PPM1A

Summary

PPM1A (protein phosphatase, Mg2+/Mn2+ dependent 1A, HGNC:9275) is a protein-coding gene on chromosome 14q23.1, encoding Protein phosphatase 1A (P35813). Enzyme with a broad specificity.

The protein encoded by this gene is a member of the PP2C family of Ser/Thr protein phosphatases. PP2C family members are known to be negative regulators of cell stress response pathways. This phosphatase dephosphorylates, and negatively regulates the activities of, MAP kinases and MAP kinase kinases. It has been shown to inhibit the activation of p38 and JNK kinase cascades induced by environmental stresses. This phosphatase can also dephosphorylate cyclin-dependent kinases, and thus may be involved in cell cycle control. Overexpression of this phosphatase is reported to activate the expression of the tumor suppressor gene TP53/p53, which leads to G2/M cell cycle arrest and apoptosis. Three alternatively spliced transcript variants encoding distinct isoforms have been described.

Source: NCBI Gene 5494 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 21 total
• Druggable target: yes
• MANE Select transcript: NM_021003

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9275
Approved symbol	PPM1A
Name	protein phosphatase, Mg2+/Mn2+ dependent 1A
Location	14q23.1
Locus type	gene with protein product
Status	Approved
Aliases	MGC9201, PP2Calpha, PP2CA
Ensembl gene	ENSG00000100614
Ensembl biotype	protein_coding
OMIM	606108
Entrez	5494

Gene structure

Transcript identifiers

Ensembl transcripts: 108 — 106 protein_coding, 2 nonsense_mediated_decay

ENST00000325642, ENST00000325658, ENST00000395076, ENST00000525399, ENST00000528241, ENST00000531143, ENST00000531937, ENST00000532036, ENST00000893041, ENST00000893042, ENST00000893043, ENST00000893044, ENST00000893045, ENST00000893046, ENST00000893047, ENST00000893048, ENST00000893049, ENST00000893050, ENST00000893051, ENST00000893052, ENST00000893053, ENST00000893054, ENST00000893055, ENST00000893056, ENST00000893057, ENST00000893058, ENST00000893059, ENST00000893060, ENST00000893061, ENST00000893062, ENST00000893063, ENST00000893064, ENST00000893065, ENST00000893066, ENST00000893067, ENST00000893068, ENST00000893069, ENST00000893070, ENST00000893071, ENST00000893072, ENST00000893073, ENST00000893074, ENST00000893075, ENST00000893076, ENST00000893077, ENST00000893078, ENST00000893079, ENST00000893080, ENST00000893081, ENST00000893082, ENST00000893083, ENST00000893084, ENST00000893085, ENST00000893086, ENST00000893087, ENST00000893088, ENST00000893089, ENST00000893090, ENST00000893091, ENST00000893092, ENST00000925842, ENST00000925843, ENST00000925844, ENST00000925845, ENST00000925846, ENST00000925847, ENST00000953911, ENST00000953912, ENST00000953913, ENST00000953914, ENST00000953915, ENST00000953916, ENST00000953917, ENST00000953918, ENST00000953919, ENST00000953920, ENST00000953921, ENST00000953922, ENST00000953923, ENST00000953924, ENST00000953925, ENST00000953926, ENST00000953927, ENST00000953928, ENST00000953929, ENST00000953930, ENST00000953931, ENST00000953932, ENST00000953933, ENST00000953934, ENST00000953935, ENST00000953936, ENST00000953937, ENST00000953938, ENST00000953939, ENST00000953940, ENST00000953941, ENST00000953942, ENST00000953943, ENST00000953944, ENST00000953945, ENST00000953946, ENST00000953947, ENST00000953948, ENST00000953949, ENST00000953950, ENST00000953951, ENST00000953952

RefSeq mRNA: 3 — MANE Select: NM_021003 NM_021003, NM_177951, NM_177952

CCDS: CCDS45120, CCDS9744, CCDS9745

Canonical transcript exons

ENST00000395076 — 6 exons

Exon	Start	End
ENSE00001818583	60292453	60299087
ENSE00001871344	60249221	60249677
ENSE00003514757	60285624	60285741
ENSE00003631918	60291397	60291454
ENSE00003638321	60282684	60283537
ENSE00003678447	60289806	60289914

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 98.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.7411 / max 401.6199, expressed in 1803 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
139874	18.8687	1796
139873	2.7872	1447
139875	0.9543	516
139876	0.7467	407
139877	0.3407	155
139870	0.0233	7
139871	0.0201	4

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	98.72	gold quality
oocyte	CL:0000023	98.01	gold quality
male germ cell	CL:0000015	97.92	gold quality
biceps brachii	UBERON:0001507	97.61	gold quality
secondary oocyte	CL:0000655	97.51	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.28	gold quality
jejunal mucosa	UBERON:0000399	97.26	gold quality
amniotic fluid	UBERON:0000173	97.09	gold quality
parotid gland	UBERON:0001831	97.09	gold quality
gluteal muscle	UBERON:0002000	96.94	gold quality
left testis	UBERON:0004533	96.94	gold quality
deltoid	UBERON:0001476	96.93	gold quality
right testis	UBERON:0004534	96.79	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.69	gold quality
jejunum	UBERON:0002115	96.67	gold quality
buccal mucosa cell	CL:0002336	96.58	gold quality
gastrocnemius	UBERON:0001388	96.57	gold quality
skeletal muscle tissue	UBERON:0001134	96.54	gold quality
heart right ventricle	UBERON:0002080	96.41	gold quality
muscle of leg	UBERON:0001383	96.40	gold quality
bone marrow	UBERON:0002371	96.40	gold quality
blood	UBERON:0000178	96.38	gold quality
muscle organ	UBERON:0001630	96.38	gold quality
left ventricle myocardium	UBERON:0006566	96.38	gold quality
nephron tubule	UBERON:0001231	96.36	gold quality
islet of Langerhans	UBERON:0000006	96.33	gold quality
endothelial cell	CL:0000115	96.15	gold quality
trabecular bone tissue	UBERON:0002483	96.14	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.11	gold quality
muscle tissue	UBERON:0002385	96.09	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-75367	yes	550.41
E-ANND-3	yes	5.32
E-MTAB-6386	no	280.26

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53

miRNA regulators (miRDB)

359 targeting PPM1A, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4531	99.99	69.70	3181

Literature-anchored findings (GeneRIF, showing 40)

• This work demonstrates that PPM1A/PP2Calpha, through dephosphorylation of Smad2/3, plays a critical role in terminating TGFbeta signaling. (PMID:16751101)
• PPM1A plays an important role in controlling BMP signaling through catalyzing Smad1 dephosphorylation (PMID:16931515)
• Aberrant location of expression/staining intensity of PTEN, PPM1A and P-Smad2 in hepatocellular carcinoma may impact disease progression. (PMID:17729405)
• PTEN abrogates TGF-beta-induced Smad2/3 phosphorylation. This study establishes a novel role for nuclear PTEN in the stabilization of PPM1A. (PMID:18482992)
• Overexpression of PPM1A and the related PPM1B greatly reduced Cdk9 T-loop phosphorylation (PMID:18829461)
• Protein phosphatase 1A is essential to terminate I-kappa B Kinase-mediated NF-kappaappaB activation through binding to the activated form of I-kappa B Kinase and dephosphorylating I-kappa B Kinase at the conserved residues Ser177 and Ser181. (PMID:18930133)
• The present data indicate that PPM1A plays a critical role in the regulation of normal placentation by inhibiting trophoblast migration and invasion. (PMID:19404668)
• High expression of LMP2 and low expression of PPM1A might play an important role in the motility and invasiveness of trophoblast cells and malignant transformation of hydatidiform mole. (PMID:22041443)
• Studies indicate that phosphatase PPM1G is a component of the spliceosome and binds to protein YB-1 to affect alternative splicing. (PMID:22519956)
• PPM1A inhibits HIV-1 infection and gene expression. PPM1A depletion in resting CD4+ T cells increases HIV-1 gene expression. (PMID:22727189)
• PPM1A negatively regulates ERK by directly dephosphorylating its pThr202 position early in epidermal growth factor stimulation. Additional kinetic studies reveal that key residues participate in phospho-ERK recognition by PPM1A. (PMID:23560844)
• a nuclear envelope-localized mechanism of inactivating TGF-beta signaling in which MAN1 competes with transcription factors for binding to Smad2 and Smad3 and facilitates their dephosphorylation by PPM1A. (PMID:23779087)
• PPM1A is a RelA phosphatase that regulates NF-kappaB activity and that PPM1A has tumor suppressor-like activity. (PMID:23812431)
• phosphatase activity toward phosphopeptide substrates by PP2Calpha and Wip1 requires the binding of a Mg(2)+ ion to the low-affinity site. (PMID:23906386)
• The TGF-beta/Smad signaling system decreases its activity through strong negative regulation. We provide evidence for a new negative feedback loop through PPM1A upregulation. (PMID:24901250)
• Loss of PPM1A is associated with the development of tumor invasion in bladder cancer patients. (PMID:25026293)
• findings demonstrate a novel regulatory circuit in which STING and TBK1 reciprocally regulate each other to enable efficient antiviral signaling activation, and PPM1A dephosphorylates STING and TBK1 (PMID:25815785)
• These data suggest that PPM1A, which had previously been shown to play a role in the antiviral response to Herpes Simplex virus infection, also governs the antibacterial response of macrophages to bacteria, or at least to Mycobacterium tuberculosis infection (PMID:27004401)
• Present study suggests that HBx-induced degradation of PPM1a is a novel mechanism for over-activation of TGF-beta pathway in HCC development. (PMID:27121309)
• Report a tumor-suppressive function of PPM1A and an independent relationship to Smad4 in pancreatic ductal adenocarcinoma. (PMID:27195906)
• In a nested case control study of ischemic stroke, there was an epigenome-wide association for cg04985020 (PPM1A; P=1.78x10(-07)) with vascular recurrence in patients treated with aspirin. (PMID:27301936)
• establish PPM1A as a novel repressor of the SMAD3 pathway in renal fibrosis (PMID:27328942)
• Here the authors establish PPM1A as a checkpoint target used by Mycobacterium tuberculosis to suppress macrophage apoptosis. Overproduction of PPM1A suppressed apoptosis of Mycobacterium tuberculosis-infected macrophages by a mechanism that involves inactivation of the c-Jun N-terminal kinase (JNK). (PMID:28176854)
• Findings show that HCV infection and replication decreased PPM1A abundance, mediated by NS3, in hepatoma cells. Compared to normal liver tissues, the expression of PPM1A was significantly decreased in the HCC tumor tissues and adjacent non-tumor tissues through its regulation by NS3 which promotes its ubiquitination and proteasomal degradation. (PMID:28283039)
• hydrogen/deuterium exchange-mass spectrometry and molecular dynamics to characterize conformational changes in PP2Calpha between the active and inactive states (PMID:28481111)
• PPM1A as a negative threshold regulator of M1-type monocyte-to-macrophage differentiation. (PMID:29343725)
• Enzyme kinetics of PPM1Acat toward a phosphopeptide substrate supported a random-order, bi-substrate mechanism, with substantial interaction between the bound substrate and the labile metal ion (PMID:29602904)
• Our findings suggest that TRIM52 up-regulation promotes proliferation, migration and invasion of HCC cells through the ubiquitination of PPM1A. (PMID:29898761)
• CSIG enhanced the phosphatase activity of PPM1A and further inhibited TGF-beta signaling. (PMID:30201805)
• Hepatitis B Virus-Encoded MicroRNA (HBV-miR-3) Regulates Host Gene PPM1A Related to Hepatocellular Carcinoma. (PMID:31686644)
• Protein phosphatase magnesium-dependent 1A induces inflammation in rheumatoid arthritis. (PMID:31791585)
• Correlation of PPM1A Downregulation with CYP3A4 Repression in the Tumor Liver Tissue of Hepatocellular Carcinoma Patients. (PMID:31792727)
• Protein phosphatase Mg(2+) /Mn(2+) dependent-1A and PTEN deregulation in renal fibrosis: Novel mechanisms and co-dependency of expression. (PMID:31909517)
• PPM1A Controls Diabetic Gene Programming through Directly Dephosphorylating PPARgamma at Ser273. (PMID:32024237)
• TRIM59 inhibits PPM1A through ubiquitination and activates TGF-beta/Smad signaling to promote the invasion of ectopic endometrial stromal cells in endometriosis. (PMID:32348176)
• PPM1A suppresses the proliferation and invasiveness of RCC cells via Smad2/3 signaling inhibition. (PMID:32878540)
• MicroRNA-487a-3p inhibits the growth and invasiveness of oral squamous cell carcinoma by targeting PPM1A. (PMID:33724144)
• lncRNA TSPEAR-AS2, a Novel Prognostic Biomarker, Promotes Oral Squamous Cell Carcinoma Progression by Upregulating PPM1A via Sponging miR-487a-3p. (PMID:34336002)
• Role of active site arginine residues in substrate recognition by PPM1A. (PMID:34637963)
• A comprehensive overview of PPM1A: From structure to disease. (PMID:34861123)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppm1aa	ENSDARG00000032155
danio_rerio	ppm1ab	ENSDARG00000043250
mus_musculus	Ppm1a	ENSMUSG00000021096
rattus_norvegicus	Ppm1a	ENSRNOG00000005916
drosophila_melanogaster	Pdp	FBGN0029958
drosophila_melanogaster	CG10376	FBGN0032702
caenorhabditis_elegans	pdp-1	WBGENE00022832

Paralogs (16): PPM1F (ENSG00000100034), TAB1 (ENSG00000100324), PPM1H (ENSG00000111110), PPM1G (ENSG00000115241), ILKAP (ENSG00000132323), PPM1B (ENSG00000138032), PPM1J (ENSG00000155367), PPM1L (ENSG00000163590), PPM1K (ENSG00000163644), PPM1M (ENSG00000164088), PDP1 (ENSG00000164951), PPM1D (ENSG00000170836), PDP2 (ENSG00000172840), PPM1E (ENSG00000175175), PP2D1 (ENSG00000183977), PPM1N (ENSG00000213889)

Protein

Protein identifiers

Protein phosphatase 1A — P35813 (reviewed: P35813)

Alternative names: Protein phosphatase 2C isoform alpha, Protein phosphatase IA

All UniProt accessions (6): P35813, E9PJN3, E9PKB5, E9PL75, E9PNE1, E9PP44

UniProt curated annotations — full annotation on UniProt →

Function. Enzyme with a broad specificity. Negatively regulates TGF-beta signaling through dephosphorylating SMAD2 and SMAD3, resulting in their dissociation from SMAD4, nuclear export of the SMADs and termination of the TGF-beta-mediated signaling. Dephosphorylates PRKAA1 and PRKAA2. Plays an important role in the termination of TNF-mediated NF-kappa-B activation through dephosphorylating and inactivating IKBKB/IKKB.

Subunit / interactions. Monomer. Interacts with SMAD2; the interaction dephosphorylates SMAD2 in its C-terminal SXS motif resulting in disruption of the SMAD2/SMAD4 complex, SMAD2 nuclear export and termination of the TGF-beta-mediated signaling. Interacts with SMAD2; the interaction dephosphorylates SMAD2 in its C-terminal SXS motif resulting in disruption of the SMAD2/SMAD4 complex, SMAD2 nuclear export and termination of the TGF-beta-mediated signaling. Interacts with the phosphorylated form of IKBKB/IKKB.

Subcellular location. Nucleus. Cytoplasm. Cytosol. Membrane.

Post-translational modifications. N-myristoylation is essential for the recognition of its substrates for dephosphorylation.

Cofactor. Binds 2 magnesium or manganese ions per subunit.

Similarity. Belongs to the PP2C family.

Isoforms (3)

UniProt ID	Names	Canonical?
P35813-1	Alpha-1	yes
P35813-2	Alpha-2
P35813-3	3

RefSeq proteins (3): NP_066283, NP_808820, NP_808821 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000222	PP2C_BS	Binding_site
IPR001932	PPM-type_phosphatase-like_dom	Domain
IPR012911	PP2C_C	Domain
IPR015655	PP2C	Family
IPR036457	PPM-type-like_dom_sf	Homologous_superfamily
IPR036580	PP2C_C_sf	Homologous_superfamily

Pfam: PF00481, PF07830

Enzyme classification (BRENDA):

• EC 3.1.3.16 — protein-serine/threonine phosphatase (BRENDA: 92 organisms, 641 substrates, 468 inhibitors, 127 Km, 67 kcat entries)

Substrate kinetics (BRENDA)

59 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
6,8-DIFLUORO-4-METHYLUMBELLIFERYL PHOSPHATE	0.023–0.862	22
4-NITROPHENYL PHOSPHATE	0.0028–12.7	13
P-NITROPHENYL PHOSPHATE	3–200	11
RRAPTVA	0.058–1.954	4
PHOSPHOCASEIN	0.0001–0.002	3
PHOSPHOHISTONE	0.0023–0.0723	3
PHOSPHORYLATED MYOSIN LIGHT CHAIN PEPTIDE	0.01–0.11	3
PHOSPHOSERINE-MYELIN BASIC PROTEIN	0.0004–0.022	3
DLDVPIPGRFDRRVSVAAE	0.0006–0.0138	2
DLDVPIPGRFDRRVY(P)VAAE	0.0025–0.023	2
PHOSPHORYLASE A	0.004–0.021	2
RRA(PT)VA	0.0536–0.308	2
80S-RIBOSOME	0.0027	1
AAAPTVA	0.206	1
AGPALSPVPPV	0.357	1

Catalyzed reactions (Rhea), 2 shown:

• O-phospho-L-seryl-[protein] + H2O = L-seryl-[protein] + phosphate (RHEA:20629)
• O-phospho-L-threonyl-[protein] + H2O = L-threonyl-[protein] + phosphate (RHEA:47004)

UniProt features (48 total): strand 15, helix 12, binding site 5, turn 4, splice variant 3, sequence conflict 2, modified residue 2, initiator methionine 1, chain 1, lipid moiety-binding region 1, mutagenesis site 1, domain 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
4RAG	X-RAY DIFFRACTION	1.85
4RA2	X-RAY DIFFRACTION	1.94
1A6Q	X-RAY DIFFRACTION	2
4RAF	X-RAY DIFFRACTION	2
3FXK	X-RAY DIFFRACTION	2.1
6B67	X-RAY DIFFRACTION	2.2
3FXL	X-RAY DIFFRACTION	2.3
3FXJ	X-RAY DIFFRACTION	2.5
3FXM	X-RAY DIFFRACTION	2.5
3FXO	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35813-F1	94.61	0.90

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (5): 60; 60; 61; 239; 282

Post-translational modifications (3): 2, 375, 377

Mutagenesis-validated functional residues (1):

Position	Phenotype
239	no effect on binding smad2.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2173795	Downregulation of SMAD2/3:SMAD4 transcriptional activity
R-HSA-380972	Energy dependent regulation of mTOR by LKB1-AMPK

MSigDB gene sets: 351 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, ATF_B, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, HORIUCHI_WTAP_TARGETS_DN, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_LIPOPROTEIN_METABOLIC_PROCESS, KEGG_MAPK_SIGNALING_PATHWAY, GCANCTGNY_MYOD_Q6, CHUNG_BLISTER_CYTOTOXICITY_DN, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP

GO Biological Process (15): negative regulation of transcription by RNA polymerase II (GO:0000122), protein dephosphorylation (GO:0006470), N-terminal protein myristoylation (GO:0006499), protein export from nucleus (GO:0006611), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), negative regulation of BMP signaling pathway (GO:0030514), regulation of canonical NF-kappaB signal transduction (GO:0043122), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of protein export from nucleus (GO:0046827), regulation of cell cycle (GO:0051726), cellular response to transforming growth factor beta stimulus (GO:0071560), positive regulation of canonical Wnt signaling pathway (GO:0090263), negative regulation of non-canonical NF-kappaB signal transduction (GO:1901223)

GO Molecular Function (10): magnesium ion binding (GO:0000287), protein serine/threonine phosphatase activity (GO:0004722), manganese ion binding (GO:0030145), calmodulin-dependent protein phosphatase activity (GO:0033192), R-SMAD binding (GO:0070412), phosphoprotein phosphatase activity (GO:0004721), protein binding (GO:0005515), hydrolase activity (GO:0016787), cation binding (GO:0043169), metal ion binding (GO:0046872)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1
MTOR signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
canonical NF-kappaB signal transduction	3
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	2
regulation of canonical NF-kappaB signal transduction	2
negative regulation of intracellular signal transduction	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
dephosphorylation	1
protein modification process	1
N-terminal protein lipidation	1
protein myristoylation	1
intracellular protein transport	1
nuclear export	1
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
regulation of intracellular signal transduction	1
positive regulation of intracellular signal transduction	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
protein export from nucleus	1
positive regulation of nucleocytoplasmic transport	1
regulation of protein export from nucleus	1
positive regulation of intracellular protein transport	1
cell cycle	1
regulation of cellular process	1
cellular response to growth factor stimulus	1
response to transforming growth factor beta	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
non-canonical NF-kappaB signal transduction	1
regulation of non-canonical NF-kappaB signal transduction	1
metal ion binding	1
phosphoprotein phosphatase activity	1
transition metal ion binding	1

Protein interactions and networks

STRING

2867 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPM1A	SMAD2	Q15796	836
PPM1A	PPTC7	Q8NI37	807
PPM1A	SMAD3	P84022	789
PPM1A	CLIC4	Q9Y696	750
PPM1A	PDP1	Q9P0J1	740
PPM1A	HIVEP2	P31629	697
PPM1A	PPP1CA	P08129	598
PPM1A	TGFB1	P01137	532
PPM1A	HIVEP1	P15822	510
PPM1A	TP53	P04637	503
PPM1A	RANBP3	Q9H6Z4	496
PPM1A	RNF5	Q99942	494
PPM1A	HRH3	Q9Y5N1	494
PPM1A	SLC16A8	O95907	493
PPM1A	MAP2K4	P45985	481

IntAct

164 interactions, top by confidence:

A	B	Type	Score
DCP1B	DDX6	psi-mi:“MI:0914”(association)	0.890
PIGS	GPAA1	psi-mi:“MI:0914”(association)	0.760
	TOMM70	psi-mi:“MI:0914”(association)	0.690
HIP1R	HIP1	psi-mi:“MI:0914”(association)	0.640
CERKL	PPM1A	psi-mi:“MI:0915”(physical association)	0.620
PPM1A	MAPK1	psi-mi:“MI:0915”(physical association)	0.610
PPM1A	MAPK1	psi-mi:“MI:0407”(direct interaction)	0.610
PPM1A	MAPK1	psi-mi:“MI:0203”(dephosphorylation reaction)	0.610
RANBP3	PPM1A	psi-mi:“MI:0407”(direct interaction)	0.600
PPM1A	RANBP3	psi-mi:“MI:0407”(direct interaction)	0.600
RANBP3	PPM1A	psi-mi:“MI:0915”(physical association)	0.600
PPM1A	RANBP3	psi-mi:“MI:0915”(physical association)	0.600
PRSS22	PPM1A	psi-mi:“MI:0915”(physical association)	0.560
PRSS22	PPM1A	psi-mi:“MI:0914”(association)	0.560

BioGRID (197): PRKAA1 (Biochemical Activity), PPM1A (Affinity Capture-MS), PPM1A (Affinity Capture-MS), PPM1A (Affinity Capture-MS), PPM1A (Affinity Capture-MS), PPM1A (Affinity Capture-MS), VWA9 (Affinity Capture-MS), INPPL1 (Affinity Capture-MS), PPM1B (Affinity Capture-MS), RTEL1 (Affinity Capture-MS), PPM1A (Affinity Capture-MS), PPM1A (Affinity Capture-MS), PPM1A (Two-hybrid), CHEK1 (Co-fractionation), MAP4K5 (Co-fractionation)

ESM2 similar proteins: A0A3L7I2I8, A3A8W2, A4IF63, A6K136, D2GXS7, D3ZQG6, F7H9X2, O60733, O62829, O62830, O75688, O88483, P20650, P35813, P35814, P35816, P42694, P49443, P93006, P97570, P97819, Q05AL2, Q15750, Q28DF4, Q2PC20, Q3UV70, Q5F361, Q5R522, Q5RA52, Q5SMK6, Q69QZ0, Q69VD9, Q6ING9, Q6NYU2, Q6ZHC8, Q7XJ53, Q7XUC5, Q84JD5, Q8AYC9, Q8BXN7

Diamond homologs: A0A7U2MSD6, A0BLX0, A0BQL0, A0CUB5, A0DSB3, A0DTY1, A3A8Q4, A3A8W2, A3A8W6, A5PJZ2, F1LNI5, G0RT93, O04719, O15355, O15743, O62829, O62830, O75688, O80871, O81716, P20650, P34221, P35813, P35814, P35815, P36993, P38089, P39966, P40371, P49443, P49444, P49593, P49595, P49596, P49597, P49598, P79126, P93006, Q09172, Q09173

SIGNOR signaling

29 interactions.

A	Effect	B	Mechanism
PPM1A	down-regulates	SMAD2	dephosphorylation
PPM1A	down-regulates	SMAD3	dephosphorylation
PPM1A	down-regulates	SMAD1	dephosphorylation
PTEN	up-regulates	PPM1A	binding
PPM1A	down-regulates	IKBKB	dephosphorylation
PPM1A	“down-regulates activity”	SMAD2	dephosphorylation
PPM1A	down-regulates	GSK3B/Axin/APC	dephosphorylation
PPM1A	“down-regulates activity”	SMAD3	dephosphorylation
PPM1A	“down-regulates activity”	IKBKB	dephosphorylation
PPM1A	“down-regulates quantity by destabilization”	AXIN1	dephosphorylation
PPM1A	“down-regulates activity”	CDK9	dephosphorylation
PPM1A	“down-regulates activity”	STING1	dephosphorylation
PPM1A	“down-regulates activity”	RELA	dephosphorylation
PPM1A	“down-regulates activity”	TBK1	dephosphorylation
PPM1A	“up-regulates activity”	YAP1	dephosphorylation
PPM1A	“down-regulates activity”	IKBKE	dephosphorylation
PPM1A	“down-regulates activity”	IRF3	dephosphorylation
PPM1A	“down-regulates activity”	MAPK14	dephosphorylation
PPM1A	down-regulates	AXIN1	dephosphorylation
PPM1A	“up-regulates activity”	PIK3R1	dephosphorylation
PPM1A	“up-regulates activity”	PI3K	dephosphorylation
PPM1A	“down-regulates activity”	PAK1	dephosphorylation
PPM1A	“down-regulates activity”	CDK2	dephosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 152 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SHC1 events in ERBB2 signaling	5	22.9×	8e-04
Signaling by ERBB2 TMD/JMD mutants	5	22.9×	8e-04
Signaling by ERBB2 KD Mutants	5	20.3×	9e-04
Downregulation of ERBB2 signaling	5	18.3×	9e-04
Signaling by ERBB2	5	16.6×	1e-03
FOXO-mediated transcription	5	16.1×	1e-03
Extra-nuclear estrogen signaling	6	9.8×	2e-03
Signaling by NOTCH	5	8.4×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to vascular endothelial growth factor stimulus	5	20.8×	1e-03
epidermal growth factor receptor signaling pathway	6	11.0×	3e-03
phosphatidylinositol 3-kinase/protein kinase B signal transduction	7	10.9×	1e-03
positive regulation of epithelial cell proliferation	6	10.8×	3e-03
negative regulation of cell differentiation	5	10.6×	8e-03
positive regulation of protein phosphorylation	5	10.2×	9e-03
insulin receptor signaling pathway	6	9.8×	5e-03
cell surface receptor protein tyrosine kinase signaling pathway	7	9.0×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

21 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	15
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1883 predictions. Top by Δscore:

Variant	Effect	Δscore
14:60249676:GG:G	donor_gain	1.0000
14:60249677:GG:G	donor_gain	1.0000
14:60283511:G:GT	donor_gain	1.0000
14:60285622:A:AG	acceptor_gain	1.0000
14:60285622:AG:A	acceptor_gain	1.0000
14:60285623:G:GG	acceptor_gain	1.0000
14:60285623:GG:G	acceptor_gain	1.0000
14:60285623:GGGAA:G	acceptor_gain	1.0000
14:60285761:A:AG	donor_gain	1.0000
14:60291389:A:AG	acceptor_gain	1.0000
14:60291391:A:AG	acceptor_gain	1.0000
14:60291392:C:G	acceptor_gain	1.0000
14:60291392:CTTA:C	acceptor_loss	1.0000
14:60291393:TTAG:T	acceptor_loss	1.0000
14:60291395:A:G	acceptor_loss	1.0000
14:60291396:G:A	acceptor_loss	1.0000
14:60291396:GGA:G	acceptor_gain	1.0000
14:60291450:ACACT:A	donor_gain	1.0000
14:60291451:CACT:C	donor_gain	1.0000
14:60291453:CT:C	donor_gain	1.0000
14:60291455:G:GG	donor_gain	1.0000
14:60292447:A:AG	acceptor_gain	1.0000
14:60292449:A:AG	acceptor_gain	1.0000
14:60292449:AAAG:A	acceptor_gain	1.0000
14:60292450:A:G	acceptor_gain	1.0000
14:60292525:A:T	donor_gain	1.0000
14:60292577:G:GT	donor_gain	1.0000
14:60249675:CGGGT:C	donor_loss	0.9900
14:60249676:GGGTA:G	donor_loss	0.9900
14:60249678:G:GG	donor_gain	0.9900

AlphaMissense

2545 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:60282707:G:A	G2R	1.000
14:60282707:G:C	G2R	1.000
14:60282708:G:A	G2E	1.000
14:60282725:C:T	P8S	1.000
14:60282726:C:A	P8Q	1.000
14:60282793:A:C	Q30H	1.000
14:60282793:A:T	Q30H	1.000
14:60282794:G:A	G31S	1.000
14:60282794:G:C	G31R	1.000
14:60282794:G:T	G31C	1.000
14:60282795:G:A	G31D	1.000
14:60282795:G:T	G31V	1.000
14:60282797:T:A	W32R	1.000
14:60282797:T:C	W32R	1.000
14:60282798:G:C	W32S	1.000
14:60282799:G:C	W32C	1.000
14:60282799:G:T	W32C	1.000
14:60282800:C:A	R33S	1.000
14:60282800:C:G	R33G	1.000
14:60282800:C:T	R33C	1.000
14:60282801:G:A	R33H	1.000
14:60282801:G:C	R33P	1.000
14:60282811:G:A	M36I	1.000
14:60282811:G:C	M36I	1.000
14:60282811:G:T	M36I	1.000
14:60282812:G:A	E37K	1.000
14:60282813:A:T	E37V	1.000
14:60282814:G:C	E37D	1.000
14:60282814:G:T	E37D	1.000
14:60282815:G:C	D38H	1.000

dbSNP variants (sampled 300 via entrez): RS1000043437 (14:60271547 C>A), RS1000075120 (14:60271807 T>C), RS1000304460 (14:60271809 C>T), RS1000306120 (14:60248313 G>C), RS1000372745 (14:60267637 T>C), RS1000425953 (14:60298941 A>G), RS1000483413 (14:60266010 T>C), RS1000572602 (14:60256297 G>A,C), RS1000613081 (14:60255262 C>G,T), RS1000624779 (14:60265686 G>A,C), RS1000635762 (14:60260514 T>C), RS1000668279 (14:60260807 A>AT), RS1000825580 (14:60287260 T>A), RS1000853080 (14:60297055 G>A), RS1000984035 (14:60294126 G>A)

Disease associations

OMIM: gene MIM:606108 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001310_6	Allergic rhinitis	2.000000e-06
GCST003993_25	Menarche (age at onset)	1.000000e-12
GCST004067_214	Hip circumference adjusted for BMI	7.000000e-09
GCST004067_23	Hip circumference adjusted for BMI	9.000000e-10
GCST006075_18	Hair color	3.000000e-18
GCST006630_1	Diastolic blood pressure	7.000000e-14
GCST006988_128	Blond vs. brown/black hair color	1.000000e-12
GCST007576_184	Chronotype	1.000000e-08
GCST009723_7	Vertical cup-disc ratio (adjusted for vertical disc diameter)	4.000000e-25
GCST009724_57	Vertical cup-disc ratio (multi-trait analysis)	1.000000e-35
GCST010002_153	Refractive error	2.000000e-40

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0008039	BMI-adjusted hip circumference
EFO:0006336	diastolic blood pressure
EFO:0003924	hair color
EFO:0008328	chronotype measurement
EFO:0006939	cup-to-disc ratio measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2437 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2273623	PPM1A		0.00	0

ChEMBL bioactivities

14 potent at pChembl≥5 of 22 total, top 13 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.52	IC50	3	nM	MICROCYSTIN-LR
6.75	IC50	180	nM	CHEMBL5566601
6.54	IC50	290	nM	CHEMBL5556587
6.23	Ki	590	nM	CHEMBL5566601
6.08	Ki	840	nM	CHEMBL5566508
5.92	IC50	1190	nM	CHEMBL5566508
5.84	IC50	1430	nM	CHEMBL5566557
5.58	IC50	2600	nM	CHEMBL5563947
5.52	IC50	3000	nM	CHEMBL40779
5.51	IC50	3060	nM	CHEMBL5565791
5.45	IC50	3560	nM	CHEMBL5562841
5.43	IC50	3720	nM	CHEMBL5561304
5.35	IC50	4510	nM	CHEMBL5563155

PubChem BioAssay actives

14 with measured affinity, of 79 total; 11 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(5R,8S,11R,12S,15S,18S,19S,22R)-15-[3-(diaminomethylideneamino)propyl]-18-[(1E,3E,5S,6S)-6-methoxy-3,5-dimethyl-7-phenylhepta-1,3-dienyl]-1,5,12,19-tetramethyl-2-methylidene-8-(2-methylpropyl)-3,6,9,13,16,20,25-heptaoxo-1,4,7,10,14,17,21-heptazacyclopentacosane-11,22-dicarboxylic acid	164496: Inhibitory concentration required against protein phosphatase 1 using pNPP assay	ic50	0.0030	uM
2-(8-ethoxy-2-fluorophenanthridin-5-ium-5-yl)ethanol bromide	2085494: Inhibition of recombinant human PPM1A using pNPP as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by absorbance based assay	ic50	0.1800	uM
2-[2-fluoro-8-methoxy-9-(4-methoxyphenyl)phenanthridin-5-ium-5-yl]ethanol bromide	2085494: Inhibition of recombinant human PPM1A using pNPP as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by absorbance based assay	ic50	0.2900	uM
2-(2-fluoro-8-methoxyphenanthridin-5-ium-5-yl)ethanol bromide	2085493: Inhibition of PPM1A (unknown origin)	ki	0.8400	uM
2-[2-fluoro-8-(trifluoromethoxy)phenanthridin-5-ium-5-yl]ethanol bromide	2085494: Inhibition of recombinant human PPM1A using pNPP as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by absorbance based assay	ic50	1.4300	uM
2-(2,8-dimethoxyphenanthridin-5-ium-5-yl)ethanol bromide	2085494: Inhibition of recombinant human PPM1A using pNPP as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by absorbance based assay	ic50	2.6000	uM
[(2R)-2-[(5S,8R)-6,9-dioxo-2-propan-2-yloxy-1,7-dioxaspiro[4.4]nonan-8-yl]-2-hydroxyethyl] hexadecanoate	164686: Compound was evaluated for inhibitory effect against protein phosphatase I (PP-I)	ic50	3.0000	uM
2-[2-methoxy-8-(trifluoromethoxy)phenanthridin-5-ium-5-yl]ethanol bromide	2085494: Inhibition of recombinant human PPM1A using pNPP as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by absorbance based assay	ic50	3.0600	uM
2-(8-butoxy-2-fluorophenanthridin-5-ium-5-yl)ethanol bromide	2085494: Inhibition of recombinant human PPM1A using pNPP as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by absorbance based assay	ic50	3.5600	uM
2-(2-fluoro-8-propan-2-yloxyphenanthridin-5-ium-5-yl)ethanol bromide	2085494: Inhibition of recombinant human PPM1A using pNPP as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by absorbance based assay	ic50	3.7200	uM
2-(2-bromo-8-methoxyphenanthridin-5-ium-5-yl)ethanol bromide	2085494: Inhibition of recombinant human PPM1A using pNPP as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by absorbance based assay	ic50	4.5100	uM

CTD chemical–gene interactions

59 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases expression	7
trichostatin A	affects cotreatment, decreases expression	3
bisphenol A	increases expression	2
entinostat	decreases expression, affects cotreatment	2
Resveratrol	affects cotreatment, increases expression, decreases expression	2
Arsenic Trioxide	affects binding, decreases reaction, decreases expression	2
Benzo(a)pyrene	increases methylation, decreases expression	2
Cisplatin	increases response to substance, decreases response to substance, increases expression, decreases phosphorylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
bisphenol F	increases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases expression, decreases reaction	1
CGP 52608	affects binding, increases reaction	1
Roflumilast	decreases expression, decreases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1

ChEMBL screening assays

16 unique, capped per target: 16 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1275005	Binding	Inhibition of PP2Calpha at 10 uM	Discovery of small molecule inhibitors of the PH domain leucine-rich repeat protein phosphatase (PHLPP) by chemical and virtual screening. — J Med Chem

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2BQ	Abcam HeLa PPM1A KO	Cancer cell line	Female
CVCL_D6SQ	CTUi001-A	Induced pluripotent stem cell	Female
CVCL_TF33	HAP1 PPM1A (-) 1	Cancer cell line	Male
CVCL_TF34	HAP1 PPM1A (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.