of ectopic endometrial stromal cells in endometriosis. American journal of physiology. Cell physiology 21 32348176
2018 A trapped human PPM1A-phosphopeptide complex reveals structural features critical for regulation of PPM protein phosphatase activity. The Journal of biological chemistry 21 29602904
2020 Hepatitis B Virus-Encoded MicroRNA (HBV-miR-3) Regulates Host Gene PPM1A Related to Hepatocellular Carcinoma. MicroRNA (Shariqah, United Arab Emirates) 20 31686644
2019 Both Peripheral Blood and Urinary miR-195-5p, miR-192-3p, miR-328-5p and Their Target Genes PPM1A, RAB1A and BRSK1 May Be Potential Biomarkers for Membranous Nephropathy. Medical science monitor : international medical journal of experimental and clinical research 19 30865617
2009 Protein phosphatase 1A (PPM1A) is involved in human cytotrophoblast cell invasion and migration. Histochemistry and cell biology 18 19404668
2019 miR-522 stimulates TGF-β/Smad signaling pathway and promotes osteosarcoma tumorigenesis by targeting PPM1A. Journal of cellular biochemistry 17 31190351
2020 MiR-1165-3p Suppresses Th2 Differentiation via Targeting IL-13 and PPM1A in a Mouse Model of Allergic Airway Inflammation. Allergy, asthma & immunology research 16 32638565
2020 PPM1A Controls Diabetic Gene Programming through Directly Dephosphorylating PPARγ at Ser273. Cells 15 32024237
2022 Knockdown of TRIM65 suppressed the proliferation and invasiveness of gastric cancer cells by restricting the ubiquitin degradation of PPM1A. Experimental cell research 14 35421368
2020 Correlation of PPM1A Downregulation with CYP3A4 Repression in the Tumor Liver Tissue of Hepatocellular Carcinoma Patients. European journal of drug metabolism and pharmacokinetics 12 31792727
2019 Genome-wide characterization and expression analysis of PP2CA family members in response to ABA and osmotic stress in Gossypium. PeerJ 12 31231596
2020 PPM1A suppresses the proliferation and invasiveness of RCC cells via Smad2/3 signaling inhibition. Journal of receptor and signal transduction research 11 32878540
2022 Myoneurin regulates BMP signaling by competing with Ppm1a for Smad binding. iScience 10 35712083
2019 Tripartite motif protein 52 (TRIM52) promoted fibrosis in LX-2 cells through PPM1A-mediated Smad2/3 pathway. Cell biology international 10 31329338
2021 A comprehensive overview of PPM1A: From structure to disease. Experimental biology and medicine (Maywood, N.J.) 9 34861123
2014 The self-limiting dynamics of TGF-β signaling in silico and in vitro, with negative feedback through PPM1A upregulation. PLoS computational biology 9 24901250
2024 Small Molecule Targeting PPM1A Activates Autophagy for Mycobacterium tuberculosis Host-Directed Therapy. Journal of medicinal chemistry 8 38958057
2012 De novo synthesis of protein phosphatase 1A, magnesium dependent, alpha isoform (PPM1A) during oocyte maturation. Cellular & molecular biology letters 8 22669481
2024 Otilonium bromide ameliorates pulmonary fibrosis in mice through activating phosphatase PPM1A. Acta pharmacologica Sinica 7 39160244
2021 PPM1A as a key target of the application of Jiawei‑Maxing‑Shigan decoction for the attenuation of radiation‑induced epithelial‑mesenchymal transition in type II alveolar epithelial cells. Molecular medicine reports 7 34558633
2021 LncRNA PPM1A-AS Regulate Tumor Development Through Multiple Signal Pathways in T-Cell Acute Lymphoblastic Leukemia. Frontiers in oncology 7 34746000
2023 Extracellular PPM1A promotes mineralization of osteoblasts differentiation in ankylosing spondylitis via the FOXO1A-RUNX2 pathway. Journal of cellular and molecular medicine 6 36756789
2021 Functional divergence of Brassica napus BnaABI1 paralogs in the structurally conserved PP2CA gene subfamily of Brassicaceae. Genomics 6 34182082
2019 Isolation of a spirolactone norditerpenoid as a yeast Ca2+ signal transduction inhibitor from Kuji amber and evaluation of its effects on PPM1A activity. Fitoterapia 5 30831200
2019 Identification and Total Synthesis of Two Previously Unreported Odd-Chain Bis-Methylene-Interrupted Fatty Acids with a Terminal Olefin that Activate Protein Phosphatase, Mg2+/Mn2+-Dependent 1A (PPM1A) in Ovaries of the Limpet Cellana toreuma. Marine drugs 5 31336763
2018 The Cellular Senescence-Inhibited Gene Is Essential for PPM1A Myristoylation To Modulate Transforming Growth Factor β Signaling. Molecular and cellular biology 5 30201805
2022 Miltefosine as a PPM1A activator improves AD-like pathology in mice by alleviating tauopathy via microglia/neurons crosstalk. Brain, behavior, & immunity - health 4 36388134
2019 Effect of miR-135b inhibitor on biological characteristics of osteosarcoma cells through up-regulating PPM1A. International journal of clinical and experimental pathology 4 31933876
2025 Knockdown of TRIM47 Overcomes Paclitaxel Resistance in Ovarian Cancer by Suppressing the TGF-β Pathway via PPM1A. American journal of reproductive immunology (New York, N.Y. : 1989) 2 40435048
2022 Platyconic acid A‑induced PPM1A upregulation inhibits the proliferation, inflammation and extracellular matrix deposition of TGF‑β1‑induced lung fibroblasts. Molecular medicine reports 2 36069235
2024 Role of TRIM59 in regulating PPM1A in the pathogenesis of silicosis and the intervention effect of tanshinone IIA. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 1 38908195
2021 Role of active site arginine residues in substrate recognition by PPM1A. Biochemical and biophysical research communications 1 34637963
2018 [Establishment of BV2 cell line with steady knockdown of Mg2+/Mn2+-dependent protein phosphatase 1A(PPM1A)]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 1 30463654
2011 [Expression and significance of LMP2 and PPM1A in gestational trophoblastic disease]. Zhonghua fu chan ke za zhi 1 22041443
2026 PPM1A dysfunction aggravates DPN pathology through NF-κB/NLRP3/p-tau axis involving Schwann cell/DRG neuron crosstalk. Journal of translational medicine 0 41501801
2026 A Bifunctional T3SS-Effector Simultaneously Cleaves Host MAP Kinase and Inhibits PPM1A Phosphatase. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41902461
2026 Otilonium bromide ameliorates paclitaxel-induced peripheral neuropathy by targeting phosphatase PPM1A. Journal of neuroinflammation 0 42098844
2025 SLC7A11-AS1 contributes to prolonged activation of activin A/Smad signaling by suppressing PPM1A myristoylation in pancreatic cancer. British journal of cancer 0 40926062
2024 Generation of a PPM1A-deficient human induced pluripotent stem cell line using CRISPR-Cas9 technology. Stem cell research 0 38643711

Missed literature

Know a paper Affinage missed for PPM1A? Flag it for the maintainers and the community.

No submissions yet.