PPP2CA

Summary

PPP2CA (protein phosphatase 2 catalytic subunit alpha, HGNC:9299) is a protein-coding gene on chromosome 5q31.1, encoding Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform (P67775). Catalytic subunit of protein phosphatase 2A (PP2A), a serine/threonine phosphatase involved in the regulation of a wide variety of enzymes, signal transduction pathways, and cellular events. It is a selective cancer dependency (DepMap: 84.5% of cell lines).

This gene encodes the phosphatase 2A catalytic subunit. Protein phosphatase 2A is one of the four major Ser/Thr phosphatases, and it is implicated in the negative control of cell growth and division. It consists of a common heteromeric core enzyme, which is composed of a catalytic subunit and a constant regulatory subunit, that associates with a variety of regulatory subunits. This gene encodes an alpha isoform of the catalytic subunit.

Source: NCBI Gene 5515 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 249 total — 14 pathogenic, 22 likely-pathogenic
• Phenotypes (HPO): 42
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 84.5% of screened cell lines
• MANE Select transcript: NM_002715

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9299
Approved symbol	PPP2CA
Name	protein phosphatase 2 catalytic subunit alpha
Location	5q31.1
Locus type	gene with protein product
Status	Approved
Aliases	PP2Calpha, PP2AC
Ensembl gene	ENSG00000113575
Ensembl biotype	protein_coding
OMIM	176915
Entrez	5515

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 13 protein_coding, 2 protein_coding_CDS_not_defined, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000231504, ENST00000472253, ENST00000481195, ENST00000495833, ENST00000522385, ENST00000523082, ENST00000703308, ENST00000703309, ENST00000703310, ENST00000703311, ENST00000703354, ENST00000703359, ENST00000869735, ENST00000869736, ENST00000869737, ENST00000917375, ENST00000917376, ENST00000968138

RefSeq mRNA: 2 — MANE Select: NM_002715 NM_001355019, NM_002715

CCDS: CCDS4173, CCDS93781

Canonical transcript exons

ENST00000481195 — 7 exons

Exon	Start	End
ENSE00000763318	134201848	134202021
ENSE00001686181	134200335	134200496
ENSE00001751835	134200985	134201074
ENSE00003511084	134205922	134206131
ENSE00003988738	134199086	134199204
ENSE00003988739	134194332	134197844
ENSE00003988741	134225760	134226073

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 98.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 113.1053 / max 1710.6031, expressed in 1828 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63452	104.4815	1828
63451	5.5030	1695
63453	2.8938	1330
63454	0.1624	42
63455	0.0647	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	98.65	gold quality
ventricular zone	UBERON:0003053	98.58	gold quality
ganglionic eminence	UBERON:0004023	98.53	gold quality
cortical plate	UBERON:0005343	98.32	gold quality
adrenal tissue	UBERON:0018303	98.19	gold quality
stromal cell of endometrium	CL:0002255	98.07	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.06	gold quality
postcentral gyrus	UBERON:0002581	97.98	gold quality
prefrontal cortex	UBERON:0000451	97.77	gold quality
substantia nigra pars compacta	UBERON:0001965	97.75	gold quality
pons	UBERON:0000988	97.72	gold quality
embryo	UBERON:0000922	97.71	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.69	gold quality
heart right ventricle	UBERON:0002080	97.69	gold quality
monocyte	CL:0000576	97.64	gold quality
upper leg skin	UBERON:0004262	97.62	gold quality
mononuclear cell	CL:0000842	97.58	gold quality
leukocyte	CL:0000738	97.48	gold quality
parietal lobe	UBERON:0001872	97.42	gold quality
biceps brachii	UBERON:0001507	97.41	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.41	gold quality
penis	UBERON:0000989	97.31	gold quality
superior frontal gyrus	UBERON:0002661	97.29	gold quality
amniotic fluid	UBERON:0000173	97.14	gold quality
oral cavity	UBERON:0000167	97.11	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.07	gold quality
colonic mucosa	UBERON:0000317	96.91	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.88	gold quality
colonic epithelium	UBERON:0000397	96.83	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.83	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-88	yes	4.13
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, ETS1, NTS, SP1, TFAP2A, THRA, TP53

miRNA regulators (miRDB)

148 targeting PPP2CA, 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-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-5688	99.96	73.23	4504
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 84.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• A functional role for the B56 alpha-subunit of protein phosphatase 2A in ceramide-mediated regulation of Bcl2 phosphorylation status and function (PMID:11929874)
• regulated by hydrogen peroxide and glutathionylation (PMID:12054646)
• role in p38 mitogen-activated protein kinase-mediated regulation of the c-Jun NH(2)-terminal kinase pathway in human neutrophils (PMID:12186863)
• Results describe the cell cycle expression, subcellular distribution, and metabolic stability of protein phosphatase 2Abeta in comparison with 2Aalpha. (PMID:12370081)
• the A subunit and alpha-4 (mTap42) require charged residues in separate but overlapping surface regions to associate with the back side of PP2Ac and modulate phosphatase activity (PMID:15252037)
• Studies suggest that the target of regulation by PP2A includes upstream kinases in the JNK MAPK pathway. (PMID:17693927)
• We propose that stabilization of this inactive, nuclear PP2A pool is a major in vivo function of PME-1. (PMID:17803990)
• down-regulation of expression of PP2A catalytic subunit in CAPE treated cells (PMID:17852432)
• PP2Calpha may possess tumor-suppressing properties, and it thereby sets the stage for more elaborate analyses on its involvement in the development and progression of cancer. (PMID:17941990)
• PP2A functions as a negative regulator in TGF-beta1-induced TAK1 activation (PMID:18299321)
• study found that the level of the catalytic subunit of PP2A(PP2Ac) was dramatically decreased in adult Down syndrome brain, and this decrease correlated negatively with tau leveland phosphorylation at several abnormal hyperphosphorylation sites (PMID:18430997)
• Aurora-B is an EB1-interacting protein; EB1 stimulates Aurora-B activity through antagonizing its dephosphorylation/inactivation by PP2A (PMID:18477699)
• These data shed new light on the significance of negative feedback regulation of NF-kappaB and identifies PP2A as the key regulator of this process. (PMID:18583989)
• 1. PAK plays a required role in hyperosmotic signaling through the PI3K/pTEN/Cdc42/PP2Calpha/p38 pathway, and 2) PAK and PP2Calpha modulate the effects of this pathway on focal adhesion dynamics. (PMID:18586681)
• PP2A appears to function as an endogenous regulator of SK1 phosphorylation (PMID:18852266)
• The activity of PP2A decreases with increasing concentration of arsenic trioxide during the apoptosis of NB4 and MR2 cells. (PMID:18928587)
• Active transport of the ubiquitin ligase MID1 along the microtubules is regulated by protein phosphatase 2A. (PMID:18949047)
• The catalytic subunit of protein phosphatase 2A (PP2A-C) is the protein interacting with GPR54. (PMID:18977201)
• The role of PP2A in the phosphorylation of P301L mutant human tau and in neurofibrillary tangle pathology in vivo was determined. (PMID:19126401)
• The PP2Ac alpha promoter defines a cyclic AMP response element (CRE) site flanked by CpG motifs in human T cells; methylation of the PP2Ac alpha promoter affects CREB binding to the CRE motif and suppresses its activity. (PMID:19155497)
• study shows that hydrogen peroxide increases the association of PP2A with occludin by a Src kinase-dependent mechanism, and that PP2A activity is involved in hydrogen peroxide-induced disruption of tight junctions in Caco-2 cell monolayers (PMID:19356149)
• Expression of tyrosine-phosphorylated PP2A (pY307-PP2A) was highly increased in the HER-2/neu positive breast tumours, and significantly correlated to tumour progression, thus enhancing its potential prognostic value. (PMID:19360341)
• a new role for mTOR and alpha4/PP2Ac in the control of STAT1 nuclear content, and the expression of interferon-gamma-sensitive genes involved in immunity and apoptosis. (PMID:19553685)
• VCP/p97-mediated inducible nitric-oxide synthase-dependent Tyr nitration of PP2A increases the levels of phosphatases PP2A and DUSP1 to contribute to the refractory response of conditioned cells (PMID:20100830)
• cAMP-stimulated protein phosphatase 2A activity associated with muscle A kinase-anchoring protein (mAKAP) signaling complexes inhibits the phosphorylation and activity of the cAMP-specific phosphodiesterase PDE4D3 (PMID:20106966)
• Data show that HUNK reconstitution in basal breast cancer cell lines prevented protein phosphatase 2-A (PP2A from binding to CFL-1. (PMID:20133759)
• Neuroprotectin D1 induces dephosphorylation of Bcl-xL in a PP2A-dependent manner during oxidative stress and promotes retinal pigment epithelial cell survival (PMID:20363734)
• Silencing of the PP2A/C subunit causes the HER-2/neu positive breast cancer cells to undergo apoptosis via p38 MAPK-related pathways. Phosphorylated Y307-PP2A plays an essential role in cell survival in these cells. (PMID:20558158)
• Cross-talk between serine/threonine protein phosphatase 2A and protein tyrosine phosphatase 1B regulates Src activation and adhesion of integrin alphaIIbbeta3 to fibrinogen. (PMID:20615878)
• identification of a PP2A trimeric holoenzyme containing B55alpha, which plays a major role in restricting the phosphorylation state of p107 and inducing its activation in human cells. (PMID:20663872)
• Results demonstrate that PP2A-B55alpha and importin-beta1 cooperate in the regulation of postmitotic assembly mechanisms in human cells. (PMID:20711181)
• Data show that the I84P mutation or the IIQ/VTR(83-85) and T89A substitutions in the Vpr(77-92) sequence prevent PP2A(1) binding. (PMID:21072166)
• protein serine/threonine phosphatase PP2Calpha activation efficiently prevents liver fibrosis (PMID:21151953)
• The recruitment of PP2A to UNC5H2/B allows the activation of DAPk via a PP2A-mediated dephosphorylation and that this mechanism is involved in angiogenesis regulation. (PMID:21172653)
• PP2Acalpha represents a new methylation-sensitive gene that contributes to the pathogenesis of systemic lupus erythematosus. (PMID:21346232)
• Protein phosphatase 2A was not associated with carcinoma progression of lung neoplasms. (PMID:21355954)
• modulation of PP2A activity may represent an alternative therapeutic approach for the treatment of advanced androgen-independent prostate cancer. (PMID:21393425)
• both the C-terminal Mid1-binding domain and the PP2Ac-binding determinants are required for Alpha4-mediated protection of PP2Ac from polyubiquitination and degradation. (PMID:21454489)
• evidence of an association between PPP2CA polymorphisms and elevated PP2Ac transcript levels in T cells, which implicates a new molecular pathway for systemic lupus erythematosus susceptibility in European Americans, Hispanic Americans, and Asians. (PMID:21590681)
• Hyperphosphorylation of autoantigenic targets of paraproteins is due to inactivation of PP2A. (PMID:21791414)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppp2cab	ENSDARG00000053404
mus_musculus	Ppp2ca	ENSMUSG00000020349
rattus_norvegicus	Ppp2cal1	ENSRNOG00000001893
drosophila_melanogaster	mts	FBGN0004177
caenorhabditis_elegans		WBGENE00002363

Paralogs (12): PPP5C (ENSG00000011485), PPEF1 (ENSG00000086717), PPP2CB (ENSG00000104695), PPP3CB (ENSG00000107758), PPP6C (ENSG00000119414), PPP3CC (ENSG00000120910), PPP3CA (ENSG00000138814), PPP4C (ENSG00000149923), PPEF2 (ENSG00000156194), PPP1CA (ENSG00000172531), PPP1CC (ENSG00000186298), PPP1CB (ENSG00000213639)

Protein

Protein identifiers

Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform — P67775 (reviewed: P67775)

Alternative names: Replication protein C

All UniProt accessions (8): P67775, A0A8V8TQA1, A0A8V8TQU8, A0A8V8TRA6, A0A8V8TRB3, B3KQ51, B3KUN1, E7ESG8

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of protein phosphatase 2A (PP2A), a serine/threonine phosphatase involved in the regulation of a wide variety of enzymes, signal transduction pathways, and cellular events. PP2A is the major phosphatase for microtubule-associated proteins (MAPs). PP2A can modulate the activity of phosphorylase B kinase casein kinase 2, mitogen-stimulated S6 kinase, and MAP-2 kinase. Cooperates with SGO2 to protect centromeric cohesin from separase-mediated cleavage in oocytes specifically during meiosis I. Can dephosphorylate various proteins, such as SV40 large T antigen, AXIN1, p53/TP53, PIM3, WEE1. Activates RAF1 by dephosphorylating it at ‘Ser-259’. Mediates dephosphorylation of WEE1, preventing its ubiquitin-mediated proteolysis, increasing WEE1 protein levels, and promoting the G2/M checkpoint. Mediates dephosphorylation of MYC; promoting its ubiquitin-mediated proteolysis: interaction with AMBRA1 enhances interaction between PPP2CA and MYC. Mediates dephosphorylation of FOXO3; promoting its stabilization: interaction with AMBRA1 enhances interaction between PPP2CA and FOXO3. Catalyzes dephosphorylation of the pyrin domain of NLRP3, promoting assembly of the NLRP3 inflammasome. Together with RACK1 adapter, mediates dephosphorylation of AKT1 at ‘Ser-473’, preventing AKT1 activation and AKT-mTOR signaling pathway. Dephosphorylation of AKT1 is essential for regulatory T-cells (Treg) homeostasis and stability. Catalyzes dephosphorylation of PIM3, promoting PIM3 ubiquitination and proteasomal degradation. Part of the striatin-interacting phosphatase and kinase (STRIPAK) complexes. STRIPAK complexes have critical roles in protein (de)phosphorylation and are regulators of multiple signaling pathways including Hippo, MAPK, nuclear receptor and cytoskeleton remodeling. Different types of STRIPAK complexes are involved in a variety of biological processes such as cell growth, differentiation, apoptosis, metabolism and immune regulation. Key mediator of a quality checkpoint during transcription elongation as part of the Integrator-PP2A (INTAC) complex. The INTAC complex drives premature transcription termination of transcripts that are unfavorably configured for transcriptional elongation: within the INTAC complex, PPP2CA catalyzes dephosphorylation of the C-terminal domain (CTD) of Pol II subunit POLR2A/RPB1 and SUPT5H/SPT5, thereby preventing transcriptional elongation.

Subunit / interactions. PP2A consists of a common heterodimeric core enzyme composed of PPP2CA, a 36 kDa catalytic subunit (subunit C), and PPP2R1A, a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B’’/PR72/PR130/PR59 and R5/B’/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules. Interacts with the PP2A A subunit PPP2R1A. Interacts with the regulatory subunit PPP2R2A. Interacts (via C-terminus) with PTPA. Interacts with NXN; the interaction is direct. Interacts with KCTD20. Interacts with BTBD10. Interacts with SGO1 and SGO2. Interacts with RAF1. Interaction with IGBP1 protects unassembled PPP2CA from degradative ubiquitination. Interacts with GSK3B (via C2 domain). Interacts with MFHAS1; retains PPP2CA into the cytoplasm and excludes it from the nucleus. Interacts with PABIR1/FAM122A. Interacts with ADCY8; interaction is phosphatase activity-dependent; antagonizes interaction between ADCY8 and calmodulin. Interacts with CRTC3 (when phosphorylated at ‘Ser-391’). Interacts with SPRY2; the interaction is inhibited by TESK1 interaction with SPRY2, possibly by vesicular sequestration of SPRY2. Interacts with TRAF3IP3. Interacts with AMBRA1 (via PxP motifs); enhancing interaction between PPP2CA and MYC or FOXO3. Forms a complex with AMBRA1 and BECN1; AMBRA1 and BECN1 components of the complex regulate MYC stability via different pathways. Part of the core of STRIPAK complexes composed of PP2A catalytic and scaffolding subunits, the striatins (PP2A regulatory subunits), the striatin-associated proteins MOB4, STRIP1 and STRIP2, PDCD10 and members of the STE20 kinases, such as STK24 and STK26. Phosphatase component of the Integrator-PP2A (INTAC) complex, composed of the Integrator core complex and protein phosphatase 2A subunits PPP2CA and PPP2R1A.

Subcellular location. Cytoplasm. Nucleus. Chromosome. Centromere. Cytoskeleton. Spindle pole.

Post-translational modifications. Reversibly methyl esterified on Leu-309 by leucine carboxyl methyltransferase 1 (LCMT1) and protein phosphatase methylesterase 1 (PPME1). Carboxyl methylation influences the affinity of the catalytic subunit for the different regulatory subunits, thereby modulating the PP2A holoenzyme’s substrate specificity, enzyme activity and cellular localization. Phosphorylation of either threonine (by autophosphorylation-activated protein kinase) or tyrosine results in inactivation of the phosphatase. Auto-dephosphorylation has been suggested as a mechanism for reactivation. Polyubiquitinated, leading to its degradation by the proteasome.

Disease relevance. Houge-Janssens syndrome 3 (HJS3) [MIM:618354] An autosomal dominant neurodevelopmental disorder characterized by global developmental delay with onset in infancy and additional variable features including hypotonia, epilepsy, brain abnormalities such as ventriculomegaly and a small corpus callosum, and autism spectrum disorder. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by the interaction between PPP2R2A and ARPP19; this inhibition is enhanced when ARPP19 is phosphorylated. Inhibited by the interaction between PPP2R2A and PABIR1/FAM122A.

Cofactor. Binds 2 metal ions per subunit. Can be two manganese ions, or one iron ion and one zinc ion.

Miscellaneous. Catalytically inactive, shows enhanced binding to IGBP1, and does not interact with the scaffolding subunit PPP2R1A.

Similarity. Belongs to the PPP phosphatase family. PP-1 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P67775-1	1, PP2Acalpha1	yes
P67775-2	2, PP2Acalpha2

RefSeq proteins (2): NP_001341948, NP_002706* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004843	Calcineurin-like_PHP	Domain
IPR006186	Ser/Thr-sp_prot-phosphatase	Domain
IPR029052	Metallo-depent_PP-like	Homologous_superfamily
IPR047129	PPA2-like	Family

Pfam: PF00149

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 (69 total): strand 18, binding site 14, sequence variant 13, helix 12, turn 5, modified residue 2, mutagenesis site 2, chain 1, active site 1, splice variant 1

Structure

Experimental structures (PDB)

50 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
4NY3	X-RAY DIFFRACTION	1.8
4I5L	X-RAY DIFFRACTION	2.43
8TWE	ELECTRON MICROSCOPY	2.55
2IE4	X-RAY DIFFRACTION	2.6
9C6B	ELECTRON MICROSCOPY	2.6
8TWI	ELECTRON MICROSCOPY	2.69
3FGA	X-RAY DIFFRACTION	2.7
3P71	X-RAY DIFFRACTION	2.7
8U1X	ELECTRON MICROSCOPY	2.7
9C7T	ELECTRON MICROSCOPY	2.7
8TTB	ELECTRON MICROSCOPY	2.77
4IYP	X-RAY DIFFRACTION	2.8
8SO0	ELECTRON MICROSCOPY	2.8
2IE3	X-RAY DIFFRACTION	2.8
3C5W	X-RAY DIFFRACTION	2.8
4I5N	X-RAY DIFFRACTION	2.8
4LAC	X-RAY DIFFRACTION	2.82
3DW8	X-RAY DIFFRACTION	2.85
3K7V	X-RAY DIFFRACTION	2.85
3K7W	X-RAY DIFFRACTION	2.96
8RC4	ELECTRON MICROSCOPY	3.1
8UWB	X-RAY DIFFRACTION	3.15
9MZW	ELECTRON MICROSCOPY	3.16
9MF5	ELECTRON MICROSCOPY	3.2
9O04	ELECTRON MICROSCOPY	3.2
8UO5	ELECTRON MICROSCOPY	3.27
2NPP	X-RAY DIFFRACTION	3.3
7K36	ELECTRON MICROSCOPY	3.3
8U89	ELECTRON MICROSCOPY	3.3
9J5I	ELECTRON MICROSCOPY	3.38

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P67775-F1	94.86	0.92

Functional residue map

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

Catalytic / active sites (1): 118 (proton donor)

Ligand- & substrate-binding residues (14): 117; 117; 167; 167; 241; 241; 57; 57; 59; 59; 85; 85 …

Post-translational modifications (2): 307, 309

Mutagenesis-validated functional residues (2):

Position	Phenotype
85	loss of phosphatase activity.
309	loss of binding to pp2a b-alpha regulatory subunit.

Function

Pathways and Gene Ontology

Reactome pathways

38 pathways

ID	Pathway
R-HSA-113501	Inhibition of replication initiation of damaged DNA by RB1/E2F1
R-HSA-1295596	Spry regulation of FGF signaling
R-HSA-141444	Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal
R-HSA-163767	PP2A-mediated dephosphorylation of key metabolic factors
R-HSA-180024	DARPP-32 events
R-HSA-195253	Degradation of beta-catenin by the destruction complex
R-HSA-196299	Beta-catenin phosphorylation cascade
R-HSA-198753	ERK/MAPK targets
R-HSA-202670	ERKs are inactivated
R-HSA-2465910	MASTL Facilitates Mitotic Progression
R-HSA-2467813	Separation of Sister Chromatids
R-HSA-2500257	Resolution of Sister Chromatid Cohesion
R-HSA-2995383	Initiation of Nuclear Envelope (NE) Reformation
R-HSA-389356	Co-stimulation by CD28
R-HSA-389513	Co-inhibition by CTLA4
R-HSA-432142	Platelet sensitization by LDL
R-HSA-4641262	Disassembly of the destruction complex and recruitment of AXIN to the membrane
R-HSA-5339716	Signaling by GSK3beta mutants
R-HSA-5358747	CTNNB1 S33 mutants aren’t phosphorylated
R-HSA-5358749	CTNNB1 S37 mutants aren’t phosphorylated
R-HSA-5358751	CTNNB1 S45 mutants aren’t phosphorylated
R-HSA-5358752	CTNNB1 T41 mutants aren’t phosphorylated
R-HSA-5467337	APC truncation mutants have impaired AXIN binding
R-HSA-5467340	AXIN missense mutants destabilize the destruction complex
R-HSA-5467348	Truncations of AMER1 destabilize the destruction complex
R-HSA-5663220	RHO GTPases Activate Formins
R-HSA-5673000	RAF activation
R-HSA-5675221	Negative regulation of MAPK pathway
R-HSA-6804757	Regulation of TP53 Degradation
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling

MSigDB gene sets: 646 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, REACTOME_INHIBITION_OF_REPLICATION_INITIATION_OF_DAMAGED_DNA_BY_RB1_E2F1, AP1_01, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, REACTOME_INNATE_IMMUNE_SYSTEM, BIOCARTA_TEL_PATHWAY, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, LU_IL4_SIGNALING, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, RORA1_01, GOBP_RESPONSE_TO_FLUID_SHEAR_STRESS, TTTGTAG_MIR520D

GO Biological Process (23): mitotic cell cycle (GO:0000278), protein dephosphorylation (GO:0006470), mesoderm development (GO:0007498), response to lead ion (GO:0010288), negative regulation of epithelial to mesenchymal transition (GO:0010719), regulation of microtubule polymerization (GO:0031113), negative regulation of hippo signaling (GO:0035331), intracellular signal transduction (GO:0035556), peptidyl-threonine dephosphorylation (GO:0035970), regulation of growth (GO:0040008), T cell homeostasis (GO:0043029), regulation of cell differentiation (GO:0045595), meiotic cell cycle (GO:0051321), negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051898), negative regulation of canonical Wnt signaling pathway (GO:0090090), vascular endothelial cell response to oscillatory fluid shear stress (GO:0097706), RNA polymerase II transcription initiation surveillance (GO:0160240), positive regulation of NLRP3 inflammasome complex assembly (GO:1900227), negative regulation of glycolytic process through fructose-6-phosphate (GO:1904539), regulation of G1/S transition of mitotic cell cycle (GO:2000045), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), transcription elongation by RNA polymerase II (GO:0006368)

GO Molecular Function (12): phosphoprotein phosphatase activity (GO:0004721), protein serine/threonine phosphatase activity (GO:0004722), protein tyrosine phosphatase activity (GO:0004725), metal ion binding (GO:0046872), protein heterodimerization activity (GO:0046982), tau protein binding (GO:0048156), GABA receptor binding (GO:0050811), RNA polymerase II CTD heptapeptide repeat S2 phosphatase activity (GO:0180006), RNA polymerase II CTD heptapeptide repeat S5 phosphatase activity (GO:0180007), RNA polymerase II CTD heptapeptide repeat S7 phosphatase activity (GO:0180008), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (19): protein phosphatase type 2A complex (GO:0000159), chromosome, centromeric region (GO:0000775), chromatin (GO:0000785), spindle pole (GO:0000922), nucleus (GO:0005634), mitochondrion (GO:0005739), cytosol (GO:0005829), plasma membrane (GO:0005886), microtubule cytoskeleton (GO:0015630), membrane (GO:0016020), membrane raft (GO:0045121), synapse (GO:0045202), extracellular exosome (GO:0070062), FAR/SIN/STRIPAK complex (GO:0090443), INTAC complex (GO:0160232), chromosome (GO:0005694), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), protein serine/threonine phosphatase complex (GO:0008287)

Reactome top-level categories

Rollup of top-22 pathways:

Category	Pathways
Regulation of T cell activation by CD28 family	2
Signaling by CTNNB1 phospho-site mutants	2
E2F mediated regulation of DNA replication	1
Negative regulation of FGFR1 signaling	1
Negative regulation of FGFR2 signaling	1
Negative regulation of FGFR3 signaling	1
Negative regulation of FGFR4 signaling	1
Amplification of signal from the kinetochores	1
Integration of energy metabolism	1
Opioid Signalling	1
Signaling by WNT	1
Degradation of beta-catenin by the destruction complex	1
Nuclear Events (kinase and transcription factor activation)	1
MAPK targets/ Nuclear events mediated by MAP kinases	1
ERK/MAPK targets	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
RNA polymerase II CTD heptapeptide repeat phosphatase activity	3
cell cycle	2
negative regulation of intracellular signal transduction	2
intracellular anatomical structure	2
phosphoprotein phosphatase activity	2
intracellular membrane-bounded organelle	2
cytoplasm	2
intracellular membraneless organelle	2
mitotic nuclear division	1
dephosphorylation	1
protein modification process	1
tissue development	1
response to metal ion	1
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
negative regulation of cell differentiation	1
negative regulation of multicellular organismal process	1
regulation of microtubule polymerization or depolymerization	1
regulation of protein polymerization	1
microtubule polymerization	1
regulation of supramolecular fiber organization	1
hippo signaling	1
regulation of hippo signaling	1
signal transduction	1
protein dephosphorylation	1
growth	1
regulation of biological process	1
lymphocyte homeostasis	1
cell differentiation	1
regulation of developmental process	1
regulation of cellular process	1
sexual reproduction	1
reproductive process	1
meiotic nuclear division	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

485 interactions, top by confidence:

A	B	Type	Score
PPP2R1A	PPP2CA	psi-mi:“MI:0407”(direct interaction)	0.990
PPP2R1A	PPP2CA	psi-mi:“MI:0915”(physical association)	0.990
PPP2CA	PPP2R1A	psi-mi:“MI:0915”(physical association)	0.990
PPP2CA	PPP2R1A	psi-mi:“MI:0407”(direct interaction)	0.990
PPP2R1A	PPP2CA	psi-mi:“MI:0414”(enzymatic reaction)	0.990
PPP2R1A	PPP2CA	psi-mi:“MI:0914”(association)	0.990
PDCD10	STK25	psi-mi:“MI:0914”(association)	0.980
PPP2R2A	PPP2R1A	psi-mi:“MI:2364”(proximity)	0.970
PPP2R1A	PPP2R2A	psi-mi:“MI:0915”(physical association)	0.970
PPP2CA	IGBP1	psi-mi:“MI:0915”(physical association)	0.960

BioGRID (951): ZFP36 (Biochemical Activity), ZFP36 (Affinity Capture-Western), PPP2CA (Affinity Capture-Western), PPP2CA (Biochemical Activity), PPP2CA (Affinity Capture-Western), VAC14 (Two-hybrid), PPP2CA (Affinity Capture-Western), PPP2CA (Affinity Capture-Western), AKT1 (Affinity Capture-Western), PPP2CA (Affinity Capture-Western), AKT1 (Biochemical Activity), PPP2CA (Affinity Capture-Western), PPP2CA (Affinity Capture-Western), DAPK1 (Biochemical Activity), PPP2R1A (Affinity Capture-Western)

ESM2 similar proteins: A0C1E4, A0CCD2, A0DJ90, A2XN40, A6H772, A8WGP3, A9JRC7, O04860, O04951, O76932, P11084, P11611, P20604, P23696, P23778, P32345, P36614, P48463, P48528, P48529, P48577, P48578, P49576, P60510, P62714, P62715, P62716, P63330, P63331, P67774, P67775, P67776, P67777, P97470, Q06009, Q07098, Q07099, Q07100, Q0P594, Q10BT5

Diamond homologs: A0C1E4, A0CCD2, A0CNL9, A0DJ90, A2X2G3, A2XN40, A2YEB4, A3C4N5, A6H772, A8WGP3, A8XE00, A9JRC7, G5EGK8, O00743, O04860, O04951, O74789, O76932, P0C5D7, P11084, P11493, P11611, P20604, P23594, P23595, P23635, P23636, P23696, P23778, P30366, P32345, P32598, P32838, P36614, P48463, P48480, P48483, P48528, P48529, P48577

SIGNOR signaling

136 interactions.

A	Effect	B	Mechanism
PPP2CA	“down-regulates activity”	MAPK1	dephosphorylation
PPP2CA	down-regulates	MAPK3	dephosphorylation
PCSK7	up-regulates	PPP2CA	phosphorylation
PPP2CA	down-regulates	RELA	dephosphorylation
PPP2CA	down-regulates	AKT	dephosphorylation
PPP2CA	up-regulates	RBL1	dephosphorylation
PPP2CA	up-regulates	RBL2	dephosphorylation
PPP2CA	down-regulates	TNNI3	dephosphorylation
PPP2CA	down-regulates	RPS3	dephosphorylation
PPP2CA	down-regulates	CILK1	dephosphorylation
PPP2R1A	up-regulates	PPP2CA	binding
PPP2CA	up-regulates	RAF1	dephosphorylation
PPP2CA	down-regulates	MAPK15	dephosphorylation
PPP2CA	down-regulates	MAPK1	dephosphorylation
PPP2CA	down-regulates	MAP3K7	dephosphorylation
PLAAT3	down-regulates	PPP2CA
PPP2CA	up-regulates	HDAC4	dephosphorylation
PPP2CA	down-regulates	RACGAP1	dephosphorylation
PPP2CA	down-regulates	SMAD3	dephosphorylation
PPP2CA	up-regulates	FOXO3	dephosphorylation
PPP2CA	“up-regulates activity”	FOXO3	dephosphorylation
PPP2CA	down-regulates	MAP3K3	dephosphorylation
PPP2CA	down-regulates	MAP2K1	dephosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 158 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
Cyclin A/B1/B2 associated events during G2/M transition	6	19.9×	1e-04
Disassembly of the destruction complex and recruitment of AXIN to the membrane	5	19.2×	2e-04
Negative regulation of the PI3K/AKT network	6	18.0×	1e-04
MAP kinase activation	5	16.6×	4e-04
Regulation of TP53 Degradation	5	15.7×	4e-04
Interleukin-17 signaling	5	13.6×	7e-04
Degradation of beta-catenin by the destruction complex	7	13.0×	1e-04
Cyclin D associated events in G1	5	12.5×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of hippo signaling	7	36.4×	6e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	22
Uncertain significance	72
Likely benign	106
Benign	9

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1335596	NM_002715.4(PPP2CA):c.401del (p.Cys133_Leu134insTer)	Pathogenic
1370149	NM_002715.4(PPP2CA):c.841_842insAA (p.Thr281fs)	Pathogenic
1372250	NM_002715.4(PPP2CA):c.3G>A (p.Met1Ile)	Pathogenic
1382033	NM_002715.4(PPP2CA):c.51_55dup (p.Glu19fs)	Pathogenic
1431864	NM_002715.4(PPP2CA):c.75_76del (p.Glu25fs)	Pathogenic
1451881	NM_002715.4(PPP2CA):c.558del (p.Gln187fs)	Pathogenic
1679293	NM_002715.4(PPP2CA):c.576+1G>A	Pathogenic
1806213	NM_002715.4(PPP2CA):c.379del (p.Tyr127fs)	Pathogenic
2016857	NM_002715.4(PPP2CA):c.852C>G (p.Tyr284Ter)	Pathogenic
2810281	NM_002715.4(PPP2CA):c.814C>T (p.Gln272Ter)	Pathogenic
4755652	NM_002715.4(PPP2CA):c.374_375insGA (p.Val126fs)	Pathogenic
620079	NM_002715.4(PPP2CA):c.438del (p.Phe146fs)	Pathogenic
620080	NM_002715.4(PPP2CA):c.373C>T (p.Gln125Ter)	Pathogenic
807663	NM_002715.4(PPP2CA):c.724C>G (p.Gln242Glu)	Pathogenic
1028042	NM_002715.4(PPP2CA):c.373C>A (p.Gln125Lys)	Likely pathogenic
1299001	NM_002715.4(PPP2CA):c.744_745del (p.Tyr248_Asn249delinsTer)	Likely pathogenic
1409655	NM_002715.4(PPP2CA):c.164G>T (p.Cys55Phe)	Likely pathogenic
1676571	NM_002715.4(PPP2CA):c.133G>A (p.Val45Met)	Likely pathogenic
1705530	NM_002715.4(PPP2CA):c.696_697insA (p.Gly233fs)	Likely pathogenic
1710068	NM_002715.4(PPP2CA):c.491del (p.Phe164fs)	Likely pathogenic
2311455	NM_002715.4(PPP2CA):c.811A>G (p.Asn271Asp)	Likely pathogenic
2631335	NM_002715.4(PPP2CA):c.796T>C (p.Cys266Arg)	Likely pathogenic
2633346	NM_002715.4(PPP2CA):c.654C>A (p.Tyr218Ter)	Likely pathogenic
2850305	NM_002715.4(PPP2CA):c.272ATT[1] (p.Tyr92del)	Likely pathogenic
3337492	NM_002715.4(PPP2CA):c.548T>C (p.Leu183Pro)	Likely pathogenic
3910674	NM_002715.4(PPP2CA):c.373del (p.Gln125fs)	Likely pathogenic
4729336	NM_002715.4(PPP2CA):c.486+1G>A	Likely pathogenic
4735092	NM_002715.4(PPP2CA):c.313-2A>T	Likely pathogenic
4819778	NM_002715.4(PPP2CA):c.729dup (p.Val244fs)	Likely pathogenic
620081	NM_002715.4(PPP2CA):c.922_924dup (p.Phe308dup)	Likely pathogenic

SpliceAI

989 predictions. Top by Δscore:

Variant	Effect	Δscore
5:134199080:A:AC	donor_gain	1.0000
5:134199081:C:CC	donor_gain	1.0000
5:134199082:TTA:T	donor_loss	1.0000
5:134199083:TA:T	donor_loss	1.0000
5:134199084:A:AC	donor_gain	1.0000
5:134199084:A:AG	donor_loss	1.0000
5:134199085:C:CA	donor_gain	1.0000
5:134199085:C:CT	donor_gain	1.0000
5:134199085:CA:C	donor_gain	1.0000
5:134199085:CAA:C	donor_gain	1.0000
5:134199085:CAAA:C	donor_gain	1.0000
5:134199085:CAAAG:C	donor_gain	1.0000
5:134199200:TATCC:T	acceptor_gain	1.0000
5:134199201:ATCC:A	acceptor_gain	1.0000
5:134199202:TCC:T	acceptor_gain	1.0000
5:134199202:TCCC:T	acceptor_loss	1.0000
5:134199203:CC:C	acceptor_gain	1.0000
5:134199203:CCC:C	acceptor_gain	1.0000
5:134199204:CC:C	acceptor_gain	1.0000
5:134199204:CCTG:C	acceptor_loss	1.0000
5:134199205:C:CC	acceptor_gain	1.0000
5:134199205:C:T	acceptor_gain	1.0000
5:134199205:CTGCA:C	acceptor_loss	1.0000
5:134199206:T:A	acceptor_loss	1.0000
5:134199208:C:CT	acceptor_gain	1.0000
5:134199209:A:T	acceptor_gain	1.0000
5:134200495:CC:C	acceptor_gain	1.0000
5:134200496:CC:C	acceptor_gain	1.0000
5:134200496:CCTAA:C	acceptor_loss	1.0000
5:134200497:C:CA	acceptor_loss	1.0000

AlphaMissense

2029 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:134197783:A:G	Y307H	1.000
5:134197835:A:C	F289L	1.000
5:134197835:A:T	F289L	1.000
5:134197837:A:G	F289L	1.000
5:134199122:G:T	A274E	1.000
5:134199123:C:G	A274P	1.000
5:134199125:G:T	A273D	1.000
5:134199130:G:C	N271K	1.000
5:134199130:G:T	N271K	1.000
5:134199132:T:C	N271D	1.000
5:134199138:A:G	C269R	1.000
5:134199141:G:T	R268S	1.000
5:134199145:A:C	C266W	1.000
5:134199146:C:T	C266Y	1.000
5:134199147:A:G	C266R	1.000
5:134199149:T:C	Y265C	1.000
5:134199150:A:G	Y265H	1.000
5:134199151:G:C	N264K	1.000
5:134199151:G:T	N264K	1.000
5:134199155:G:A	P263L	1.000
5:134199155:G:T	P263Q	1.000
5:134199158:G:T	A262D	1.000
5:134199160:A:C	S261R	1.000
5:134199160:A:T	S261R	1.000
5:134199162:T:G	S261R	1.000
5:134199163:G:C	F260L	1.000
5:134199163:G:T	F260L	1.000
5:134199164:A:C	F260C	1.000
5:134199164:A:G	F260S	1.000
5:134199165:A:C	F260V	1.000

dbSNP variants (sampled 300 via entrez): RS1000046540 (5:134209394 A>T), RS1000058427 (5:134213889 G>A), RS1000151518 (5:134216559 T>A,G), RS1000154698 (5:134225320 G>A), RS1000193256 (5:134197065 T>C), RS1000194606 (5:134206643 C>G), RS1000225862 (5:134196674 CAATAT>C), RS1000257661 (5:134203359 G>A,C), RS1000277781 (5:134225530 G>A,T), RS1000341614 (5:134215007 G>A,C), RS1000359005 (5:134196696 A>T), RS1000391618 (5:134197158 A>G), RS1000393793 (5:134203415 A>C), RS1000520354 (5:134204440 C>T), RS1000524504 (5:134209699 A>G)

Disease associations

OMIM: gene MIM:176915 | disease phenotypes: MIM:618354

GenCC curated gene-disease

Disease	Classification	Inheritance
Houge-Janssens syndrome 3	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (2): Houge-Janssens syndrome 3 (MONDO:0032697), prostate cancer (MONDO:0008315)

Orphanet (1): Familial prostate cancer (Orphanet:1331)

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000337	Broad forehead
HP:0000455	Broad nasal tip
HP:0000485	Megalocornea
HP:0000505	Visual impairment
HP:0000520	Proptosis
HP:0000629	Periorbital fullness
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000750	Delayed speech and language development
HP:0000954	Single transverse palmar crease
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001357	Plagiocephaly
HP:0001537	Umbilical hernia
HP:0001631	Atrial septal defect
HP:0002007	Frontal bossing
HP:0002069	Bilateral tonic-clonic seizure
HP:0002079	Hypoplasia of the corpus callosum
HP:0002119	Ventriculomegaly
HP:0002121	Generalized non-motor (absence) seizure
HP:0002188	Delayed CNS myelination
HP:0002365	Hypoplasia of the brainstem

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4703 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 4,679 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL48449	CANTHARIDIN	4	4,679

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Protein phosphatase catalytic subunits

Most potent curated ligand interactions (4 total), top 4:

Ligand	Action	Affinity	Parameter
microcystin-LR	Inhibition	10.0	pIC50
okadaic acid	Inhibition	9.0	pIC50
calyculin A	Inhibition	8.7	pIC50
cantharidin	Inhibition	6.7	pIC50

ChEMBL bioactivities

14 potent at pChembl≥5 of 15 total, top 14 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.60	IC50	0.25	nM	CALYCULIN A
8.15	IC50	7	nM	OKADAIC ACID
7.66	IC50	22	nM	CHEMBL17130
7.21	IC50	62	nM	CHEMBL1366322
6.80	IC50	160	nM	CANTHARIDIN
6.70	IC50	200	nM	CHEMBL4750435
6.52	IC50	304	nM	CHEMBL2368224
6.40	IC50	400	nM	CHEMBL1366322
6.40	IC50	400	nM	CHEMBL5270968
6.28	IC50	520	nM	CHEMBL3718369
6.19	IC50	640	nM	CHEMBL3716789
6.10	IC50	800	nM	CHEMBL3719114
6.05	IC50	900	nM	CHEMBL4210922
6.04	IC50	920	nM	CHEMBL3715079

PubChem BioAssay actives

7 with measured affinity, of 23 total; 7 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
[(2R,3R,5R,7R,8S,9S)-2-[(1S,3S,4S,5R,6R,7E,9E,11E,13Z)-14-cyano-3,5-dihydroxy-1-methoxy-4,6,8,9,13-pentamethyltetradeca-7,9,11,13-tetraenyl]-9-[(E)-3-[2-[(2S)-4-[[(2S,3S,4S)-4-(dimethylamino)-2,3-dihydroxy-5-methoxypentanoyl]amino]butan-2-yl]-1,3-oxazol-4-yl]prop-2-enyl]-7-hydroxy-4,4,8-trimethyl-1,10-dioxaspiro[4.5]decan-3-yl] dihydrogen phosphate	1924794: Inhibition of human PP2AC using [3H]-phosphohistone as substrate	ic50	0.0003	uM
(2R)-3-[(2S,6R,8S,11R)-2-[(E,2R)-4-[(2S,2’R,4R,4aS,6R,8aR)-4-hydroxy-2-[(1S,3S)-1-hydroxy-3-[(2S,3R,6S)-3-methyl-1,7-dioxaspiro[5.5]undecan-2-yl]butyl]-3-methylidenespiro[4a,7,8,8a-tetrahydro-4H-pyrano[3,2-b]pyran-6,5’-oxolane]-2’-yl]but-3-en-2-yl]-11-hydroxy-4-methyl-1,7-dioxaspiro[5.5]undec-4-en-8-yl]-2-hydroxy-2-methylpropanoic acid	164512: Inhibitory concentration against Protein phosphatase 2A (25 nM) isolated from bovine myocardial tissue	ic50	0.0070	uM
Cantharidin	1924790: Inhibition of PP2A (unknown origin)	ic50	0.1600	uM
4-[1-(4-methoxyphenyl)-3-(2-oxochromen-7-yl)pyrrolo[2,3-b]pyridin-5-yl]benzoic acid	1706918: Inhibition of PP2A alpha (unknown origin) pre-incubated for 20 mins followed by fluorescence substrate addition and measured after 120 mins by DiFMUP assay	ic50	0.2000	uM
(2R)-3-[(2S,6R,8S,11R)-2-[(E,2R)-4-[(2S,2’R,4R,4aS,6R,8aR)-4-hydroxy-2-(hydroxymethyl)-3-methylidenespiro[4a,7,8,8a-tetrahydro-4H-pyrano[3,2-b]pyran-6,5’-oxolane]-2’-yl]but-3-en-2-yl]-11-hydroxy-4-methyl-1,7-dioxaspiro[5.5]undec-4-en-8-yl]-2-hydroxy-2-methylpropanoic acid	164512: Inhibitory concentration against Protein phosphatase 2A (25 nM) isolated from bovine myocardial tissue	ic50	0.3040	uM
(1S,4S)-3-(4-methylpiperazine-1-carbonyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid	1924794: Inhibition of human PP2AC using [3H]-phosphohistone as substrate	ic50	0.4000	uM
(5R,8S,11R,15S,18S,19S,22R)-15-benzyl-1,5,18,19-tetramethyl-8-(2-methylpropyl)-3,6,9,13,16,20,25-heptaoxo-1,4,7,10,14,17,21-heptazacyclopentacosane-11,22-dicarboxylic acid	1371991: Inhibition of recombinant human PP2A catalytic subunit L309 deletion mutant using DIFMUP as substrate pretreated for 10 mins followed by substrate addition measured every 15 secs for 30 mins by fluorescence assay	ic50	0.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Okadaic Acid	decreases methylation, decreases reaction, increases phosphorylation, increases reaction, decreases response to substance (+2 more)	4
hydroquinone	affects localization, decreases phosphorylation, decreases reaction, increases expression, affects reaction (+2 more)	3
Cadmium Chloride	increases phosphorylation, affects binding, affects reaction, decreases methylation, increases reaction (+3 more)	3
cyanoginosin LR	increases expression, increases methylation, increases phosphorylation, affects expression, increases response to substance (+2 more)	2
4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole	decreases reaction, increases expression	2
(+)-JQ1 compound	affects binding, affects response to substance	2
Arsenic Trioxide	decreases reaction, affects reaction, affects binding, increases reaction, decreases expression	2
Acetaminophen	increases expression, affects localization, affects reaction, decreases phosphorylation	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Aflatoxin B1	decreases methylation	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	increases expression	1
dicrotophos	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
uranyl acetate	affects expression	1
deoxynivalenol	increases expression	1
sodium arsenate	decreases expression, increases abundance	1
arsenite	affects binding, increases reaction	1
mono-(2-ethylhexyl)phthalate	increases activity, decreases reaction, decreases expression	1
sodium arsenite	affects reaction, decreases phosphorylation	1
tetrabromobisphenol A	decreases expression	1
aspartyl-glutamyl-valyl-aspartal	affects binding, decreases reaction, increases 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
morroniside	decreases activity, decreases methylation, decreases reaction, increases phosphorylation, increases activity (+1 more)	1
bisphenol B	increases expression	1
abrine	increases expression	1

ChEMBL screening assays

19 unique, capped per target: 19 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3721027	Binding	Inhibition of recombinant PP2A1 (unknown origin) pre-incubated for 15 mins with enzyme before 32P-labeled MBP substrate addition	Tautomycetin and Tautomycetin analog biosynthesis

Cellosaurus cell lines

2 cell lines: 1 telomerase immortalized cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C3KC	N/Tert-1 PP2CA	Telomerase immortalized cell line	Male
CVCL_C9JA	WAe009-A-C	Embryonic stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer