PLPP3

Summary

PLPP3 (phospholipid phosphatase 3, HGNC:9229) is a protein-coding gene on chromosome 1p32.2, encoding Phospholipid phosphatase 3 (O14495). Magnesium-independent phospholipid phosphatase of the plasma membrane that catalyzes the dephosphorylation of a variety of glycerolipid and sphingolipid phosphate esters including phosphatidate/PA, lysophosphatidate/LPA, diacylglycerol pyrophosphate/DGPP, sphingosine 1-phosphate….

The protein encoded by this gene is a member of the phosphatidic acid phosphatase (PAP) family. PAPs convert phosphatidic acid to diacylglycerol, and function in de novo synthesis of glycerolipids as well as in receptor-activated signal transduction mediated by phospholipase D. This protein is a membrane glycoprotein localized at the cell plasma membrane. It has been shown to actively hydrolyze extracellular lysophosphatidic acid and short-chain phosphatidic acid. The expression of this gene is found to be enhanced by epidermal growth factor in Hela cells.

Source: NCBI Gene 8613 — RefSeq curated summary.

At a glance

• GWAS associations: 41
• Clinical variants (ClinVar): 38 total
• MANE Select transcript: NM_003713

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9229
Approved symbol	PLPP3
Name	phospholipid phosphatase 3
Location	1p32.2
Locus type	gene with protein product
Status	Approved
Aliases	PAP-2b, LPP3
Ensembl gene	ENSG00000162407
Ensembl biotype	protein_coding
OMIM	607125
Entrez	8613

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000371250, ENST00000459962, ENST00000461655, ENST00000472957, ENST00000476206, ENST00000892824, ENST00000892825, ENST00000959565

RefSeq mRNA: 1 — MANE Select: NM_003713 NM_003713

CCDS: CCDS604

Canonical transcript exons

ENST00000371250 — 6 exons

Exon	Start	End
ENSE00001064879	56524277	56524554
ENSE00001064884	56523823	56523880
ENSE00001454749	56578878	56579563
ENSE00001898322	56494761	56496676
ENSE00003471407	56536955	56537112
ENSE00003480094	56511976	56512152

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 99.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 49.6803 / max 1407.9595, expressed in 1605 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
12531	21.0241	1548
12533	16.0153	1027
12534	8.4181	824
12535	1.0410	628
12528	0.9007	471
12532	0.5581	335
12525	0.4137	220
12516	0.3760	188
12515	0.3385	149
12527	0.1983	98

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endocervix	UBERON:0000458	99.17	gold quality
decidua	UBERON:0002450	99.17	gold quality
ventricular zone	UBERON:0003053	98.91	gold quality
right lobe of thyroid gland	UBERON:0001119	98.88	gold quality
urethra	UBERON:0000057	98.70	gold quality
thyroid gland	UBERON:0002046	98.63	gold quality
left lobe of thyroid gland	UBERON:0001120	98.62	gold quality
left uterine tube	UBERON:0001303	98.61	gold quality
skin of hip	UBERON:0001554	98.50	gold quality
calcaneal tendon	UBERON:0003701	98.49	gold quality
synovial joint	UBERON:0002217	98.48	gold quality
placenta	UBERON:0001987	98.37	gold quality
mammalian vulva	UBERON:0000997	98.21	gold quality
vena cava	UBERON:0004087	98.09	gold quality
subcutaneous adipose tissue	UBERON:0002190	98.07	gold quality
cartilage tissue	UBERON:0002418	97.99	gold quality
olfactory bulb	UBERON:0002264	97.98	gold quality
tibial nerve	UBERON:0001323	97.64	gold quality
ectocervix	UBERON:0012249	97.64	gold quality
mucosa of stomach	UBERON:0001199	97.61	gold quality
seminal vesicle	UBERON:0000998	97.59	gold quality
popliteal artery	UBERON:0002250	97.59	gold quality
tibial artery	UBERON:0007610	97.58	gold quality
omental fat pad	UBERON:0010414	97.45	gold quality
peritoneum	UBERON:0002358	97.44	gold quality
superficial temporal artery	UBERON:0001614	97.37	gold quality
adipose tissue of abdominal region	UBERON:0007808	97.36	gold quality
layer of synovial tissue	UBERON:0007616	97.30	gold quality
gall bladder	UBERON:0002110	97.18	gold quality
lateral globus pallidus	UBERON:0002476	97.11	gold quality

Single-cell (SCXA)

Detected in 25 experiment(s), a significant marker in 23.

Experiment	Marker?	Max mean expression
E-MTAB-10553	yes	1960.75
E-GEOD-134144	yes	1585.23
E-GEOD-93593	yes	518.64
E-MTAB-8142	yes	116.61
E-MTAB-6701	yes	61.80
E-GEOD-135922	yes	60.12
E-MTAB-8410	yes	57.45
E-HCAD-10	yes	42.38
E-HCAD-5	yes	37.40
E-CURD-46	yes	27.76
E-CURD-119	yes	24.46
E-HCAD-9	yes	21.00
E-HCAD-4	yes	20.65
E-HCAD-1	yes	18.69
E-GEOD-84465	yes	13.91

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXC1, MYC, STAT3

miRNA regulators (miRDB)

177 targeting PLPP3, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4533	100.00	69.48	2758
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-3120-5P	100.00	65.56	965
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
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-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939

Literature-anchored findings (GeneRIF, showing 18)

• there are marked differences in biochemical activity between fly Wun and mammalian lipid phosphate phosphatase (LPPs), with Wun having a narrower activity range than has been reported for the mammalian LPPs (PMID:12856002)
• LPP1 and LPP3 are distributed in distinct lipid rafts that may provide unique microenvironments defining their non-redundant physiological functions. (PMID:17005594)
• LPP3 acted as an ecto-phosphatase on FTY720-P. (PMID:17555747)
• endogenous LPP2 and LPP3 form homo- and hetero-oligomers, which differ in their subcellular localization and which may confer differing spatial regulation of phosphatidic acid and sphingosine 1-phosphate signalling (PMID:18215144)
• Results identify a key role for LPP3 in orchestrating PTEN-mediated beta-catenin/LEF-1 signaling in EC migration, cell-cell adhesion, and formation of branching point structures. (PMID:20123964)
• expression of LPP3 in human colon tumor (SW480) cells potentiated tumor growth via increased beta-catenin stability and CYCLIN-D1 synthesis (PMID:21569306)
• PPAP2B gene rearrangement is associated with lipomas. (PMID:23508853)
• study concludes polymorphisms of TGM5, PPAP2B and PSMA4 are not major contributors tonon-small cell lung cancer susceptibility in never-smoking hinese population, this primarily can be attributed to the significantly distinct genetic background of Asian populations from western populations (PMID:24518713)
• Mechanosensitive PPAP2B plays a critical role in promoting anti-inflammatory phenotype and maintaining vascular integrity of endothelial monolayer under atheroprotective flow. (PMID:26034042)
• LPP3 is a negative regulator of inflammatory cytokines, leucocyte adhesion, cell survival, and migration in HAECs, suggesting a protective role of LPP3 against endothelial dysfunction. (PMID:27694435)
• Data show gender-related differences in the association between phosphatidic acid phosphatase type 2B (PPAP2B) gene single nucleotide polymorphisms (SNPs) and coronary heart disease (CHD) susceptibility in the Chinese Han population. (PMID:28061459)
• LPP3 is the key enzyme in the breakdown of LPA by melanoma cells. (PMID:28871044)
• ENPP2 was in silico discovered to be genetically altered in some patients with lung cancer, whereas increased autotaxin (ATX) staining and activity were detected in patients and mouse models, accompanied by a downregulation of PLPP3 expression. Most importantly, genetic deletion of Enpp2 or Lpar1 in mice resulted in disease attenuation, thus confirming a pro-carcinogenic role of ATX/LPA in the lung. (PMID:29724718)
• DNA methylation of a MIR-based enhancer downregulates the expression of PLPP3 and promotes the mineralization of the aortic valve in calcific aortic valve disease. (PMID:29726894)
• Findings indicate that up-regulation of PLPP3 during inflammation and atherosclerosis results from canonical activation of the NF-kappaB signaling cascade to increase PLPP3 expression through nuclear import and binding of RelA and RelB transcription factors to the PLPP3 promoter and suggest a mechanism by which the LPP3 substrate, LPA, can regulate PLPP3 expression. (PMID:31362988)
• Roles for lysophosphatidic acid signaling in vascular development and disease. (PMID:32376340)
• Autotaxin-LPA-LPP3 Axis in Energy Metabolism and Metabolic Disease. (PMID:34502491)
• Lipid phosphate phosphatase 3 maintains NO-mediated flow-mediated dilatation in human adipose resistance arterioles. (PMID:36575638)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	plpp3	ENSDARG00000059933
mus_musculus	Plpp3	ENSMUSG00000028517
rattus_norvegicus	Plpp3	ENSRNOG00000008116
drosophila_melanogaster	wun	FBGN0016078
drosophila_melanogaster	laza	FBGN0037163
drosophila_melanogaster	CG11438	FBGN0037164
drosophila_melanogaster	CG11437	FBGN0037165
drosophila_melanogaster	CG11426	FBGN0037166
drosophila_melanogaster	CG11425	FBGN0037167
drosophila_melanogaster	CG12746	FBGN0037341
drosophila_melanogaster	wun2	FBGN0041087
caenorhabditis_elegans		WBGENE00018756

Paralogs (9): PLPP1 (ENSG00000067113), PLPPR2 (ENSG00000105520), PLPPR5 (ENSG00000117598), PLPPR4 (ENSG00000117600), PLPPR3 (ENSG00000129951), PLPP2 (ENSG00000141934), PLPP5 (ENSG00000147535), PLPPR1 (ENSG00000148123), PLPP4 (ENSG00000203805)

Protein

Protein identifiers

Phospholipid phosphatase 3 — O14495 (reviewed: O14495)

Alternative names: Lipid phosphate phosphohydrolase 3, PAP2-beta, Phosphatidate phosphohydrolase type 2b, Phosphatidic acid phosphatase 2b, Vascular endothelial growth factor and type I collagen-inducible protein

All UniProt accessions (1): O14495

UniProt curated annotations — full annotation on UniProt →

Function. Magnesium-independent phospholipid phosphatase of the plasma membrane that catalyzes the dephosphorylation of a variety of glycerolipid and sphingolipid phosphate esters including phosphatidate/PA, lysophosphatidate/LPA, diacylglycerol pyrophosphate/DGPP, sphingosine 1-phosphate/S1P and ceramide 1-phosphate/C1P. Also acts on N-oleoyl ethanolamine phosphate/N-(9Z-octadecenoyl)-ethanolamine phosphate, a potential physiological compound. Has both an extracellular and an intracellular phosphatase activity, allowing the hydrolysis and the cellular uptake of these bioactive lipid mediators from the milieu, regulating signal transduction in different cellular processes. Through the dephosphorylation of extracellular sphingosine-1-phosphate and the regulation of its extra- and intracellular availability, plays a role in vascular homeostasis, regulating endothelial cell migration, adhesion, survival, proliferation and the production of pro-inflammatory cytokines. By maintaining the appropriate levels of this lipid in the cerebellum, also ensure its proper development and function. Through its intracellular lipid phosphatase activity may act in early compartments of the secretory pathway, regulating the formation of Golgi to endoplasmic reticulum retrograde transport carriers. Independently of this phosphatase activity may also function in the Wnt signaling pathway and the stabilization of beta-catenin/CTNNB1, thereby regulating cell proliferation, migration and differentiation in angiogenesis or yet in tumor growth. Also plays a role in integrin-mediated cell-cell adhesion in angiogenesis.

Subunit / interactions. Forms functional homodimers and homooligomers that are not required for substrate recognition and catalytic activity. Can also form heterooligomers with other PLPP2 and PLPP3. Interacts with CTNND1; negatively regulates the PLPP3-mediated stabilization of beta-catenin/CTNNB1.

Subcellular location. Cell membrane. Basolateral cell membrane. Endoplasmic reticulum membrane. Endoplasmic reticulum-Golgi intermediate compartment membrane. Golgi apparatus membrane. Golgi apparatus. trans-Golgi network membrane. Membrane raft.

Tissue specificity. Ubiquitously expressed. Highly expressed in heart and placenta.

Post-translational modifications. N-glycosylated. Contains high-mannose oligosaccharides.

Activity regulation. Magnesium-independent phospholipid phosphatase. Insensitive to N-ethylmaleimide. Inhibited by sphingosine, zinc ions and modestly by propanolol.

Domain organisation. The integrin-binding motif mediates the binding to integrin alpha-5/beta-1 (ITGA5:ITGB1) and integrin alpha-V/beta-3 (ITGAV:ITGB3) and is required for the function in integrin-mediated cell-cell adhesion. The dityrosine basolateral targeting motif mediates localization to the basolateral membrane in polarized cells.

Induction. By EGF, VEGF, FGF2 and phorbol myristate acetate (PMA).

Pathway. Lipid metabolism; phospholipid metabolism.

Similarity. Belongs to the PA-phosphatase related phosphoesterase family.

RefSeq proteins (1): NP_003704* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000326	PAP2/HPO	Domain
IPR036938	PAP2/HPO_sf	Homologous_superfamily
IPR043216	PAP-like	Family

Pfam: PF01569

Enzyme classification (BRENDA):

• EC 3.1.3.4 — phosphatidate phosphatase (BRENDA: 31 organisms, 190 substrates, 196 inhibitors, 44 Km, 3 kcat entries)

Substrate kinetics (BRENDA)

10 substrates with measured Km, best-characterized 10. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PHOSPHATIDIC ACID	0.0054–1.2	17
LYSOPHOSPHATIDATE	0.046–0.179	3
PHOSPHATIDATE	0.284–0.369	3
SPHINGOSINE-1-PHOSPHATE	0.028–0.26	3
CERAMIDE-1-PHOSPHATE	0.022–0.052	2
DIACYLGLYCEROL DIPHOSPHATE	0.041–0.104	2
LYSOPHOSPHATIDIC ACID	0.295–0.58	2
1,2-DIACYL-SN-GLYCEROL-3-PHOSPHATE	0.5954	1
2-(4,4-DIFLUORO-5,7-DIMETHYL-4-BORA-3A,4A-DIAZA-	0.024	1
DIOCTANOYL PHOSPHATIDIC ACID	1.4	1

Catalyzed reactions (Rhea), 9 shown:

• a 1,2-diacyl-sn-glycero-3-phosphate + H2O = a 1,2-diacyl-sn-glycerol + phosphate (RHEA:27429)
• sphing-4-enine 1-phosphate + H2O = sphing-4-enine + phosphate (RHEA:27518)
• an N-acylsphing-4-enine 1-phosphate + H2O = an N-acylsphing-4-enine + phosphate (RHEA:33743)
• 1,2-dihexadecanoyl-sn-glycero-3-phosphate + H2O = 1,2-dihexadecanoyl-sn-glycerol + phosphate (RHEA:43236)
• 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphate + H2O = 1,2-di-(9Z-octadecenoyl)-sn-glycerol + phosphate (RHEA:43244)
• a monoacyl-sn-glycero-3-phosphate + H2O = a monoacylglycerol + phosphate (RHEA:46736)
• (9Z)-octadecenoyl-sn-glycero-3-phosphate + H2O = (9Z-octadecenoyl)-glycerol + phosphate (RHEA:50884)
• N-(octanoyl)-sphing-4-enine-1-phosphate + H2O = N-octanoylsphing-4-enine + phosphate (RHEA:62040)
• N-(9Z-octadecenoyl)-ethanolamine phosphate + H2O = N-(9Z-octadecenoyl) ethanolamine + phosphate (RHEA:62160)

UniProt features (31 total): topological domain 7, transmembrane region 6, region of interest 4, mutagenesis site 4, short sequence motif 2, active site 2, sequence conflict 2, chain 1, site 1, modified residue 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14495-F1	84.44	0.69

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 (3): 199 (proton donors); 251 (nucleophile); 255 (stabilizes the active site histidine for nucleophilic attack)

Post-translational modifications (1): 19

Glycosylation sites (1): 170

Mutagenesis-validated functional residues (4):

Position	Phenotype
106	no effect on basolateral localization in polarized cells.
109	loss of basolateral localization in polarized cells.
110	loss of basolateral localization in polarized cells.
184	loss of binding to integrin. loss of function in integrin-mediated cell-cell interaction.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9845614	Sphingolipid catabolism

MSigDB gene sets: 490 (showing top): GOBP_LIPID_MODIFICATION, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, FREAC2_01, WWTAAGGC_UNKNOWN, NKX25_02, PEREZ_TP63_TARGETS, GOBP_SPHINGOLIPID_MEDIATED_SIGNALING_PATHWAY, GOBP_PHOSPHOLIPID_DEPHOSPHORYLATION, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, MATTIOLI_MGUS_VS_PCL, GOBP_POLYOL_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, DITTMER_PTHLH_TARGETS_UP, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP

GO Biological Process (23): blood vessel development (GO:0001568), gastrulation with mouth forming second (GO:0001702), phospholipid metabolic process (GO:0006644), sphingosine metabolic process (GO:0006670), ceramide metabolic process (GO:0006672), retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum (GO:0006890), signal transduction (GO:0007165), integrin-mediated signaling pathway (GO:0007229), positive regulation of endothelial cell migration (GO:0010595), regulation of Wnt signaling pathway (GO:0030111), sphingolipid catabolic process (GO:0030149), cell-cell adhesion mediated by integrin (GO:0033631), positive regulation of homotypic cell-cell adhesion (GO:0034112), positive regulation of transcription by RNA polymerase II (GO:0045944), phospholipid dephosphorylation (GO:0046839), protein stabilization (GO:0050821), Bergmann glial cell differentiation (GO:0060020), cell-cell adhesion (GO:0098609), regulation of sphingolipid mediated signaling pathway (GO:1902068), positive regulation of intracellular signal transduction (GO:1902533), positive regulation of endothelial cell-matrix adhesion (GO:1904906), lipid metabolic process (GO:0006629), cell adhesion (GO:0007155)

GO Molecular Function (8): integrin binding (GO:0005178), phosphatidate phosphatase activity (GO:0008195), sphingosine-1-phosphate phosphatase activity (GO:0042392), delta-catenin binding (GO:0070097), ceramide-1-phosphate phosphatase activity (GO:0106235), protein binding (GO:0005515), hydrolase activity (GO:0016787), lipid phosphatase activity (GO:0042577)

GO Cellular Component (14): Golgi membrane (GO:0000139), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), trans-Golgi network (GO:0005802), plasma membrane (GO:0005886), adherens junction (GO:0005912), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), endoplasmic reticulum-Golgi intermediate compartment membrane (GO:0033116), membrane raft (GO:0045121), endoplasmic reticulum exit site (GO:0070971), sperm midpiece (GO:0097225), sperm principal piece (GO:0097228), endoplasmic reticulum (GO:0005783)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Sphingolipid metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
lipid phosphatase activity	3
sphingolipid metabolic process	2
regulation of signal transduction	2
bounding membrane of organelle	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
sperm flagellum	2
vasculature development	1
anatomical structure development	1
gastrulation	1
lipid metabolic process	1
organophosphate metabolic process	1
diol metabolic process	1
sphingoid metabolic process	1
Golgi vesicle transport	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell surface receptor signaling pathway	1
regulation of endothelial cell migration	1
positive regulation of cell migration	1
endothelial cell migration	1
Wnt signaling pathway	1
lipid catabolic process	1
cell adhesion mediated by integrin	1
cell-cell adhesion	1
positive regulation of cell-cell adhesion	1
homotypic cell-cell adhesion	1
regulation of homotypic cell-cell adhesion	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
dephosphorylation	1
lipid modification	1
regulation of protein stability	1
astrocyte differentiation	1

Protein interactions and networks

STRING

1512 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLPP3	GPLD1	P80108	761
PLPP3	LPIN2	Q92539	741
PLPP3	LPIN1	Q14693	726
PLPP3	EPHX2	P34913	625
PLPP3	LPIN3	Q9BQK8	613
PLPP3	ENPP2	Q13822	582
PLPP3	S1PR3	Q99500	565
PLPP3	AGPAT2	O15120	553
PLPP3	DGAT1	O75907	544
PLPP3	MBOAT2	Q6ZWT7	528
PLPP3	AGPAT4	Q9NRZ5	525
PLPP3	LPAR1	P78351	516
PLPP3	AGPAT3	Q9NRZ7	486
PLPP3	CDIPT	O14735	485
PLPP3	SGPP2	Q8IWX5	482

IntAct

38 interactions, top by confidence:

A	B	Type	Score
PLPP3	CTNND1	psi-mi:“MI:0915”(physical association)	0.640
PLPP3	CTNND1	psi-mi:“MI:0403”(colocalization)	0.640
CTNND1	PLPP3	psi-mi:“MI:0403”(colocalization)	0.640
CTNND1	PLPP3	psi-mi:“MI:0915”(physical association)	0.640
PLPP3	PGAM2	psi-mi:“MI:0915”(physical association)	0.400
GPC1	SNAP23	psi-mi:“MI:0915”(physical association)	0.400
GPC1	GANAB	psi-mi:“MI:0915”(physical association)	0.400
ITGA5	PLPP3	psi-mi:“MI:0915”(physical association)	0.400
ITGAV	PLPP3	psi-mi:“MI:0915”(physical association)	0.400
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
TNFRSF10C	SLC22A23	psi-mi:“MI:0914”(association)	0.350
PLPP2	PLPP1	psi-mi:“MI:0914”(association)	0.350
TNFRSF10C	PLPP3	psi-mi:“MI:0914”(association)	0.350
BCAM	AGRN	psi-mi:“MI:0914”(association)	0.350
DLK1	PLPP3	psi-mi:“MI:0914”(association)	0.350
LGALS3	SDCBP	psi-mi:“MI:0914”(association)	0.350
SAAL1	TMEM223	psi-mi:“MI:0914”(association)	0.350
SDC1	TCAF2	psi-mi:“MI:0914”(association)	0.350
SPACA1	PLPP3	psi-mi:“MI:0914”(association)	0.350
FLVCR2	PLPP1	psi-mi:“MI:0914”(association)	0.350
SLC16A10	STXBP3	psi-mi:“MI:0914”(association)	0.350
SLC34A2	SNAP23	psi-mi:“MI:0914”(association)	0.350
SLC43A1	PLPP1	psi-mi:“MI:0914”(association)	0.350

BioGRID (48): PPAP2B (Affinity Capture-Western), PPAP2B (Synthetic Growth Defect), PPAP2B (Affinity Capture-Western), CTNND1 (Affinity Capture-Western), PPAP2B (Affinity Capture-Western), PPAP2B (Far Western), CTNND1 (Reconstituted Complex), PPAP2B (Affinity Capture-Western), PPAP2B (Affinity Capture-Western), PPAP2C (Affinity Capture-Western), PPAP2B (Affinity Capture-Western), PPAP2A (Affinity Capture-Western), PPAP2B (Proximity Label-MS), PPAP2B (Proximity Label-MS), PPAP2B (Proximity Label-MS)

ESM2 similar proteins: A0AAS4, A2AGA4, A2AJN7, A2AWR3, F4JBM4, O14495, O42153, O82756, P20350, P58872, P58873, P70553, P97544, Q0WQX7, Q12270, Q19821, Q3SZE3, Q3TWI9, Q4JM44, Q4R763, Q4V3B8, Q53P98, Q58EK4, Q5R9A7, Q5T3F8, Q695T9, Q6NLA5, Q7T3T4, Q7TSX5, Q7Z3F1, Q810K3, Q86VZ5, Q8IWX5, Q8LF05, Q8NBS3, Q8NHU3, Q8RXW0, Q8VC82, Q8VCQ6, Q8VZ48

Diamond homologs: O08564, O14494, O14495, O43688, O88956, P60588, P97544, Q04396, Q0VBU9, Q0WNG6, Q10022, Q2HJ61, Q3SZE3, Q3UMZ3, Q5VZY2, Q61469, Q6GQ62, Q6IQH6, Q86AF0, Q8K593, Q8LFD1, Q8NEB5, Q99JY8, Q9DAX2, Q9V576, Q9XI60, B0CM95, B0KWE9, B1MTH4, Q86YN1, Q9ZU49, Q29RT8, Q54PR7, Q6GM05, Q6WAY2, Q7Z2D5, Q8BFZ2, Q8TBJ4, B2KI79, Q32ZL2

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 37 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
Axon guidance	5	7.3×	7e-03
Nervous system development	5	6.9×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	29
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

993 predictions. Top by Δscore:

Variant	Effect	Δscore
1:56496675:ACCTA:A	acceptor_loss	1.0000
1:56496677:C:CC	acceptor_gain	1.0000
1:56496677:CTAG:C	acceptor_loss	1.0000
1:56496678:T:A	acceptor_loss	1.0000
1:56511968:CTACT:C	donor_loss	1.0000
1:56511969:TACTT:T	donor_loss	1.0000
1:56511970:ACTTA:A	donor_loss	1.0000
1:56511971:CTT:C	donor_loss	1.0000
1:56511972:TTAC:T	donor_loss	1.0000
1:56511973:TA:T	donor_loss	1.0000
1:56511974:A:AC	donor_gain	1.0000
1:56511974:ACT:A	donor_loss	1.0000
1:56511975:C:CA	donor_gain	1.0000
1:56511975:CT:C	donor_gain	1.0000
1:56511975:CTA:C	donor_gain	1.0000
1:56511975:CTAT:C	donor_gain	1.0000
1:56511975:CTATG:C	donor_gain	1.0000
1:56512148:TATAG:T	acceptor_gain	1.0000
1:56512149:ATAG:A	acceptor_gain	1.0000
1:56512150:TAG:T	acceptor_gain	1.0000
1:56512151:AG:A	acceptor_gain	1.0000
1:56512153:C:CC	acceptor_gain	1.0000
1:56524271:TCTCA:T	donor_loss	1.0000
1:56524272:CTCAC:C	donor_loss	1.0000
1:56524273:TCACC:T	donor_loss	1.0000
1:56524274:CA:C	donor_loss	1.0000
1:56524276:C:CT	donor_loss	1.0000
1:56536948:CACTT:C	donor_loss	1.0000
1:56536949:ACTTA:A	donor_loss	1.0000
1:56536950:CTTA:C	donor_loss	1.0000

AlphaMissense

2057 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:56511999:C:G	G263R	1.000
1:56511999:C:T	G263R	1.000
1:56512010:C:T	G259E	1.000
1:56524397:C:T	G152E	1.000
1:56524408:T:A	K148N	1.000
1:56524408:T:G	K148N	1.000
1:56524409:T:A	K148I	1.000
1:56511998:C:T	G263E	0.999
1:56512010:C:A	G259V	0.999
1:56512011:C:G	G259R	0.999
1:56512011:C:T	G259R	0.999
1:56512022:T:A	D255V	0.999
1:56512022:T:C	D255G	0.999
1:56512022:T:G	D255A	0.999
1:56512023:C:A	D255Y	0.999
1:56512023:C:G	D255H	0.999
1:56512033:G:C	H251Q	0.999
1:56512033:G:T	H251Q	0.999
1:56512035:G:C	H251D	0.999
1:56512052:C:G	R245P	0.999
1:56512053:G:T	R245S	0.999
1:56512058:A:G	L243P	0.999
1:56512061:C:T	G242E	0.999
1:56512062:C:G	G242R	0.999
1:56512062:C:T	G242R	0.999
1:56523854:G:A	S201F	0.999
1:56523859:A:C	H199Q	0.999
1:56523859:A:T	H199Q	0.999
1:56523875:G:A	S194F	0.999
1:56524310:C:G	C181S	0.999

dbSNP variants (sampled 300 via entrez): RS1000013662 (1:56527596 A>G), RS1000033977 (1:56545650 T>C,G), RS1000110492 (1:56520604 C>A), RS1000111438 (1:56527841 G>A), RS1000176281 (1:56519117 G>A), RS1000185543 (1:56527997 C>T), RS1000220578 (1:56508322 C>T), RS1000230171 (1:56570276 T>C), RS1000249531 (1:56557491 C>T), RS1000303175 (1:56575523 T>A), RS1000307140 (1:56533569 T>A), RS1000316405 (1:56514071 TA>T,TAA), RS1000441717 (1:56552130 A>G), RS1000447825 (1:56570330 T>A), RS1000475309 (1:56507577 G>A)

Disease associations

OMIM: gene MIM:607125 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

41 associations (top):

Study	Trait	p-value
GCST000998_7	Coronary heart disease	4.000000e-19
GCST000999_15	Coronary heart disease	2.000000e-07
GCST001185_2	Coronary heart disease	3.000000e-07
GCST001621_14	Airflow obstruction	5.000000e-07
GCST002287_11	Coronary artery disease or ischemic stroke	3.000000e-08
GCST002289_5	Coronary artery disease	1.000000e-08
GCST002290_10	Coronary artery disease or large artery stroke	2.000000e-08
GCST003116_20	Coronary artery disease	5.000000e-14
GCST003117_38	Myocardial infarction	2.000000e-09
GCST003338_3	Waist-to-hip ratio adjusted for body mass index	3.000000e-07
GCST004278_15	Pulse pressure	7.000000e-12
GCST004278_61	Pulse pressure	1.000000e-10
GCST004611_109	High light scatter reticulocyte count	5.000000e-16
GCST004612_149	High light scatter reticulocyte percentage of red cells	2.000000e-15
GCST004619_176	Reticulocyte fraction of red cells	1.000000e-13
GCST004622_105	Reticulocyte count	8.000000e-14
GCST004787_15	Coronary artery disease (myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, angina or chromic ischemic heart disease)	2.000000e-12
GCST005194_15	Coronary artery disease	1.000000e-27
GCST005194_16	Coronary artery disease	8.000000e-14
GCST005195_39	Coronary artery disease	8.000000e-28
GCST005196_182	Coronary artery disease	1.000000e-25
GCST005196_183	Coronary artery disease	4.000000e-13
GCST006004_7	Low density lipoprotein cholesterol levels	1.000000e-27
GCST006979_977	Heel bone mineral density	5.000000e-09
GCST007096_105	Pulse pressure	3.000000e-14
GCST007097_141	Pulse pressure	3.000000e-06
GCST007097_142	Pulse pressure	1.000000e-07
GCST007099_91	Systolic blood pressure	2.000000e-09
GCST007929_56	Medication use (calcium channel blockers)	6.000000e-09
GCST007930_38	Medication use (agents acting on the renin-angiotensin system)	3.000000e-12

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0005763	pulse pressure measurement
EFO:0007986	reticulocyte count
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0009270	heel bone mineral density
EFO:0006335	systolic blood pressure
EFO:0009930	Calcium channel blocker use measurement
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0004615	apolipoprotein B measurement
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Lipid phosphate phosphatases

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	6
sodium arsenite	increases abundance, increases expression, decreases expression, affects cotreatment	5
bisphenol A	affects cotreatment, increases methylation, decreases expression, decreases methylation, increases expression	4
Estradiol	affects cotreatment, decreases expression, increases expression	4
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	3
Valproic Acid	affects expression, decreases expression, increases expression	3
Cyclosporine	decreases expression	3
Asbestos, Crocidolite	affects expression, increases expression	3
Air Pollutants	decreases expression, increases abundance	2
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Methotrexate	decreases expression, increases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
Genistein	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance	2
GSK-J4	increases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	increases expression	1
securinine	decreases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	decreases expression	1
deoxynivalenol	decreases expression	1
beta-lapachone	decreases expression	1
nickel chloride	increases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	decreases expression	1
perfluorooctanoic acid	decreases expression	1
chloroquine diphosphate	decreases expression	1
tobacco tar	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1

Clinical trials (associated diseases)

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