PEBP4

Summary

PEBP4 (phosphatidylethanolamine binding protein 4, HGNC:28319) is a protein-coding gene on chromosome 8p21.3, encoding Phosphatidylethanolamine-binding protein 4 (Q96S96). Promotes AKT phosphorylation, suggesting a possible role in the PI3K-AKT signaling pathway.

The phosphatidylethanolamine (PE)-binding proteins, including PEBP4, are an evolutionarily conserved family of proteins with pivotal biologic functions, such as lipid binding and inhibition of serine proteases (Wang et al., 2004 [PubMed 15302887]).

Source: NCBI Gene 157310 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 60 total
• MANE Select transcript: NM_144962

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28319
Approved symbol	PEBP4
Name	phosphatidylethanolamine binding protein 4
Location	8p21.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC22776, CORK1, hPEBP4
Ensembl gene	ENSG00000134020
Ensembl biotype	protein_coding
OMIM	612473
Entrez	157310

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 8 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000256404, ENST00000521284, ENST00000522278, ENST00000901322, ENST00000901323, ENST00000901324, ENST00000901325, ENST00000922027, ENST00000968058

RefSeq mRNA: 2 — MANE Select: NM_144962 NM_001363233, NM_144962

CCDS: CCDS43724

Canonical transcript exons

ENST00000256404 — 7 exons

Exon	Start	End
ENSE00001042346	22727175	22727220
ENSE00001042352	22724843	22724956
ENSE00001253934	22927823	22927914
ENSE00001314917	22713251	22713536
ENSE00003546304	22817637	22817735
ENSE00003562363	22920184	22920310
ENSE00003680312	22927584	22927720

Expression profiles

Bgee: expression breadth ubiquitous, 201 present calls, max score 98.99.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.6528 / max 326.0853, expressed in 137 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
92272	0.8037	113
92271	0.7484	105
92273	0.0674	20
92270	0.0334	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
vastus lateralis	UBERON:0001379	98.99	gold quality
biceps brachii	UBERON:0001507	98.95	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.90	gold quality
quadriceps femoris	UBERON:0001377	98.83	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.79	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.77	gold quality
left ventricle myocardium	UBERON:0006566	98.64	gold quality
apex of heart	UBERON:0002098	98.53	gold quality
skeletal muscle tissue	UBERON:0001134	98.29	gold quality
cardiac muscle of right atrium	UBERON:0003379	98.18	gold quality
corpus epididymis	UBERON:0004359	98.16	gold quality
right atrium auricular region	UBERON:0006631	97.79	gold quality
cardiac atrium	UBERON:0002081	97.74	gold quality
heart left ventricle	UBERON:0002084	97.52	gold quality
cardiac ventricle	UBERON:0002082	97.44	gold quality
deltoid	UBERON:0001476	97.36	gold quality
gastrocnemius	UBERON:0001388	97.02	gold quality
heart right ventricle	UBERON:0002080	96.73	gold quality
myocardium	UBERON:0002349	96.67	gold quality
muscle of leg	UBERON:0001383	96.46	gold quality
tibialis anterior	UBERON:0001385	95.90	gold quality
upper lobe of left lung	UBERON:0008952	95.29	gold quality
upper lobe of lung	UBERON:0008948	95.02	gold quality
body of tongue	UBERON:0011876	94.95	gold quality
muscle tissue	UBERON:0002385	94.86	gold quality
heart	UBERON:0000948	93.96	gold quality
right lobe of thyroid gland	UBERON:0001119	93.87	gold quality
lower lobe of lung	UBERON:0008949	93.71	gold quality
left lobe of thyroid gland	UBERON:0001120	92.94	gold quality
right lung	UBERON:0002167	92.76	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-15	yes	528.60
E-GEOD-86618	yes	167.72
E-HCAD-1	yes	97.83
E-GEOD-130148	yes	9.13
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

5 targeting PEBP4, 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-6124	99.87	69.78	3551
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-3179	98.22	65.90	1445
HSA-MIR-541-3P	96.07	66.11	1271
HSA-MIR-654-5P	96.07	66.18	1280

Literature-anchored findings (GeneRIF, showing 21)

• Silencing of hPEBP4, an important potential target, may be a promising approach for the treatment of ovarian cancer. (PMID:16865237)
• Data show that PEBP4 participates in the control of muscle cell differentiation by modulating the activity of MEK and ERK. (PMID:19197339)
• Data show that PEBP4 protein overexpression was associated with the occurrence, invasion, and metastasis of lung squamous cell carcinoma. (PMID:21887552)
• PEBP4 over-expression may promote the invasion and metastasis of non-small cell lung cancer. (PMID:22076923)
• The over-expression of PEBP4 protein may be related to the tumorigenesis, development, metastasis, and invasion of colorectal cancer. (PMID:22125029)
• the independent predictive values of hPEBP4 in response of rectal cancer to preoperative radiotherapy, are reported. (PMID:22801881)
• PEBP4 enhanced cell proliferation and invasion ability and inhibited apoptosis. Decreased PEBP4 expression may play a role in the reduced invasion ability and increased apoptosis of the human non-small cell lung cancer cell line HCC827. (PMID:22983920)
• hPEBP4 knockdown potentiated the chemosensitization of the rituximab in B-cell lymphoma cells by regulating the expression of Bcl-xl, Cycline E, p21(waf/cip1) and p53 and the activation of caspase-3 and caspase-9. (PMID:23451095)
• Human PEBP4 expression correlates negatively with estrogen and progesterone receptors in endometrial carcinoma. (PMID:23818363)
• in human breast cancer hPEBP4 is a novel and clinically relevant metastasis accelerator gene (PMID:24276246)
• overexpression of PEBP4, which we show to be a target of miR-34a, reduces the sensitivity of lung cancer cells to cisplatin (PMID:25038915)
• Increased miR-15b expression in lung adenocarcinoma patients treated with cisplatin-based chemotherapy was correlated with low expression of PEBP4, decreased sensitivity to cisplatin and poor prognosis. (PMID:25721211)
• this study suggested that PEBP4 might promote the progression of pancreatic ductal adenocarcinoma (PMID:26311050)
• Increased expression of phosphatidylethanolamine-binding protein 4 strongly associates with gliomas grade. (PMID:26725095)
• PEBP4 is a secreted protein and has multiple functions, including a role in Akt phosphorylation. (PMID:27033522)
• knockdown of PEBP4 inhibited hypoxia-induced epithelial-to-mesenchymal transition in prostate cancer cells. (PMID:27261570)
• High PEBP4 expression is associated with glioma cell growth and invasiveness. (PMID:30255656)
• these results suggest that PEBP4 may promote tumorigenesis in non-small cell lung cancer by regulating cell proliferation and epithelial-to-mesenchymal transition via activation of the Shh signaling pathway. (PMID:30367510)
• PEBP4 colocalised with IgA and CD19. (PMID:31402200)
• Diagnostic value of phosphatidylethanolamine binding protein 4 levels in patients receiving nursing interventions for advanced chronic kidney disease. (PMID:33752499)
• Overexpression of phosphatidylethanolamine-binding protein 4 (PEBP4) associates with recurrence of meningiomas. (PMID:35158167)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	PEBP4	ENSDARG00000107065
mus_musculus	Pebp4	ENSMUSG00000022085
rattus_norvegicus	Pebp4	ENSRNOG00000026247
drosophila_melanogaster	a5	FBGN0011294
drosophila_melanogaster	CG10298	FBGN0037432
drosophila_melanogaster	CG17919	FBGN0037433

Paralogs (2): PEBP1 (ENSG00000089220), MRPL38 (ENSG00000204316)

Protein

Protein identifiers

Phosphatidylethanolamine-binding protein 4 — Q96S96 (reviewed: Q96S96)

Alternative names: Protein cousin-of-RKIP 1

All UniProt accessions (2): E5RIK3, Q96S96

UniProt curated annotations — full annotation on UniProt →

Function. Promotes AKT phosphorylation, suggesting a possible role in the PI3K-AKT signaling pathway.

Subcellular location. Secreted.

Similarity. Belongs to the phosphatidylethanolamine-binding protein family.

RefSeq proteins (2): NP_001350162, NP_659399* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001858	Phosphatidylethanolamine-bd_CS	Conserved_site
IPR008914	PEBP	Family
IPR035810	PEBP_euk	Family
IPR036610	PEBP-like_sf	Homologous_superfamily

Pfam: PF01161

UniProt features (8 total): region of interest 2, sequence variant 2, signal peptide 1, chain 1, compositionally biased region 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96S96-F1	86.10	0.72

Functional residue map

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

Glycosylation sites (1): 169

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 28 (showing top): chr8p21, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, ZHENG_BOUND_BY_FOXP3, MARTENS_BOUND_BY_PML_RARA_FUSION, ZWANG_TRANSIENTLY_UP_BY_2ND_EGF_PULSE_ONLY, GSE10240_CTRL_VS_IL17_STIM_PRIMARY_BRONCHIAL_EPITHELIAL_CELLS_UP, SFMBT1_TARGET_GENES, ZSCAN30_TARGET_GENES, BDP1_TARGET_GENES, TRAVAGLINI_LUNG_ALVEOLAR_EPITHELIAL_TYPE_1_CELL, TRAVAGLINI_LUNG_ALVEOLAR_EPITHELIAL_TYPE_2_CELL, TRAVAGLINI_LUNG_SIGNALING_ALVEOLAR_EPITHELIAL_TYPE_2_CELL, GAUTAM_EYE_IRIS_CILIARY_BODY_COL9A1_HIGH_CILIARY_BODY_CELLS, GAVISH_3CA_MALIGNANT_METAPROGRAM_31_ALVEOLAR, GAVISH_3CA_METAPROGRAM_EPITHELIAL_ALVEOLAR

GO Biological Process (0):

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (3): extracellular exosome (GO:0070062), extracellular region (GO:0005576), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
binding	1
extracellular vesicle	1

Protein interactions and networks

STRING

2292 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PEBP4	MAP2K1	Q02750	615
PEBP4	CFAP161	Q6P656	561
PEBP4	SRC	P12931	548
PEBP4	MORN5	Q5VZ52	525
PEBP4	C16orf89	Q6UX73	504
PEBP4	CHI3L1	P30923	503
PEBP4	WFDC2	Q14508	501
PEBP4	TNFSF10	P50591	497
PEBP4	RAF1	P04049	472
PEBP4	CCER1	Q8TC90	471
PEBP4	AGR2	O95994	457
PEBP4	CIMIP4	O43247	452
PEBP4	ODF2	Q5BJF6	447
PEBP4	MAPK3	P27361	415
PEBP4	RHPN2	Q8IUC4	412

IntAct

9 interactions, top by confidence:

A	B	Type	Score
MAP2K1	RAF1	psi-mi:“MI:0914”(association)	0.960
RAF1	MAP2K1	psi-mi:“MI:0914”(association)	0.960
PEBP4	RAF1	psi-mi:“MI:0915”(physical association)	0.600
PEBP4	RAF1	psi-mi:“MI:0914”(association)	0.600
PEBP4	AKT1	psi-mi:“MI:0915”(physical association)	0.520
PEBP4	HNRNPM	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (10): MAP2K1 (Affinity Capture-Western), RAF1 (Affinity Capture-Western), RAF1 (Reconstituted Complex), MAP2K1 (Reconstituted Complex), PEBP4 (Affinity Capture-RNA), PEBP4 (Proximity Label-MS), PEBP4 (Cross-Linking-MS (XL-MS)), RNF13 (Cross-Linking-MS (XL-MS)), RAF1 (Affinity Capture-Western), PEBP4 (Reconstituted Complex)

ESM2 similar proteins: A4IGL3, A6X935, A7Z050, O43278, O75339, P09172, P16368, P36992, Q05754, Q08420, Q08E66, Q3V5L5, Q5EAB6, Q5RCB9, Q5RDF1, Q5XIN7, Q60963, Q64237, Q64663, Q66K08, Q68CI2, Q6DFV8, Q6PFW1, Q6W3E5, Q765H6, Q7T2Z5, Q7TQN3, Q8BLY1, Q8C8H8, Q8IZJ1, Q8N2E2, Q8NBH2, Q8TEU8, Q8WY21, Q8WZA1, Q91X88, Q93WI9, Q96PQ0, Q96S96, Q99M80

Diamond homologs: A0A0Q3IBS1, I1H0V9, O16264, O82088, P13696, P14306, P30086, P31044, P31729, P48737, P54185, P54186, P54187, P54188, P54189, P54190, P70296, P93003, Q3YIX4, Q41261, Q5R4R0, Q656A5, Q8MK67, Q8VIN1, Q8VWH2, Q93WI9, Q96S96, Q9ASJ1, Q9D9G2, Q9FIT4, Q9S7R5, Q9SXZ2, Q9XFK7, Q9XH42, Q9XH43, Q9XH44, Q9ZNV5, Q06252, Q3ZBF3, Q5PQN9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	54
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2566 predictions. Top by Δscore:

Variant	Effect	Δscore
8:22727173:A:AC	donor_gain	1.0000
8:22727173:ACC:A	donor_loss	1.0000
8:22727174:C:CC	donor_gain	1.0000
8:22727219:CCCTG:C	acceptor_loss	1.0000
8:22920178:A:AC	donor_gain	1.0000
8:22920179:C:CC	donor_gain	1.0000
8:22920182:A:AC	donor_gain	1.0000
8:22920183:C:CC	donor_gain	1.0000
8:22927578:ACTT:A	donor_loss	1.0000
8:22927581:TACT:T	donor_loss	1.0000
8:22927582:A:AC	donor_gain	1.0000
8:22927583:C:CC	donor_gain	1.0000
8:22927583:CT:C	donor_gain	1.0000
8:22927583:CTG:C	donor_gain	1.0000
8:22927583:CTGG:C	donor_gain	1.0000
8:22724836:GTCTT:G	donor_loss	0.9900
8:22724837:TCTTA:T	donor_loss	0.9900
8:22724838:CTTA:C	donor_loss	0.9900
8:22724839:TTACC:T	donor_loss	0.9900
8:22724840:TACC:T	donor_loss	0.9900
8:22724841:A:AT	donor_loss	0.9900
8:22724842:C:T	donor_loss	0.9900
8:22724842:CCT:C	donor_gain	0.9900
8:22724957:C:CC	acceptor_gain	0.9900
8:22727170:CTCA:C	donor_gain	0.9900
8:22727173:AC:A	donor_gain	0.9900
8:22727174:CC:C	donor_gain	0.9900
8:22727217:CGCC:C	acceptor_gain	0.9900
8:22727219:CC:C	acceptor_gain	0.9900
8:22727220:CC:C	acceptor_gain	0.9900

AlphaMissense

1503 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:22713529:C:A	W175C	0.994
8:22713529:C:G	W175C	0.994
8:22920206:A:T	V79D	0.994
8:22817661:T:A	R111S	0.992
8:22817661:T:G	R111S	0.992
8:22713469:G:C	F195L	0.991
8:22713469:G:T	F195L	0.991
8:22713471:A:G	F195L	0.991
8:22724918:G:C	H148D	0.991
8:22817653:A:G	L114P	0.991
8:22713470:A:G	F195S	0.988
8:22713531:A:G	W175R	0.988
8:22713531:A:T	W175R	0.988
8:22724914:C:G	R149P	0.987
8:22817719:A:G	L92P	0.987
8:22817662:C:G	R111T	0.986
8:22920260:A:T	V61D	0.984
8:22713470:A:C	F195C	0.981
8:22713515:A:C	F180C	0.981
8:22713515:A:G	F180S	0.980
8:22724899:A:T	V154D	0.980
8:22920212:G:T	P77Q	0.980
8:22713514:A:C	F180L	0.979
8:22713514:A:T	F180L	0.979
8:22713516:A:G	F180L	0.979
8:22817660:G:C	H112D	0.979
8:22817667:G:C	F109L	0.978
8:22817667:G:T	F109L	0.978
8:22817669:A:G	F109L	0.978
8:22724944:G:T	P139H	0.977

dbSNP variants (sampled 300 via entrez): RS1000013560 (8:22853793 A>G), RS1000014727 (8:22725732 G>A), RS1000020429 (8:22926178 G>A), RS1000034078 (8:22748405 T>A), RS1000042789 (8:22899979 CAAG>C), RS1000068449 (8:22889914 C>G), RS1000080356 (8:22894493 G>A), RS1000082753 (8:22931425 C>A,T), RS1000083425 (8:22744331 T>C), RS1000095649 (8:22775290 G>T), RS1000106210 (8:22738336 CA>C), RS1000107575 (8:22932959 C>A,G,T), RS1000113083 (8:22832135 T>C), RS1000120391 (8:22856970 A>G), RS1000143834 (8:22815192 T>G)

Disease associations

OMIM: gene MIM:612473 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001525_1	Visceral fat	7.000000e-06
GCST006988_134	Blond vs. brown/black hair color	2.000000e-12
GCST008163_475	Height	1.000000e-06
GCST012306_6	Bipolar disorder	4.000000e-07
GCST012489_18	Heel bone mineral density x serum urate levels interaction	6.000000e-11
GCST012490_127	Femur bone mineral density x serum urate levels interaction	2.000000e-08
GCST012490_271	Femur bone mineral density x serum urate levels interaction	3.000000e-09
GCST90002388_238	Lymphocyte count	1.000000e-13
GCST90002389_170	Lymphocyte percentage of white cells	2.000000e-10

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0003924	hair color
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density
EFO:0004587	lymphocyte count
EFO:0007993	lymphocyte percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs17685420	Efficacy	3	methylphenidate	Attention Deficit Disorder with Hyperactivity

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs17685420	PEBP4	3	0.00	1	methylphenidate

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases mutagenesis	4
bisphenol A	affects cotreatment, increases methylation, decreases methylation	1
sodium arsenite	decreases expression	1
aflatoxin B2	increases methylation	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	decreases expression	1
Calcitriol	increases expression, affects cotreatment	1
Doxorubicin	decreases expression	1
Hydralazine	affects cotreatment, increases expression	1
Testosterone	affects cotreatment, increases expression	1
Toluene	increases expression, decreases methylation	1
Valproic Acid	affects cotreatment, increases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

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