PPP2R2A

Summary

PPP2R2A (protein phosphatase 2 regulatory subunit Balpha, HGNC:9304) is a protein-coding gene on chromosome 8p21.2, encoding Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform (P63151). Substrate-recognition subunit of protein phosphatase 2A (PP2A) that plays a key role in cell cycle by controlling mitosis entry and exit. In precision oncology, PPP2R2A Mutation confers sensitivity to Olaparib in Castration-resistant Prostate Carcinoma (CIViC Level B). It is a selective cancer dependency (DepMap: 19.8% of cell lines).

The product of this gene belongs to the phosphatase 2 regulatory subunit B family. Protein phosphatase 2 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. The B regulatory subunit might modulate substrate selectivity and catalytic activity. This gene encodes an alpha isoform of the regulatory subunit B55 subfamily. Alternatively spliced transcript variants have been described.

Source: NCBI Gene 5520 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 56 total
• Druggable target: yes
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Cancer dependency (DepMap): dependent in 19.8% of screened cell lines
• MANE Select transcript: NM_002717

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9304
Approved symbol	PPP2R2A
Name	protein phosphatase 2 regulatory subunit Balpha
Location	8p21.2
Locus type	gene with protein product
Status	Approved
Aliases	PR52A, PR55A, B55A, PR55alpha, B55alpha
Ensembl gene	ENSG00000221914
Ensembl biotype	protein_coding
OMIM	604941
Entrez	5520

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 11 protein_coding, 10 protein_coding_CDS_not_defined, 7 retained_intron, 3 nonsense_mediated_decay

ENST00000315985, ENST00000380737, ENST00000517754, ENST00000518208, ENST00000518215, ENST00000518254, ENST00000518397, ENST00000518890, ENST00000519439, ENST00000519636, ENST00000520329, ENST00000521095, ENST00000521484, ENST00000521557, ENST00000522150, ENST00000522482, ENST00000522535, ENST00000523473, ENST00000523925, ENST00000523964, ENST00000524099, ENST00000524169, ENST00000657943, ENST00000660435, ENST00000665751, ENST00000665949, ENST00000666129, ENST00000667651, ENST00000885492, ENST00000919755, ENST00000957406

RefSeq mRNA: 2 — MANE Select: NM_002717 NM_001177591, NM_002717

CCDS: CCDS34867, CCDS55213

Canonical transcript exons

ENST00000380737 — 10 exons

Exon	Start	End
ENSE00002091806	26370134	26372680
ENSE00002131643	26291508	26291826
ENSE00003468358	26363721	26363890
ENSE00003472689	26338890	26338987
ENSE00003484306	26360169	26360281
ENSE00003499681	26362684	26362848
ENSE00003506789	26354468	26354633
ENSE00003508265	26360974	26361151
ENSE00003521886	26293666	26293740
ENSE00003613559	26366315	26366406

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 97.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 47.1696 / max 588.4982, expressed in 1825 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
88031	36.8335	1824
88032	7.9928	1707
88033	1.4620	859
88035	0.3212	122
88036	0.3150	154
88034	0.2451	112

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	97.65	gold quality
esophagus mucosa	UBERON:0002469	96.96	gold quality
tongue squamous epithelium	UBERON:0006919	96.65	gold quality
lower esophagus mucosa	UBERON:0035834	96.65	gold quality
oral cavity	UBERON:0000167	96.57	gold quality
pharyngeal mucosa	UBERON:0000355	96.39	gold quality
colonic epithelium	UBERON:0000397	96.38	gold quality
ventricular zone	UBERON:0003053	96.23	gold quality
gluteal muscle	UBERON:0002000	95.94	gold quality
secondary oocyte	CL:0000655	95.84	gold quality
skin of leg	UBERON:0001511	95.75	gold quality
skin of abdomen	UBERON:0001416	95.73	gold quality
ganglionic eminence	UBERON:0004023	95.51	gold quality
corpus callosum	UBERON:0002336	95.43	gold quality
ectocervix	UBERON:0012249	95.15	gold quality
zone of skin	UBERON:0000014	95.07	gold quality
gastrocnemius	UBERON:0001388	95.07	gold quality
muscle of leg	UBERON:0001383	95.05	gold quality
vagina	UBERON:0000996	94.92	gold quality
embryo	UBERON:0000922	94.90	gold quality
tonsil	UBERON:0002372	94.76	gold quality
esophagus	UBERON:0001043	94.75	gold quality
esophagus squamous epithelium	UBERON:0006920	94.53	gold quality
epithelium of esophagus	UBERON:0001976	94.49	gold quality
omental fat pad	UBERON:0010414	94.49	gold quality
peritoneum	UBERON:0002358	94.48	gold quality
tibial nerve	UBERON:0001323	94.42	gold quality
muscle organ	UBERON:0001630	94.32	gold quality
skeletal muscle organ	UBERON:0014892	94.32	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.30	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.39
E-MTAB-8060	no	197.23

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

140 targeting PPP2R2A, 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-4533	100.00	69.48	2758
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548N	99.98	71.94	4170
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-106A-5P	99.90	73.94	2683

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 19.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• cyclin G2 also associates with various PP2A B’ regulatory subunits, as previously shown for cyclin G1 (PMID:11956189)
• CFTR is regulated by a direct interaction with the protein phosphatase 2A (PMID:16239222)
• PP2A ABalphaC and ABdeltaC holoenzymes function as positive regulators of Raf1-MEK1/2-ERK1/2 signaling by targeting Raf1 (PMID:16239230)
• hAR is a direct target of LEF-1/TCF transcriptional regulation in PCa cells; expression of the hAR protein is suppressed by a degradation pathway regulated by cross-talk of Wnt, Akt, and PP2A (PMID:16474850)
• Bub1 targets PP2A to centromeres, which in turn maintains Sgo1 at centromeres by counteracting Plk1-mediated chromosome removal of Sgo1. (PMID:16580887)
• deregulation of CHEK2 and/or PPP2R2A is of pathogenetic importance in at least a subset of germ cell tumors (PMID:16790090)
• The scaffolding subunit exhibits considerable conformational flexibility, which is proposed to play an essential role in PP2A function. (PMID:17055435)
• PP2A binding to Sprouty2 and phosphorylation changes are a prerequisite for ERK inhibition downstream of FGFR stimulation (PMID:17255109)
• Protein phosphatase 2A and separase form a complex regulated by separase autocleavage (PMID:17604273)
• the protein phosphatase 2A regulatory subunit alpha4 has a novel role in the regulation of cell spreading and migration (PMID:17693407)
• PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions. (PMID:18339811)
• Homozygous deletions in a number of biologically important genes were found in prostate cancer cell lines, including PPP2R2A and BNIP3L identified in this study. (PMID:18670647)
• These highly related members of the same subfamily of PP2A regulatory subunits differentially regulate TGF-beta/Activin/Nodal signalling to elicit opposing biological outcomes. (PMID:18697906)
• The authors show that E4orf4 protein interacts uniquely with B55 family subunits and that cell killing increases with the level of E4orf4 expression. (PMID:19535438)
• The results suggest that PR55 alpha specifically regulates PP2A-mediated beta-catenin dephosphorylation and plays an essential role in Wnt signaling. (PMID:19556239)
• Results demonstrate that PP2A-B55alpha and importin-beta1 cooperate in the regulation of postmitotic assembly mechanisms in human cells. (PMID:20711181)
• The interaction of human adenovirus E4orf4 with both Cdc55 and B55 involves residues within blades 1 and 2, a finding that is consistent with the idea that E4orf4 binding may block the dephosphorylation of at least some PP2A substrates. (PMID:21047956)
• These data demonstrate that B55alpha acts to antagonize Cyclin A/Cdk-dependent activation of FoxM1, to ensure that FoxM1 activity is restricted to the G(2) phase of the cell cycle. (PMID:21813648)
• Somatic deletion rather than germline sequence variants of PPP2R2A may play a more important role in prostate cancer susceptibility. (PMID:21872824)
• Both B55alpha and nuclear forkhead box O1 protein (FOXO1) levels are increased under hyperglycemic conditions in transgenic db/db mouse islets, an animal model of type 2 diabetes. (PMID:22417654)
• PPP2R2A status may serve as a marker to predict therapeutic efficacy to PARP inhibition. (PMID:23087057)
• miR-136 promotes Erk1/2 phosphorylation through targeting PPP2R2A in NSCLC cells and suggest that it may serve as a therapeutic target in NSCLC therapy. (PMID:23959478)
• Identification of the adenovirus E4orf4 protein binding site on the B55alpha and Cdc55 regulatory subunits of PP2A: Implications for PP2A (PMID:24244166)
• The suppression of B55alpha activates signaling pathways that could support leukemia cell survival. (PMID:24858343)
• Data suggest livers of biliary atresia subjects exhibit overexpression of MIR222 (microRNA 222); this appears to contribute to liver fibrosis (and in vitro cell proliferation) by targeting PPP2R2A (protein phosphatase 2A subunit B) and Akt signaling. (PMID:25238119)
• miR-136 may play an important role during TGF-beta1-induced proliferation arrest by targeting PPP2R2A in keratinocytes. (PMID:25654102)
• Data show that breast cancer (BC) with PPP2R2A deletions are associated with worse overall survival, and the combination of altered PPP2R2A and high CCND1 expression define a subgroup of luminal-like BC patients with a high risk of relapse and death. (PMID:25879784)
• overexpression of miR-892a may provide a selective growth promotion for colorectal cancer cells by direct suppression of PPP2R2A expression. (PMID:26054685)
• miR-556-5p functions as an onco-miRNA and participates in prostate cancer carcinogenesis by suppressing PPP2R2A expression. (PMID:26297546)
• Concurrent mTORC1 inactivation and PP2A-B55alpha stimulation fuel ULK1-dependent autophagy. (PMID:26310906)
• miR-222 targets protein phosphatase 2A subunit B in bladder cancer cells. (PMID:26800397)
• we propose that the Smad4-Pitx2-PPP2R2A axis, a new signaling pathway, suppresses the pancreatic carcinogenesis (PMID:26848620)
• results suggest that PR55alpha promotes pancreatic cancer development by sustaining hyperactivity of multiple oncogenic signaling pathways, including AKT, ERK, and Wnt (PMID:26893480)
• B55alpha-PP2A mutations in acute myeloid leukemia have roles in leukemogenesis by promoting AKT T308 phosphorylation and sensitivity to AKT inhibitor-induced growth arrest (PMID:27531894)
• These data unravel B55alpha as a PHD2 substrate and highlight a role for PHD2-B55alpha in the response to nutrient deprivation. (PMID:28329677)
• these results provide a novel insight into the role of PP2A-B55alpha as a novel meiotic and embryonic competence factor at the onset of life. (PMID:28439046)
• the data suggested that miR614 promoted cell proliferation and inhibited cell apoptosis of ovarian cancer (OC) cells by targeting PPP2R2A, and may therefore act as a potential target for OC therapy in the future. (PMID:29532877)
• we provide evidence that PPP2R2A represents a new miR-21 direct target and regulator of the ERK pathway and bladder cancer cell growth. (PMID:29703843)
• Taken together, the results suggest that miR-222 promotes tumor invasion and metastasis in thyroid cancer by targeting PPP2R2A. (PMID:29882471)
• Data show that SAM Domain and HD Domain-Containing Protein 1 (SAMHD1) is specifically targeted by protein phosphatase 2 regulatory subunit Balpha protein (PP2A-B55alpha) holoenzymes during mitotic exit. (PMID:29884836)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ppp2r2a	ENSMUSG00000022052
rattus_norvegicus	Ppp2r2a	ENSRNOG00000011158
caenorhabditis_elegans	sur-6	WBGENE00006352

Paralogs (3): PPP2R2C (ENSG00000074211), PPP2R2B (ENSG00000156475), PPP2R2D (ENSG00000175470)

Protein

Protein identifiers

Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform — P63151 (reviewed: P63151)

Alternative names: PP2A subunit B isoform B55-alpha, PP2A subunit B isoform PR55-alpha, PP2A subunit B isoform R2-alpha, PP2A subunit B isoform alpha

All UniProt accessions (9): A0A140VJT0, A0A590UJJ1, A0A590UJY3, E5RFR9, E5RHQ2, E5RIY1, E5RJV1, E5RJV2, P63151

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-recognition subunit of protein phosphatase 2A (PP2A) that plays a key role in cell cycle by controlling mitosis entry and exit. Involved in chromosome clustering during late mitosis by mediating dephosphorylation of MKI67. Essential for serine/threonine-protein phosphatase 2A-mediated dephosphorylation of WEE1, preventing its ubiquitin-mediated proteolysis, increasing WEE1 protein levels, and promoting the G2/M checkpoint.

Subunit / interactions. PP2A consists of a common heterodimeric core enzyme, composed of a 36 kDa catalytic subunit (subunit C) and 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 C catalytic subunit PPP2CA. Interacts with the PP2A A subunit PPP2R1A. Interacts with TP53. Interacts with IER5. Interacts with MFHAS1; the interaction is direct. Interacts with PABIR1/FAM122A (via its N-terminus); the interaction is direct and inhibits PP2A activity. Interacts with ARPP19; the interaction is direct and inhibits PP2A activity. Interacts with CRTC3.

Tissue specificity. Expressed in all tissues examined.

Domain organisation. Has an extended WD 2 repeat that is important for the interaction with PPP2R1A.

Similarity. Belongs to the phosphatase 2A regulatory subunit B family.

Isoforms (2)

UniProt ID	Names	Canonical?
P63151-1	1	yes
P63151-2	2

RefSeq proteins (2): NP_001171062, NP_002708* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000009	PP2A_PR55	Family
IPR001680	WD40_rpt	Repeat
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR018067	PP2A_PR55_CS	Conserved_site
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily

UniProt features (56 total): strand 32, helix 9, repeat 7, turn 4, initiator methionine 1, chain 1, splice variant 1, modified residue 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
8TWE	ELECTRON MICROSCOPY	2.55
9C6B	ELECTRON MICROSCOPY	2.6
9C7T	ELECTRON MICROSCOPY	2.7
8TTB	ELECTRON MICROSCOPY	2.77
8SO0	ELECTRON MICROSCOPY	2.8
3DW8	X-RAY DIFFRACTION	2.85
9MZW	ELECTRON MICROSCOPY	3.16
8UO5	ELECTRON MICROSCOPY	3.27
9N0Z	ELECTRON MICROSCOPY	3.5
9N0Y	ELECTRON MICROSCOPY	3.71

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P63151-F1	92.73	0.79

Functional residue map

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

Post-translational modifications (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

20 pathways

ID	Pathway
R-HSA-2995383	Initiation of Nuclear Envelope (NE) Reformation
R-HSA-69231	Cyclin D associated events in G1
R-HSA-69273	Cyclin A/B1/B2 associated events during G2/M transition
R-HSA-975957	Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)
R-HSA-9860927	Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells
R-HSA-1640170	Cell Cycle
R-HSA-2555396	Mitotic Metaphase and Anaphase
R-HSA-2995410	Nuclear Envelope (NE) Reassembly
R-HSA-453274	Mitotic G2-G2/M phases
R-HSA-453279	Mitotic G1 phase and G1/S transition
R-HSA-68882	Mitotic Anaphase
R-HSA-68886	M Phase
R-HSA-69236	G1 Phase
R-HSA-69275	G2/M Transition
R-HSA-69278	Cell Cycle, Mitotic
R-HSA-8953854	Metabolism of RNA
R-HSA-8953897	Cellular responses to stimuli
R-HSA-927802	Nonsense-Mediated Decay (NMD)
R-HSA-9855142	Cellular responses to mechanical stimuli
R-HSA-9860931	Response of endothelial cells to shear stress

MSigDB gene sets: 305 (showing top): ATF_B, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, YAGI_AML_WITH_INV_16_TRANSLOCATION, CCAWYNNGAAR_UNKNOWN, ENK_UV_RESPONSE_KERATINOCYTE_UP, BECKER_TAMOXIFEN_RESISTANCE_UP, KEGG_TIGHT_JUNCTION, CREBP1_Q2, MEF2_02, CREB_Q4, IRF7_01, MORF_SKP1A, GOBP_RESPONSE_TO_ALKALOID, chr8p21, GOBP_REGULATION_OF_CHROMOSOME_SEGREGATION

GO Biological Process (3): protein dephosphorylation (GO:0006470), response to morphine (GO:0043278), regulation of chromosome segregation (GO:0051983)

GO Molecular Function (6): protein phosphatase regulator activity (GO:0019888), protein-containing complex binding (GO:0044877), tau protein binding (GO:0048156), protein phosphatase 2A binding (GO:0051721), enzyme-substrate adaptor activity (GO:0140767), protein binding (GO:0005515)

GO Cellular Component (5): protein phosphatase type 2A complex (GO:0000159), nucleoplasm (GO:0005654), cytosol (GO:0005829), glutamatergic synapse (GO:0098978), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Cell Cycle, Mitotic	3
Nuclear Envelope (NE) Reassembly	1
G1 Phase	1
G2/M Transition	1
Nonsense-Mediated Decay (NMD)	1
Response of endothelial cells to shear stress	1
M Phase	1
Mitotic Anaphase	1
Mitotic Metaphase and Anaphase	1
Mitotic G1 phase and G1/S transition	1
Mitotic G2-G2/M phases	1
Cell Cycle	1
Metabolism of RNA	1
Cellular responses to stimuli	1
Cellular responses to mechanical stimuli	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein phosphatase binding	2
binding	2
cellular anatomical structure	2
dephosphorylation	1
protein modification process	1
response to isoquinoline alkaloid	1
chromosome segregation	1
regulation of cell cycle process	1
phosphoprotein phosphatase activity	1
phosphatase regulator activity	1
cytoskeletal protein binding	1
protein-macromolecule adaptor activity	1
protein serine/threonine phosphatase complex	1
nuclear lumen	1
cytoplasm	1
synapse	1
cell junction	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

271 interactions, top by confidence:

A	B	Type	Score
PPP2CA	PPP2R1A	psi-mi:“MI:0915”(physical association)	0.990
PPP2R2A	PPP2R1A	psi-mi:“MI:2364”(proximity)	0.970
PPP2R1A	PPP2R2A	psi-mi:“MI:0915”(physical association)	0.970
PPP2R1A	PPP2R2A	psi-mi:“MI:0914”(association)	0.970
PPP2R1A	STRN	psi-mi:“MI:0914”(association)	0.880
PPP2R1A	STRN	psi-mi:“MI:2364”(proximity)	0.880
PABIR1	PPP2R1A	psi-mi:“MI:0914”(association)	0.880
PPP2CA	STRN	psi-mi:“MI:0914”(association)	0.840
PPP2CB	STRN	psi-mi:“MI:0914”(association)	0.790
CDCA4	PPP2R1A	psi-mi:“MI:0914”(association)	0.790
PPP2R1B	PPP2R2A	psi-mi:“MI:0915”(physical association)	0.730
PPP2R1B	STRN	psi-mi:“MI:0914”(association)	0.730
PPP2R2D	YEATS4	psi-mi:“MI:0914”(association)	0.730
PPP2CB	CEP43	psi-mi:“MI:0914”(association)	0.730
SERTAD4	PPP2R1A	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710

BioGRID (446): PPP2R2A (Affinity Capture-MS), PPP2R2A (Affinity Capture-MS), PPP2R2A (Affinity Capture-MS), PPP2R2A (Affinity Capture-MS), PPP2R2A (Affinity Capture-MS), PPP2R2A (Affinity Capture-MS), PPP2CA (Co-fractionation), PPP2CB (Co-fractionation), PPP2R1A (Co-fractionation), PPP2R1B (Co-fractionation), PPP2R2A (Co-fractionation), PPP2R2A (Co-fractionation), PPP2R2A (Co-fractionation), PPP2R2A (Co-fractionation), PPP2R2A (Affinity Capture-MS)

ESM2 similar proteins: A1L3L9, A2X2K3, B0R0D7, B6VA23, O35142, O55029, P35606, P36876, P36877, P50410, P54614, P56932, P63150, P63151, P97888, Q00005, Q00006, Q0D2F4, Q0E2P1, Q29090, Q38821, Q39247, Q4R4I8, Q4R7Z4, Q4R8L3, Q5E9Q7, Q5R4A2, Q5R664, Q5Z8Z7, Q5ZIY5, Q66LE6, Q6AY57, Q6DIY3, Q6NY64, Q6P1F6, Q6QEF8, Q6ZWR4, Q7ZWU5, Q7ZX64, Q80W47

Diamond homologs: A1L3L9, A2X2K3, B6VA23, G5EDR3, P36872, P36876, P36877, P50410, P53031, P54614, P56932, P63150, P63151, P97888, Q00005, Q00006, Q00362, Q0D2F4, Q0E2P1, Q12702, Q29090, Q38821, Q39247, Q4R7Z4, Q4R8L3, Q54Q99, Q5E9Q7, Q5R4A2, Q5Z8Z7, Q5ZIY5, Q66LE6, Q6DIY3, Q6NY64, Q6P1F6, Q6ZWR4, Q7ZX64, Q8BG02, Q925E7, Q95LP0, Q9Y2T4

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
PPP2R2A	“down-regulates activity”	PPP2CA	binding
TGFB1	“up-regulates activity”	PPP2R2A	binding
PPP2R2A	up-regulates	TGFBR1	binding
PPP2R2A	“up-regulates activity”	RAF1	binding
PPP2R2A	“form complex”	PP2CA_R1A_R2A	binding
PABIR1	“down-regulates activity”	PPP2R2A	binding
PPP2R2A	“up-regulates quantity by stabilization”	WEE1	dephosphorylation
PPP2R2A	“down-regulates activity”	AKT	binding
PPP2R2A	“down-regulates activity”	AKT1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 182 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
Spry regulation of FGF signaling	6	34.8×	5e-06
Signaling by GSK3beta mutants	5	30.9×	3e-05
CTNNB1 S33 mutants aren’t phosphorylated	5	30.9×	3e-05
CTNNB1 S37 mutants aren’t phosphorylated	5	30.9×	3e-05
CTNNB1 S45 mutants aren’t phosphorylated	5	30.9×	3e-05
CTNNB1 T41 mutants aren’t phosphorylated	5	30.9×	3e-05
Beta-catenin phosphorylation cascade	5	27.3×	4e-05
ERK/MAPK targets	5	27.3×	4e-05

GO biological processes:

GO term	Partners	Fold	FDR
response to lead ion	5	30.8×	2e-04
insulin-like growth factor receptor signaling pathway	6	19.6×	2e-04
protein import into nucleus	8	7.6×	4e-03
intracellular signal transduction	17	4.3×	2e-04

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	7
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

2599 predictions. Top by Δscore:

Variant	Effect	Δscore
8:26293661:TCCAG:T	acceptor_loss	1.0000
8:26293664:A:AG	acceptor_gain	1.0000
8:26293665:G:A	acceptor_loss	1.0000
8:26293665:G:GG	acceptor_gain	1.0000
8:26293665:GGA:G	acceptor_gain	1.0000
8:26303228:TTA:T	donor_gain	1.0000
8:26338880:A:AG	acceptor_gain	1.0000
8:26338881:A:AG	acceptor_gain	1.0000
8:26338882:T:G	acceptor_gain	1.0000
8:26338884:A:AG	acceptor_gain	1.0000
8:26338885:T:G	acceptor_gain	1.0000
8:26338885:TACA:T	acceptor_loss	1.0000
8:26338886:A:AG	acceptor_gain	1.0000
8:26338886:ACAG:A	acceptor_loss	1.0000
8:26338887:C:G	acceptor_gain	1.0000
8:26338887:CA:C	acceptor_loss	1.0000
8:26338888:A:AG	acceptor_gain	1.0000
8:26338888:A:AT	acceptor_loss	1.0000
8:26338889:G:GT	acceptor_gain	1.0000
8:26338889:GC:G	acceptor_gain	1.0000
8:26338889:GCA:G	acceptor_gain	1.0000
8:26338889:GCAGA:G	acceptor_gain	1.0000
8:26338984:GGAG:G	donor_gain	1.0000
8:26338985:G:GT	donor_gain	1.0000
8:26338985:GAG:G	donor_gain	1.0000
8:26338986:AGG:A	donor_loss	1.0000
8:26338987:GGTA:G	donor_loss	1.0000
8:26338988:G:GG	donor_gain	1.0000
8:26338988:GTAA:G	donor_loss	1.0000
8:26354461:A:AG	acceptor_gain	1.0000

AlphaMissense

3016 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:26293692:T:A	W12R	1.000
8:26293692:T:C	W12R	1.000
8:26338913:T:C	F36L	1.000
8:26338914:T:C	F36S	1.000
8:26338915:T:A	F36L	1.000
8:26338915:T:G	F36L	1.000
8:26338926:G:T	G40V	1.000
8:26338935:T:C	L43P	1.000
8:26338937:G:C	A44P	1.000
8:26338938:C:A	A44E	1.000
8:26338943:G:A	G46R	1.000
8:26338943:G:C	G46R	1.000
8:26338944:G:A	G46E	1.000
8:26338944:G:T	G46V	1.000
8:26338946:G:C	D47H	1.000
8:26338947:A:C	D47A	1.000
8:26338947:A:T	D47V	1.000
8:26338955:G:C	G50R	1.000
8:26338955:G:T	G50C	1.000
8:26338956:G:A	G50D	1.000
8:26338956:G:T	G50V	1.000
8:26338960:A:C	R51S	1.000
8:26338960:A:T	R51S	1.000
8:26338962:T:A	V52D	1.000
8:26338965:T:A	V53D	1.000
8:26338971:T:C	F55S	1.000
8:26354516:T:C	F77L	1.000
8:26354517:T:C	F77S	1.000
8:26354518:C:A	F77L	1.000
8:26354518:C:G	F77L	1.000

dbSNP variants (sampled 300 via entrez): RS1000034981 (8:26362496 C>T), RS1000061152 (8:26314032 A>C), RS1000086513 (8:26303385 A>G), RS1000137222 (8:26306305 G>A), RS1000156121 (8:26294449 A>G), RS1000209389 (8:26294183 A>T), RS1000213407 (8:26336342 T>C), RS1000352148 (8:26340325 A>G,T), RS1000368125 (8:26346589 T>C), RS1000380170 (8:26340079 A>C), RS1000439161 (8:26303056 A>G), RS1000439369 (8:26343076 A>C), RS1000469139 (8:26306546 C>G), RS1000515718 (8:26324611 C>A,G,T), RS1000546024 (8:26320628 C>T)

Disease associations

OMIM: gene MIM:604941 | disease phenotypes:

GenCC curated gene-disease

Mondo (2): hereditary breast ovarian cancer syndrome (MONDO:0003582), hereditary neoplastic syndrome (MONDO:0015356)

Orphanet (2): Hereditary breast and/or ovarian cancer syndrome (Orphanet:145), Inherited cancer-predisposing syndrome (Orphanet:140162)

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001956_19	Height	4.000000e-08
GCST004946_17	Schizophrenia	2.000000e-11
GCST006190_46	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	2.000000e-07
GCST006193_29	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	3.000000e-09
GCST006193_69	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	2.000000e-06
GCST006195_59	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	4.000000e-06
GCST012147_6	Declining hemoglobin trajectory in blood donors	9.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0006527	smoking status measurement
EFO:0006335	systolic blood pressure
EFO:0600027	hemoglobin change measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4284 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
PPP2R2A Mutation	Olaparib	Castration-resistant Prostate Carcinoma	Sensitivity/Response	CIViC B	EID11206

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
10.19	IC50	0.065	nM	MICROCYSTIN-LR
6.42	Kd	377.5	nM	CHEMBL5653589
6.42	ED50	377.5	nM	CHEMBL5653589
5.43	Kd	3676	nM	CHEMBL3752910
5.43	ED50	3676	nM	CHEMBL3752910

PubChem BioAssay actives

3 with measured affinity, of 12 total; 3 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	164526: Observed inhibition activity of the compounds against protein phosphatases 2A (PP2A)	ic50	0.0001	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149054: Binding affinity to human PPP2R2A incubated for 45 mins by Kinobead based pull down assay	kd	0.3775	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149054: Binding affinity to human PPP2R2A incubated for 45 mins by Kinobead based pull down assay	kd	3.6760	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	affects reaction, decreases phosphorylation, increases abundance, increases expression	3
Tobacco Smoke Pollution	affects expression, increases expression	3
cyanoginosin LR	decreases expression, affects localization, increases expression	2
Metribolone	increases reaction, decreases expression, affects binding	2
aristolochic acid I	decreases expression, increases expression	1
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
riddelliine	decreases expression, increases metabolic processing	1
arsenite	affects binding, increases reaction	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
beta-methylcholine	affects expression	1
U 0126	affects expression, affects reaction	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, decreases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
Bortezomib	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Arsenic	increases abundance, increases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4223740	Binding	Reversal of okadaic acid mediated PP2A PR55alpha B regulatory subunit inactivation in human SH-SY5Y cells assessed as residual activity at 0.1 uM preincubated for 24 hrs followed by cotreatment with PPA2 inhibitor okadaic acid for 18 hrs me	Substituent effect of N-benzylated gramine derivatives that prevent the PP2A inhibition and dissipate the neuronal Ca2+ overload, as a multitarget strategy for the treatment of Alzheimer’s disease. — Bioorg Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7Y5	Ubigene A-549 PPP2R2A KO	Cancer cell line	Male
CVCL_E0LH	Ubigene HeLa PPP2R2A KO	Cancer cell line	Female
CVCL_E2HH	HAP1 PPP2R2A (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT00673335	PHASE3	COMPLETED	Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
NCT00685256	PHASE3	COMPLETED	Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children
NCT03162276	PHASE3	UNKNOWN	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00253539	PHASE2	COMPLETED	Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer
NCT00305695	PHASE2	COMPLETED	Zoledronate or Observation in Maintaining Bone Mineral Density in Patients Who Are Undergoing Surgery to Remove Both Ovaries
NCT00321633	PHASE2	COMPLETED	Carboplatin or Docetaxel in Treating Women With Metastatic Genetic Breast Cancer
NCT01333748	PHASE2	COMPLETED	Search Allelic Imbalance of Expression of BRCA Genes in Hereditary Risk of Breast and/or Ovarian Cancer
NCT01367639	PHASE2	COMPLETED	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00535119	PHASE1	COMPLETED	Veliparib, Carboplatin, and Paclitaxel in Treating Patients With Advanced Solid Cancer
NCT00892736	PHASE1	COMPLETED	Veliparib in Treating Patients With Malignant Solid Tumors That Do Not Respond to Previous Therapy
NCT03832985	EARLY_PHASE1	COMPLETED	Pediatric Reporting of Adult-Onset Genomic Results
NCT00005095	Not specified	RECRUITING	Specimen and Data Study for Ovarian Cancer Early Detection and Prevention
NCT00609505	Not specified	COMPLETED	Telemedicine vs. Face-to-Face Cancer Genetic Counseling
NCT01273909	Not specified	UNKNOWN	Outcomes After Perforator Flap Reconstruction for Breast Reconstruction and/or Lymphedema Treatment
NCT01445275	Not specified	WITHDRAWN	Cost of Cancer Risk Management in Women at Elevated Genetic Risk for Ovarian Cancer Who Participated on GOG-0199
NCT01608074	Not specified	ACTIVE_NOT_RECRUITING	Radical Fimbriectomy for Young BRCA Mutation Carriers
NCT02087592	Not specified	COMPLETED	Feasibility of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02302742	Not specified	RECRUITING	Triple Negative Breast Cancer and Germline Hereditary Breast and Ovarian Cancer Mutation Carrier Registry
NCT02324062	Not specified	COMPLETED	Cancer Genetics Hereditary Cancer Panel Testing
NCT02516540	Not specified	UNKNOWN	Efficacy of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02653105	Not specified	ACTIVE_NOT_RECRUITING	Women at Risk of Breast Cancer and OLFM4
NCT02705924	Not specified	TERMINATED	Impact of a Psychoeducational Intervention on Expectations and Coping in Young Women Exposed to a High HBOC Risk
NCT02760849	Not specified	ACTIVE_NOT_RECRUITING	Surgery in Preventing Ovarian Cancer in Patients With Genetic Mutations
NCT02786147	Not specified	COMPLETED	Identification and Referral of Women at Risk for Hereditary Breast/Ovarian Cancer
NCT02956681	Not specified	COMPLETED	Statewide Communication to Reach Diverse Low Income Women
NCT03015376	Not specified	UNKNOWN	Inherited Susceptible Genes Among Epithelial Ovarian Cancer
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT03075540	Not specified	COMPLETED	Enhancing At-risk Latina Women’s Use of Genetic Counseling for Hereditary Breast and Ovarian Cancer
NCT03124212	Not specified	RECRUITING	Cascade Genetic Testing for Hereditary Breast/Ovarian Cancer and Lynch Syndrome in Switzerland
NCT03246841	Not specified	ACTIVE_NOT_RECRUITING	Investigation of Tumour Spectrum of Germline Mutations in Breast and Ovarian Cancer Genes.
NCT03294343	Not specified	UNKNOWN	Risk-Reducing Surgeries for Hereditary Ovarian Cancer
NCT03421327	Not specified	COMPLETED	Genetic Risk: Whether, When, and How to Tell Adolescents
NCT03510689	Not specified	COMPLETED	Genetics and Heart Health After Cancer Therapy
NCT03511690	Not specified	COMPLETED	Testing an Intelligent Tutoring System to Enhance Genetic Risk Assessment
NCT03784859	Not specified	COMPLETED	Tissue Expansion in Breast Reconstruction Without Drains
NCT03979612	Not specified	UNKNOWN	Evaluation of the Adhesion to the GENEPY Network
NCT04197856	Not specified	ACTIVE_NOT_RECRUITING	Direct Information to At-risk Relatives
NCT04407611	Not specified	COMPLETED	Scalable Communication Modalities for Returning Genetic Research Results
NCT04508764	Not specified	TERMINATED	Implementation of the Families Accelerating Cascade Testing Toolkit (FACTT) for Hereditary Breast and Ovarian Cancer and Lynch Syndrome