PPP3CB

Summary

PPP3CB (protein phosphatase 3 catalytic subunit beta, HGNC:9315) is a protein-coding gene on chromosome 10q22.2, encoding Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform (P16298). Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-mediated signals.

Enables several functions, including calmodulin binding activity; calmodulin-dependent protein phosphatase activity; and protein phosphatase 2B binding activity. Involved in several processes, including calcineurin-NFAT signaling cascade; positive regulation of lysosome organization; and positive regulation of protein localization to nucleus. Located in cytoplasm. Part of calcineurin complex. Implicated in aortic valve stenosis. Biomarker of focal segmental glomerulosclerosis and schizophrenia.

Source: NCBI Gene 5532 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 30 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_021132

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9315
Approved symbol	PPP3CB
Name	protein phosphatase 3 catalytic subunit beta
Location	10q22.2
Locus type	gene with protein product
Status	Approved
Aliases	CALNA2, CNA2, PP2Bbeta
Ensembl gene	ENSG00000107758
Ensembl biotype	protein_coding
OMIM	114106
Entrez	5532

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 20 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000342558, ENST00000360663, ENST00000394828, ENST00000394829, ENST00000430762, ENST00000495897, ENST00000885952, ENST00000885953, ENST00000885954, ENST00000885955, ENST00000885956, ENST00000885957, ENST00000885958, ENST00000925233, ENST00000960339, ENST00000960340, ENST00000960341, ENST00000960342, ENST00000960343, ENST00000960344, ENST00000960345

RefSeq mRNA: 5 — MANE Select: NM_021132 NM_001142353, NM_001142354, NM_001289968, NM_001289969, NM_021132

CCDS: CCDS44436, CCDS44437, CCDS7328

Canonical transcript exons

ENST00000360663 — 14 exons

Exon	Start	End
ENSE00000987067	73444725	73444822
ENSE00001169323	73446492	73446573
ENSE00001922899	73436433	73438420
ENSE00002471389	73471468	73471613
ENSE00002484334	73467553	73467678
ENSE00002493589	73478499	73478623
ENSE00002507180	73474919	73475030
ENSE00002510207	73439872	73439901
ENSE00002706184	73495805	73496024
ENSE00003474724	73470887	73470964
ENSE00003517541	73479317	73479517
ENSE00003525698	73454412	73454489
ENSE00003634924	73471070	73471209
ENSE00003640412	73470687	73470781

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.49.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 44.7304 / max 565.1746, expressed in 1824 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
110070	41.8806	1824
110068	1.5354	990
110069	1.0761	638
110067	0.1459	58
110065	0.0881	19
110064	0.0043	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.49	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.44	gold quality
biceps brachii	UBERON:0001507	99.38	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.33	gold quality
middle temporal gyrus	UBERON:0002771	99.16	gold quality
vastus lateralis	UBERON:0001379	99.10	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.94	gold quality
skeletal muscle tissue	UBERON:0001134	98.90	gold quality
superior frontal gyrus	UBERON:0002661	98.88	gold quality
quadriceps femoris	UBERON:0001377	98.82	gold quality
orbitofrontal cortex	UBERON:0004167	98.77	gold quality
gluteal muscle	UBERON:0002000	98.73	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.67	gold quality
parietal lobe	UBERON:0001872	98.66	gold quality
postcentral gyrus	UBERON:0002581	98.66	gold quality
deltoid	UBERON:0001476	98.64	gold quality
entorhinal cortex	UBERON:0002728	98.56	gold quality
cortical plate	UBERON:0005343	98.56	gold quality
tibialis anterior	UBERON:0001385	98.49	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.41	gold quality
triceps brachii	UBERON:0001509	98.32	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.32	gold quality
muscle tissue	UBERON:0002385	98.24	gold quality
muscle organ	UBERON:0001630	98.01	gold quality
diaphragm	UBERON:0001103	97.98	gold quality
prefrontal cortex	UBERON:0000451	97.87	gold quality
occipital lobe	UBERON:0002021	97.85	gold quality
CA1 field of hippocampus	UBERON:0003881	97.76	gold quality
pons	UBERON:0000988	97.68	gold quality
muscle of leg	UBERON:0001383	97.66	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.55

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
IL2	Activation
IL6	Activation

miRNA regulators (miRDB)

113 targeting PPP3CB, 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-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248

Literature-anchored findings (GeneRIF, showing 22)

• calcineurin regulates AUF1 posttranslationally in vitro and PTH gene expression in vivo but still allows its physiological regulation by calcium and phosphate (PMID:15514034)
• depressed NCX activity might contribute to the etiology of in vivo cardiac hypertrophy and dysfunction occurring under conditions in which both calcineurin and protein kinase C are chronically activated (PMID:15557343)
• Calcineurin A beta expression is an additional means of regulating calcineurin activity in the heart. (PMID:16024800)
• Data show that the calcineurin pathway is activated in hypertrophic myocardium as demonstrated by increased calcineurin activity and expression of calcineurin A-beta and B, and GATA-4, and a shift of cytoplasmic NFAT-3 into the nucleus. (PMID:18034994)
• We describe a case of Calcineurin inhibitor-mediated bilateral hippocampal injury after bone marrow transplantation. (PMID:18458866)
• TAK1-TAB1-TAB2 selectively induces calcineurin-NFAT signalling through direct phosphorylation of RCAN1, while calcineurin activation diminishes TAK1 signalling by dephosphorylation of TAK1 and TAB1. (PMID:19136967)
• Study demonstrates that all CaN isoforms display the same cytoplasmic subcellular distribution and are expressed in each tested cell line, differences in substrate specificities may determine specific physiological functions of the distinct isoforms. (PMID:19154138)
• calcineurin is inhibited by cyclosporine A, which then exerts multiple effects on human melanoma cell lines HT168 and WM35 (PMID:19287956)
• calcineurin can dephosphorylate GSK-3beta at Ser-9 and form a stable complex with GSK-3beta, suggesting the possibility that calcineurin regulates the dephosphorylation and activation of GSK-3betain vivo (PMID:19659461)
• [review] The nuclear localization sequence, a region spanning amino acids 172-183 of calcineurin A beta, is essential for recognition and shuttling of calcineurin into the nucleus by importin beta. (PMID:19925438)
• two new complementary roles for calcineurin in the regulation of the early UPR (Unfolded Protein Responses) (PMID:20700529)
• The C allele of protein phosphatase 3 subunit alpha rs3804358 polymorphism was overrepresented in athletes compared with controls, whereas the T allele of protein phosphatase 3 subunit beta rs3763679 polymorphism was underrepresented in athletes. (PMID:21233773)
• A novel-splicing variant of calcineurin Ass CnAss-FK, which is encoded by an intron-retaining mRNA and is deficient in the autoinhibitory domain, is predominantly expressed in mature follicular keratinocytes. (PMID:21423799)
• ANXA7, PPP3CB, DNAJC9, and ZMYND17 genes are potential candidate genes for schizophrenia, especially in patients with deficits in sustained attention and executive function. (PMID:21531385)
• The expression of a constitutively active Calcineurin stimulates myoblast differentiation, whereas a Calcineurin antisense has the opposite effect. (PMID:21664352)
• Present findings indicate that downregulation of hemoxygenase-1 expression in neutrophils from hypertensive subjects is likely mediated by CN, which acts by hindering translocation to the nucleus of the transcription factor NRF2. (PMID:22739212)
• lower expression of PPP3CA and PPP3CB genes in atrium myocardium can be related to expressed postinfarction LV remodeling. (PMID:23888774)
• These findings therefore provide initial support for the novel mechanistic hypothesis that oxidation-induced global and/or local conformational changes within calcineurin (PMID:25286016)
• The mRNA expressions of PPP3CB and MEF2C were significantly up-regulated, and CAMK1 and PPP3R1 were significantly down-regulated in mitral regurgitation(MR) patients compared to normal subjects. Moreover, MR patients had significantly increased mRNA levels of PPP3CB, MEF2C and PLCE1 compared to aortic valve disease patients (PMID:27907007)
• High PPP3CB expression is associated with neuroblastoma. (PMID:30457174)
• Study demonstrates that PPP3CB overexpression inhibits EMT and migration of G401 kidney cell line and promotes tumor proliferation. Depletion of PPP3CB leads to acquisition of a mesenchymal state, thus enhancing cell migration. (PMID:30641937)
• PPP3CB overexpression mediates EGFR TKI resistance in lung tumors via calcineurin/MEK/ERK signaling. (PMID:39353739)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ppp3cb	ENSMUSG00000021816
rattus_norvegicus	Ppp3cb	ENSRNOG00000054782
drosophila_melanogaster	CanA1	FBGN0010015
drosophila_melanogaster	Pp2B-14D	FBGN0011826
drosophila_melanogaster	CanA-14F	FBGN0267912
caenorhabditis_elegans		WBGENE00006527

Paralogs (12): PPP5C (ENSG00000011485), PPEF1 (ENSG00000086717), PPP2CB (ENSG00000104695), PPP2CA (ENSG00000113575), PPP6C (ENSG00000119414), PPP3CC (ENSG00000120910), PPP3CA (ENSG00000138814), PPP4C (ENSG00000149923), PPEF2 (ENSG00000156194), PPP1CA (ENSG00000172531), PPP1CC (ENSG00000186298), PPP1CB (ENSG00000213639)

Protein

Protein identifiers

Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform — P16298 (reviewed: P16298)

Alternative names: CAM-PRP catalytic subunit, Calmodulin-dependent calcineurin A subunit beta isoform

All UniProt accessions (3): P16298, Q5F2F8, Q5F2G0

UniProt curated annotations — full annotation on UniProt →

Function. Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-mediated signals. Dephosphorylates TFEB in response to lysosomal Ca(2+) release, resulting in TFEB nuclear translocation and stimulation of lysosomal biogenesis. Dephosphorylates and activates transcription factor NFATC1. Dephosphorylates and inactivates transcription factor ELK1. Dephosphorylates DARPP32. Negatively regulates MAP3K14/NIK signaling via inhibition of nuclear translocation of the transcription factors RELA and RELB. May play a role in skeletal muscle fiber type specification.

Subunit / interactions. Forms a complex composed of a calmodulin-dependent catalytic subunit (also known as calcineurin A) and a regulatory Ca(2+)-binding subunit (also known as calcineurin B). There are three catalytic subunits, each encoded by a separate gene (PPP3CA, PPP3CB, and PPP3CC) and two regulatory subunits which are also encoded by separate genes (PPP3R1 and PPP3R2). In response to an increase in Ca(2+) intracellular levels, forms a complex composed of PPP3CB/calcineurin A, calcineurin B and calmodulin. Interacts (via calcineurin B binding domain) with regulatory subunit PPP3R1/calcineurin B. Interacts (via calmodulin-binding domain) with calmodulin; the interaction depends on calmodulin binding to Ca(2+). Interacts with SLC12A1. Interacts with SORL1. Interacts with UNC119. Interacts with MAP3K14/NIK (via C-terminus and kinase domain). Interacts with TRAF3. Interacts with SPATA33 (via PQIIIT motif). Interacts with IRGM; promoting its association with TFEB and TFEB dephosphorylation.

Subcellular location. Cytoplasm.

Activity regulation. Activated by Ca(2+)-bound calmodulin following an increase in intracellular Ca(2+). At low Ca(2+) concentrations, the catalytic subunit (also known as calcineurin A) is inactive and is bound to the regulatory subunit (also known as calcineurin B) in which only two high-affinity binding sites are occupied by Ca(2+). In response to elevated calcium levels, the occupancy of the low-affinity sites on calcineurin B by Ca(2+) causes a conformational change of the C-terminal regulatory domain of calcineurin A, resulting in the exposure of the calmodulin-binding domain and in the partial activation of calcineurin A. The subsequent binding of Ca(2+)-bound calmodulin leads to the displacement of the autoinhibitory domain from the active site and possibly of the autoinhibitory segment from the substrate binding site which fully activates calcineurin A.

Cofactor. Binds 1 Fe(3+) ion per subunit. Binds 1 zinc ion per subunit.

Domain organisation. The poly-Pro domain may confer substrate specificity. The autoinhibitory domain prevents access to the catalytic site. The autoinhibitory segment prevents access to the substrate binding site. Possible isomerization of Pro-318 within the SAPNY motif triggers a conformation switch which affects the organization and thus accessibility of the active site and the substrate binding region (PxIxIF motif). The trans- to cis-transition may favor calcineurin A activation and substrate binding. The reverse cis- to trans-transition may be enhanced by peptidyl-prolyl isomerases such as PPIA.

Miscellaneous. Unlike for protein substrates, PPP3CB activity towards synthetic phosphatase substrate p-nitrophenyl phosphate (pNPP) is increased in presence of the immunosuppressant complex FKBP12-FK506.

Similarity. Belongs to the PPP phosphatase family. PP-2B subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
P16298-1	1	yes
P16298-2	2
P16298-3	3
P16298-4	4

RefSeq proteins (5): NP_001135825, NP_001135826, NP_001276897, NP_001276898, NP_066955* (*=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
IPR041751	MPP_PP2B	Domain
IPR043360	PP2B	Family

Pfam: PF00149

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 (81 total): mutagenesis site 17, helix 17, strand 16, binding site 7, turn 7, region of interest 6, splice variant 4, modified residue 2, initiator methionine 1, chain 1, active site 1, short sequence motif 1, compositionally biased region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
4OR9	X-RAY DIFFRACTION	2.23
4ORC	X-RAY DIFFRACTION	2.7
4ORA	X-RAY DIFFRACTION	2.75

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P16298-F1	85.79	0.61

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): 160 (proton donor)

Ligand- & substrate-binding residues (7): 99; 101; 127; 127; 159; 208; 290

Post-translational modifications (2): 2, 478

Mutagenesis-validated functional residues (17):

Position	Phenotype
2–21	increases catalytic efficiency towards nfatc1 and darpp32 but not towards a peptide substrate. does not affect cytoplasm
352	severe loss of calmodulin-mediated activation. probably prevents recognition of substrates.
353	reduction of basal catalytic activity in absence of calmodulin.
356	modest increase in catalytic activity in absence of calmodulin.
357–524	loss of catalytic activity. loss of interaction with ppp3r1/calreticulin b and calmodulin.
361	severe reduction of basal catalytic activity in absence of calmodulin. severe loss of calmodulin-mediated activation. pr
365	moderate loss of calmodulin-mediated activation. probably prevents recognition of substrates.
398–524	increases catalytic activity independently of calmodulin. loss of interaction with calmodulin. does not affect interacti
415–524	increases catalytic activity independently of calmodulin. does not affect interaction with ppp3r1/calreticulin b and cal
417	modest increase in catalytic activity in absence of calmodulin. does not affect interaction with calmodulin.
418	does not affect catalytic activity in absence of calmodulin. does not affect interaction with calmodulin.
419	modest increase in catalytic activity in absence of calmodulin. does not affect interaction with calmodulin.
420	does not affect catalytic activity in absence of calmodulin. does not affect interaction with calmodulin.
421	modest increase in catalytic activity in absence of calmodulin. does not affect interaction with calmodulin.
422	modest increase in catalytic activity in absence of calmodulin. does not affect interaction with calmodulin.
423	modest increase in catalytic activity in absence of calmodulin. does not affect interaction with calmodulin.
451–524	increases basal catalytic activity. does not affect interaction with ppp3r1/calreticulin b and calmodulin.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-180024	DARPP-32 events
R-HSA-2025928	Calcineurin activates NFAT
R-HSA-2871809	FCERI mediated Ca+2 mobilization
R-HSA-4086398	Ca2+ pathway
R-HSA-5607763	CLEC7A (Dectin-1) induces NFAT activation
R-HSA-9010642	ROBO receptors bind AKAP5

MSigDB gene sets: 489 (showing top): PID_BCR_5PATHWAY, GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GOBP_MEMORY, RNGTGGGC_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, AAGCAAT_MIR137, BIOCARTA_FMLP_PATHWAY, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_COGNITION, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_BEHAVIOR, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_VACUOLE_ORGANIZATION

GO Biological Process (39): T cell mediated cytotoxicity (GO:0001913), negative regulation of T cell mediated cytotoxicity (GO:0001915), lymphangiogenesis (GO:0001946), protein phosphorylation (GO:0006468), protein dephosphorylation (GO:0006470), response to stress (GO:0006950), signal transduction (GO:0007165), heart development (GO:0007507), learning (GO:0007612), memory (GO:0007613), dephosphorylation (GO:0016311), calcium-ion regulated exocytosis (GO:0017156), negative regulation of signaling (GO:0023057), T cell differentiation (GO:0030217), locomotion involved in locomotory behavior (GO:0031987), calcineurin-NFAT signaling cascade (GO:0033173), response to cytokine (GO:0034097), positive regulation of insulin secretion involved in cellular response to glucose stimulus (GO:0035774), T cell proliferation (GO:0042098), T cell activation (GO:0042110), T cell homeostasis (GO:0043029), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of synaptic plasticity (GO:0048167), axon extension (GO:0048675), skeletal muscle fiber development (GO:0048741), regulation of insulin secretion (GO:0050796), positive regulation of calcineurin-NFAT signaling cascade (GO:0070886), calcineurin-mediated signaling (GO:0097720), positive regulation of protein localization to nucleus (GO:1900182), regulation of synaptic vesicle endocytosis (GO:1900242), positive regulation of calcium ion import across plasma membrane (GO:1905665), positive regulation of lysosome organization (GO:1905673), negative regulation of calcium ion import across plasma membrane (GO:1905949), lysosome organization (GO:0007040), regulation of gene expression (GO:0010468), negative regulation of innate immune response (GO:0045824), antibacterial innate immune response (GO:0140367), negative regulation of protein localization to nucleus (GO:1900181)

GO Molecular Function (11): protein serine/threonine phosphatase activity (GO:0004722), calcium ion binding (GO:0005509), calmodulin binding (GO:0005516), enzyme binding (GO:0019899), protein phosphatase 2B binding (GO:0030346), calmodulin-dependent protein phosphatase activity (GO:0033192), protein dimerization activity (GO:0046983), phosphoprotein phosphatase activity (GO:0004721), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (9): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), calcineurin complex (GO:0005955), protein serine/threonine phosphatase complex (GO:0008287), Z disc (GO:0030018), T-tubule (GO:0030315), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Opioid Signalling	1
Downstream signaling events of B Cell Receptor (BCR)	1
Fc epsilon receptor (FCERI) signaling	1
Beta-catenin independent WNT signaling	1
CLEC7A (Dectin-1) signaling	1
Signaling by ROBO receptors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
protein binding	3
protein modification process	2
signaling	2
learning or memory	2
T cell activation	2
leukocyte mediated cytotoxicity	1
T cell mediated immunity	1
negative regulation of leukocyte mediated cytotoxicity	1
T cell mediated cytotoxicity	1
regulation of T cell mediated cytotoxicity	1
negative regulation of T cell mediated immunity	1
anatomical structure morphogenesis	1
lymph vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
phosphorylation	1
dephosphorylation	1
response to stimulus	1
cell communication	1
cellular process	1
regulation of cellular process	1
cellular response to stimulus	1
animal organ development	1
circulatory system development	1
phosphate-containing compound metabolic process	1
regulated exocytosis	1
regulation of signaling	1
negative regulation of biological process	1
lymphocyte differentiation	1
locomotory behavior	1
locomotion	1
calcineurin-mediated signaling	1
response to peptide	1
positive regulation of insulin secretion	1
insulin secretion involved in cellular response to glucose stimulus	1
regulation of insulin secretion involved in cellular response to glucose stimulus	1
lymphocyte proliferation	1
lymphocyte activation	1
phosphoprotein phosphatase activity	1
metal ion binding	1

Protein interactions and networks

STRING

3564 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPP3CB	PPP3R1	P06705	963
PPP3CB	PPP3CA	Q08209	868
PPP3CB	CALM1	P02593	829
PPP3CB	SLC4A7	Q9Y6M7	795
PPP3CB	CALML3	P27482	753
PPP3CB	CALML5	Q9NZT1	748
PPP3CB	PPP3R2	Q96LZ3	739
PPP3CB	CALML4	Q96GE6	737
PPP3CB	CALML6	Q8TD86	731
PPP3CB	RCAN3	Q9UKA8	693
PPP3CB	PPP3CC	P48454	685
PPP3CB	NFATC2	Q13469	592
PPP3CB	NFATC3	Q12968	577
PPP3CB	RCAN2	Q14206	572
PPP3CB	RCAN1	P53805	570

IntAct

76 interactions, top by confidence:

A	B	Type	Score
GSK3A	AXIN1	psi-mi:“MI:0914”(association)	0.800
PPP1CC	CCDC85C	psi-mi:“MI:0914”(association)	0.740
RCAN1	PPP3CB	psi-mi:“MI:0914”(association)	0.660
SH3KBP1	USP27X	psi-mi:“MI:0914”(association)	0.640
KLRG2	GLRX3	psi-mi:“MI:0914”(association)	0.640
KLRG2	GXYLT2	psi-mi:“MI:0914”(association)	0.530
DEFA1	MANBA	psi-mi:“MI:0914”(association)	0.530
PPP3CC	NFATC1	psi-mi:“MI:0914”(association)	0.530
TMEM200A	STX6	psi-mi:“MI:0914”(association)	0.530
TMEM200A	PPP3CB	psi-mi:“MI:0914”(association)	0.530
PPP1R13B	CCDC85C	psi-mi:“MI:0914”(association)	0.530
IRF2	PPP3CB	psi-mi:“MI:0915”(physical association)	0.500
PPP3CB	Irak1	psi-mi:“MI:0915”(physical association)	0.500
TFEB	PPP3CB	psi-mi:“MI:0915”(physical association)	0.400
PPP3CB	GRB2	psi-mi:“MI:0915”(physical association)	0.400
	AGPS	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
PPP3CB	CACNA1H	psi-mi:“MI:0915”(physical association)	0.400
PPP3CB	TBC1D10C	psi-mi:“MI:0915”(physical association)	0.370
PPP3CB	LMTK2	psi-mi:“MI:0915”(physical association)	0.370
PPP3CB	AATK	psi-mi:“MI:0915”(physical association)	0.370
PPP3CB	EGFR	psi-mi:“MI:0915”(physical association)	0.370
PPP3CB	ROR2	psi-mi:“MI:0915”(physical association)	0.370
PPP3CB	PTK7	psi-mi:“MI:0915”(physical association)	0.370
PPP3CB	COX5A	psi-mi:“MI:0914”(association)	0.350
PRNP	WDR91	psi-mi:“MI:0914”(association)	0.350
GRB10	POLRMT	psi-mi:“MI:0914”(association)	0.350
GABARAPL2		psi-mi:“MI:0914”(association)	0.350

BioGRID (108): PPP3CB (Affinity Capture-MS), PPP3CB (Affinity Capture-MS), PPP3CB (Affinity Capture-MS), PPP3CB (Affinity Capture-MS), PPP3CB (Affinity Capture-MS), PPP3CB (Affinity Capture-MS), PPP3CB (Affinity Capture-MS), HSPA9 (Affinity Capture-MS), RAD51 (Affinity Capture-MS), COX5A (Affinity Capture-MS), RSRC1 (Affinity Capture-MS), PHF5A (Affinity Capture-MS), RBM17 (Affinity Capture-MS), AHNAK (Affinity Capture-MS), C6orf211 (Affinity Capture-MS)

ESM2 similar proteins: A0A365, A0QHM5, A0QX51, A1KIW9, A4FIS6, B1W5F4, B8ZR76, O88956, P00165, P16298, P20651, P31350, P37273, P48452, P48453, P63328, P63329, P65263, P9WK98, P9WK99, Q06GW7, Q06RA2, Q08209, Q0G9I9, Q0G9T2, Q0ZIY9, Q1KXS9, Q2KJ61, Q2PMQ5, Q332U7, Q33C02, Q3C1M5, Q4R7Q7, Q4VZI6, Q5HZM6, Q5RIC0, Q5ZHS1, Q68RX7, Q6ENT4, Q6EW22

Diamond homologs: A0C1E4, A0CCD2, A0DJ90, G5EBX9, O04858, O14829, O14830, O35385, O35655, O74789, P14747, P16298, P20604, P20651, P23287, P26570, P32345, P32838, P32945, P33329, P34430, P36614, P40421, P48452, P48453, P48454, P48455, P48456, P48457, P48528, P48529, P49576, P53043, P63328, P63329, Q05681, Q08209, Q09496, Q0G819, Q10298

SIGNOR signaling

37 interactions.

A	Effect	B	Mechanism
CALM1	up-regulates	PPP3CB	binding
“cyclosporin A”	down-regulates	PPP3CB	“chemical inhibition”
“tacrolimus (anhydrous)”	down-regulates	PPP3CB	“chemical inhibition”
PPP3CB	up-regulates	NFATC2	dephosphorylation
PPP3CB	“up-regulates activity”	DNM1L	dephosphorylation
PPP3CB	“down-regulates quantity by destabilization”	FLNA	dephosphorylation
PPP3CB	“up-regulates activity”	NFATC2	dephosphorylation
PPP3CB	“up-regulates activity”	BAD	dephosphorylation
PPP3CB	“up-regulates activity”	TFEB	dephosphorylation
CALM2	up-regulates	PPP3CB	binding
CALM3	up-regulates	PPP3CB	binding
PPP3CB	up-regulates	MEF2C
PPP3CB	up-regulates	NFATC1	relocalization
PPP3CB	up-regulates	NFATC2	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 93 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
Infectious disease	11	4.3×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
calcineurin-NFAT signaling cascade	6	59.5×	2e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	17
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2478 predictions. Top by Δscore:

Variant	Effect	Δscore
10:73446581:CAA:C	acceptor_gain	1.0000
10:73446583:A:AC	acceptor_gain	1.0000
10:73446583:A:C	acceptor_gain	1.0000
10:73454488:CA:C	acceptor_gain	1.0000
10:73454490:C:CC	acceptor_gain	1.0000
10:73454494:T:C	acceptor_gain	1.0000
10:73467547:TTATA:T	donor_loss	1.0000
10:73467548:TATAC:T	donor_loss	1.0000
10:73467550:TA:T	donor_loss	1.0000
10:73467551:A:AT	donor_loss	1.0000
10:73467552:C:CT	donor_loss	1.0000
10:73467676:CAG:C	acceptor_gain	1.0000
10:73467679:C:CC	acceptor_gain	1.0000
10:73470881:TCTTA:T	donor_loss	1.0000
10:73470882:CTTA:C	donor_loss	1.0000
10:73470883:TTACC:T	donor_loss	1.0000
10:73470884:TACCC:T	donor_loss	1.0000
10:73470885:A:AC	donor_gain	1.0000
10:73470885:A:AG	donor_loss	1.0000
10:73470885:AC:A	donor_gain	1.0000
10:73470886:C:CC	donor_gain	1.0000
10:73470886:CC:C	donor_gain	1.0000
10:73470886:CCCTG:C	donor_gain	1.0000
10:73470960:GATAG:G	acceptor_gain	1.0000
10:73470962:TAG:T	acceptor_gain	1.0000
10:73470962:TAGC:T	acceptor_loss	1.0000
10:73470963:AG:A	acceptor_gain	1.0000
10:73470963:AGC:A	acceptor_loss	1.0000
10:73470964:GC:G	acceptor_loss	1.0000
10:73470965:C:CA	acceptor_loss	1.0000

AlphaMissense

3449 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:73444769:A:G	L441S	1.000
10:73444796:A:G	L432P	1.000
10:73444796:A:T	L432H	1.000
10:73446492:C:A	R423M	1.000
10:73446495:A:G	L422P	1.000
10:73446495:A:T	L422H	1.000
10:73446503:G:C	F419L	1.000
10:73446503:G:T	F419L	1.000
10:73446505:A:G	F419L	1.000
10:73446514:C:G	A416P	1.000
10:73446516:A:C	M415R	1.000
10:73446516:A:T	M415K	1.000
10:73446522:C:T	G413D	1.000
10:73446525:A:T	I412N	1.000
10:73446529:C:G	A411P	1.000
10:73446531:C:G	R410P	1.000
10:73446534:A:C	I409S	1.000
10:73446534:A:G	I409T	1.000
10:73446534:A:T	I409N	1.000
10:73446536:T:A	K408N	1.000
10:73446536:T:G	K408N	1.000
10:73446537:T:A	K408I	1.000
10:73446538:T:C	K408E	1.000
10:73446546:A:T	I405K	1.000
10:73454465:A:G	L378P	1.000
10:73454468:A:T	V377D	1.000
10:73454477:A:G	L374S	1.000
10:73454480:A:C	M373R	1.000
10:73454480:A:T	M373K	1.000
10:73467561:C:T	G367E	1.000

dbSNP variants (sampled 300 via entrez): RS1000032232 (10:73482194 G>A), RS1000041539 (10:73438247 G>A), RS1000042074 (10:73489607 C>T), RS1000146114 (10:73482418 C>G,T), RS1000257955 (10:73463626 A>C), RS1000322201 (10:73488402 C>G), RS1000356092 (10:73451126 A>G), RS1000366504 (10:73494734 G>A), RS1000400684 (10:73436765 A>C), RS1000411307 (10:73457688 A>G), RS1000525812 (10:73477114 C>CTCAG), RS1000544543 (10:73482574 A>C), RS1000579641 (10:73477428 T>C,G), RS1000747731 (10:73456169 T>C), RS1000811965 (10:73451541 T>C)

Disease associations

OMIM: gene MIM:114106 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5278 (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: 397 (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
CHEMBL1241348	FALDAPREVIR	3	397

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

ChEMBL bioactivities

1 potent at pChembl≥5 of 2 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.05	IC50	9000	nM	FALDAPREVIR

PubChem BioAssay actives

1 with measured affinity, of 7 total; 1 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
trans-(1R,2S)-1-[[(2S,4R)-4-[8-bromo-7-methoxy-2-[2-(2-methylpropanoylamino)-1,3-thiazol-4-yl]quinolin-4-yl]oxy-1-[(2S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl]pyrrolidine-2-carbonyl]amino]-2-ethenylcyclopropane-1-carboxylic acid	575882: Inhibition of human PP2B	ic50	9.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation, increases expression, affects localization, affects reaction, increases phosphorylation (+1 more)	3
Valproic Acid	decreases methylation, increases expression, affects expression	3
bisphenol F	decreases reaction, increases expression, affects cotreatment, decreases expression, increases methylation	2
cobaltous chloride	decreases expression	2
ochratoxin A	decreases expression	2
Cyclosporine	increases expression, decreases expression, decreases reaction	2
Cadmium Chloride	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
4-(4-fluorophenyl)sulfonyl-5-methylthio-2-phenyloxazole	affects binding, affects localization, decreases reaction	1
triphenyl phosphate	affects expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
periodate-oxidized adenosine	affects expression	1
beta-methylcholine	affects expression	1
bafilomycin A	affects cotreatment, increases lipidation, increases reaction	1
di-n-butylphosphoric acid	affects expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	decreases expression	1
4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo(1,5-a)pyrimidin-3-yl)phenol	decreases reaction, increases expression	1
(+)-JQ1 compound	increases expression	1
Irinotecan	decreases expression	1
Arsenic Trioxide	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	increases expression	1
Glyphosate	increases expression	1
Air Pollutants	increases abundance, decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Atrazine	increases expression	1
Vehicle Emissions	decreases 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
CHEMBL1275004	Binding	Inhibition of protein phosphatase 2B 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 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9P9	Ubigene HEK293 PPP3CB KO	Transformed cell line	Female
CVCL_E0LK	Ubigene HeLa PPP3CB KO	Cancer cell line	Female
CVCL_TG16	HAP1 PPP3CB (-) 1	Cancer cell line	Male
CVCL_TG17	HAP1 PPP3CB (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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