EFNB2

Summary

EFNB2 (ephrin B2, HGNC:3227) is a protein-coding gene on chromosome 13q33.3, encoding Ephrin-B2 (P52799). Cell surface transmembrane ligand for Eph receptors, a family of receptor tyrosine kinases which are crucial for migration, repulsion and adhesion during neuronal, vascular and epithelial development.

This gene encodes a member of the ephrin (EPH) family. The ephrins and EPH-related receptors comprise the largest subfamily of receptor protein-tyrosine kinases and have been implicated in mediating developmental events, especially in the nervous system and in erythropoiesis. Based on their structures and sequence relationships, ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. This gene encodes an EFNB class ephrin which binds to the EPHB4 and EPHA3 receptors.

Source: NCBI Gene 1948 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart disease (Limited, ClinGen)
• GWAS associations: 6
• Clinical variants (ClinVar): 38 total — 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_004093

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3227
Approved symbol	EFNB2
Name	ephrin B2
Location	13q33.3
Locus type	gene with protein product
Status	Approved
Aliases	LERK5, Htk-L, HTKL, MGC126226, MGC126227, MGC126228
Ensembl gene	ENSG00000125266
Ensembl biotype	protein_coding
OMIM	600527
Entrez	1948

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000643990, ENST00000646441, ENST00000955444

RefSeq mRNA: 3 — MANE Select: NM_004093 NM_001372056, NM_001372057, NM_004093

CCDS: CCDS9507

Canonical transcript exons

ENST00000646441 — 5 exons

Exon	Start	End
ENSE00000854052	106494881	106494994
ENSE00000995278	106495748	106495840
ENSE00001654984	106512529	106512812
ENSE00003815177	106489745	106493428
ENSE00003825873	106534843	106535662

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.41.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.3900 / max 713.7709, expressed in 1368 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
138139	18.3900	1368

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.41	gold quality
ganglionic eminence	UBERON:0004023	98.74	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.65	gold quality
visceral pleura	UBERON:0002401	98.30	gold quality
colonic mucosa	UBERON:0000317	97.96	gold quality
embryo	UBERON:0000922	97.46	gold quality
amniotic fluid	UBERON:0000173	97.40	gold quality
parietal pleura	UBERON:0002400	97.18	gold quality
pleura	UBERON:0000977	97.05	gold quality
cortical plate	UBERON:0005343	97.03	gold quality
periodontal ligament	UBERON:0008266	96.94	gold quality
secondary oocyte	CL:0000655	96.46	gold quality
nipple	UBERON:0002030	96.35	gold quality
hair follicle	UBERON:0002073	96.21	gold quality
endothelial cell	CL:0000115	95.83	gold quality
metanephric glomerulus	UBERON:0004736	95.51	gold quality
seminal vesicle	UBERON:0000998	95.49	gold quality
upper leg skin	UBERON:0004262	95.20	gold quality
urethra	UBERON:0000057	95.07	gold quality
mammalian vulva	UBERON:0000997	94.96	gold quality
renal glomerulus	UBERON:0000074	94.76	gold quality
pylorus	UBERON:0001166	94.76	gold quality
cervix squamous epithelium	UBERON:0006922	94.74	gold quality
gingival epithelium	UBERON:0001949	94.50	gold quality
gingiva	UBERON:0001828	94.40	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.13	gold quality
pericardium	UBERON:0002407	93.97	gold quality
skin of hip	UBERON:0001554	93.80	gold quality
trigeminal ganglion	UBERON:0001675	93.72	gold quality
middle temporal gyrus	UBERON:0002771	93.27	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-135922	yes	842.15
E-MTAB-8271	yes	763.94
E-ANND-3	yes	14.39
E-MTAB-10553	yes	6.85
E-MTAB-6678	no	2.41

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ACVRL1, GLI1, HES1, HEY1, HEY2, MAZ, NOTCH1, NR2F2, PAX6, RBPJ, SP1, VEGFA, ZBTB17, ZNF384

miRNA regulators (miRDB)

169 targeting EFNB2, 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-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4283	100.00	66.42	2097
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-513A-5P	100.00	69.77	2465
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-548AW	99.99	72.57	3559
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
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-4666A-3P	99.96	71.71	3434

Literature-anchored findings (GeneRIF, showing 40)

• expressed differentially in colon carcinoma and normal mucosa specimens and may play a role in progression of colon carcinoma (PMID:11920461)
• Endogenous ephrin B2 from human umbilical artery endothelial cells activates a kinase that phosphorylates murine GST-ephrin-B1 cytoplasmic domain fusion proteins. (PMID:11983165)
• role of ephrin-B2 in erythropoiesis (PMID:12051776)
• Expression profile of this ligand of EPHB2 in gastric cancer (PMID:12136247)
• The entire cytoplasmic domain of ephrin-B2 and its N-terminal fragment, residues 253-300, lack the ability to fold into a well-defined three dimensional structure and are particularly prone to aggregation. (PMID:12206665)
• These data identify distinct propulsive and repulsive effector functions of endothelial ephrinB2 and EphB4 that mediate spatial positional signals during angiogenesis and vessel assembly. (PMID:12734395)
• ephrin B2 is present in human retinal endothelial cells and vascular growth may be modulated in the retina through activation of the PI3K pathway. (PMID:14499344)
• Overexpression of ephrin-B2 suppresses tumour cell growth and vascular function in an in vivo colon cancer model (PMID:15083195)
• in hyperinflammatory lesions, ephrinB2 was predominantly expressed in macrophage-like cells and EphB4 in small venules; syntenin and syndecan-1 were up-regulated in EphB4-positive endothelial cells after stimulation with preclustered ephrinB2 (PMID:15126321)
• EphB4 and ephrin-B2 molecules, which have specific expression patterns during artery and vein development, respectively, were expressed in the placenta (PMID:15193868)
• Ephrin B2 is an important novel factor in Kaposi sarcoma biology and a potential target for therapy. (PMID:15471957)
• defined the expression patterns of human ephrinB2, EphB4, and EphB2 in normal vessels of neonates (i.e. umbilici) and adults and compared them with those in congenital venous malformations (PMID:15718372)
• analysis of binding between the Tyr-phosphorylated human ephrinB2 and Nck2 SH2 domain (PMID:15764601)
• ephrin-B signaling might represent a novel protective mechanism that promotes intestinal epithelial wound healing, with potential impact on epithelial restitution in Crohn disease. (PMID:15996027)
• ephrin-B2 was found capable of rendering HeLa-USU cells permissive for Hendra virus and Nipah virus-mediated cell fusion as well as infection by live virus. (PMID:15998730)
• ephrinB2 is a functional receptor for Nipah virus (PMID:16007075)
• EphB4 and ephrin-B2 are instrumental in the establishment of a functional placental structure and of the utero-placental circulation. (PMID:16343615)
• endothelial cell ephrinB2 expression is controlled by microenvironmental determinants rather than being an intrinsic endothelial cell differentiation marker (PMID:16357318)
• Dll4 stimulation but not Jagged1 markedly induced ephrinB2 expression (PMID:16430858)
• The results provide critical information on the EphB4*ephrinB2 protein interfaces and their mode of interaction, which will facilitate development of small molecule compounds inhibiting the EphB4*ephrinB2 interaction as novel cancer therapeutics. (PMID:16867992)
• indicate that stimulated lymphocytes express EphrinB2, which has the potential to activate endothelial cells (PMID:17123494)
• High ephrinB2 is associated with carcinogenesis and portal vein tumor thrombus formation in human hepatocellular (PMID:17167981)
• demonstrates that Eph B4 and Ephrin B2 interaction may play an important role in the oncogenesis and angiogenesis of cervical carcinomas (PMID:17196593)
• EphB/ephrin-B molecules play a role in restricting dental pulp stem cell attachment and migration to maintain Dthesse cells within their stem cell niche under steady-state conditions. (PMID:17204606)
• Lubrol-RAFTs probably represent the platform for tumor-promoting ephrin-B2-integrin-beta1 interaction, which could become an interesting target for future antitumoral therapies (PMID:17380111)
• EFNB2 gene expression may be a biological marker and a useful prognostic indicator in patients with oesophageal squamous cell carcinoma. (PMID:17611172)
• Overexpression of ephrinB2 is associated with tumour advancement of ovarian cancers (PMID:18231102)
• The ephrin-B2 ectodomain binds to EphB2 with a K(d) of 22.3 nM to form a tight complex in which the tip of the C-D loop and the C-terminus still remain largely flexible. (PMID:18300229)
• expression of ephrinB2 in adult endothelial cells is up-regulated during arterial remodeling and controlled by cyclic stretch (PMID:18445690)
• crystal structures of both Nipah and Hendra attachment glycoproteins in complex with human EFNB2 (PMID:18488039)
• Platelet-derived growth factor signaling through ephrin-b2 regulates hepatic vascular structure and function. (PMID:18570897)
• polymorphisms in the EFNB2 gene do not appear to contribute in a substantial way to non-diabetic, diabetic or all-cause ESRD susceptibility in African-Americans (PMID:18580054)
• MMP7 and MMP9-mediated cleavage of EphB2 is induced by receptor-ligand interactions at the cell surface and that this event triggers cell-repulsive responses (PMID:18713744)
• We demonstrated limited Eph/Ephrin expression; notably, the only ligand highly expressed is EphrinB2 in Kaposi sarcoma (PMID:18836096)
• EphBR-ephrinB interactions lead to monocyte adhesion and transmigration through the vascular endothelium. (PMID:18957513)
• EphB4 receptor activation by ephrin B2 in osteoarthritis subchondral bone could affect abnormal metabolism in this tissue by inhibiting resorption factors and their activities (PMID:19035475)
• EB2 is not only necessary but also sufficient to allow the establishment of a productive NiV infection. (PMID:19036148)
• Ephrin-B2 signaling influence cell-to cell fusion and virus entry by the ratio between the NiV envelope glycoproteins and surface receptors. (PMID:19108727)
• High ephrin-B2 is associated with malignant urogenital tissue. (PMID:19272799)
• Localization of EphnB2 is dominantly in the cancer cells of uterine cervical cancers of all cases given. (PMID:19356789)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	efnb2a	ENSDARG00000020164
danio_rerio	efnb2b	ENSDARG00000074050
mus_musculus	Efnb2	ENSMUSG00000001300
rattus_norvegicus	Efnb2	ENSRNOG00000078208
drosophila_melanogaster	Ephrin	FBGN0040324
caenorhabditis_elegans		WBGENE00001163
caenorhabditis_elegans		WBGENE00001164
caenorhabditis_elegans		WBGENE00001165
caenorhabditis_elegans		WBGENE00006869

Paralogs (7): EFNB1 (ENSG00000090776), EFNA2 (ENSG00000099617), EFNB3 (ENSG00000108947), EFNA3 (ENSG00000143590), EFNA1 (ENSG00000169242), EFNA5 (ENSG00000184349), EFNA4 (ENSG00000243364)

Protein

Protein identifiers

Ephrin-B2 — P52799 (reviewed: P52799)

Alternative names: EPH-related receptor tyrosine kinase ligand 5, HTK ligand

All UniProt accessions (1): P52799

UniProt curated annotations — full annotation on UniProt →

Function. Cell surface transmembrane ligand for Eph receptors, a family of receptor tyrosine kinases which are crucial for migration, repulsion and adhesion during neuronal, vascular and epithelial development. Binds promiscuously Eph receptors residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Binds to receptor tyrosine kinase including EPHA4, EPHA3 and EPHB4. Together with EPHB4 plays a central role in heart morphogenesis and angiogenesis through regulation of cell adhesion and cell migration. EPHB4-mediated forward signaling controls cellular repulsion and segregation from EFNB2-expressing cells. May play a role in constraining the orientation of longitudinally projecting axons. (Microbial infection) Acts as a receptor for Hendra virus and Nipah virus.

Subunit / interactions. Interacts with PDZRN3. Binds to the receptor tyrosine kinases EPHA4, EPHB4 and EPHA3. (Microbial infection) Interacts with Hendra virus and Nipah virus G protein.

Subcellular location. Cell membrane. Cell junction. Adherens junction.

Tissue specificity. Lung and kidney.

Post-translational modifications. Inducible phosphorylation of tyrosine residues in the cytoplasmic domain.

Similarity. Belongs to the ephrin family.

RefSeq proteins (3): NP_001358985, NP_001358986, NP_004084* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001799	Ephrin_RBD	Domain
IPR008972	Cupredoxin	Homologous_superfamily
IPR019765	Ephrin_CS	Conserved_site
IPR031328	Ephrin	Family
IPR034255	Ephrin-B_Ecto	Domain

Pfam: PF00812

UniProt features (34 total): strand 11, modified residue 3, helix 3, glycosylation site 2, disulfide bond 2, turn 2, topological domain 2, compositionally biased region 2, signal peptide 1, chain 1, mutagenesis site 1, transmembrane region 1, domain 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
4UF7	X-RAY DIFFRACTION	1.7
2VSM	X-RAY DIFFRACTION	1.8
2HLE	X-RAY DIFFRACTION	2.05
2WO2	X-RAY DIFFRACTION	2.45
3GXU	X-RAY DIFFRACTION	2.5
6PDL	X-RAY DIFFRACTION	2.7
6P7Y	X-RAY DIFFRACTION	2.84
9DVD	ELECTRON MICROSCOPY	2.9
2VSK	X-RAY DIFFRACTION	3.3
2I85	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P52799-F1	71.60	0.37

Antibody-complex structures (SAbDab): 1 — 9DVD

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 (3): 260, 274, 277

Disulfide bonds (2): 62–101, 89–153

Glycosylation sites (2): 36, 139

Mutagenesis-validated functional residues (1):

Position	Phenotype
121–122	complete loss of nipah protein g binding.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-2682334	EPH-Ephrin signaling
R-HSA-3928662	EPHB-mediated forward signaling
R-HSA-3928664	Ephrin signaling
R-HSA-3928665	EPH-ephrin mediated repulsion of cells

MSigDB gene sets: 401 (showing top): GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELL_ACTIVATION, BROWNE_HCMV_INFECTION_4HR_UP, WILLIAMS_ESR1_TARGETS_DN, MODULE_92, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, TSENG_IRS1_TARGETS_UP, GOBP_SYNAPSE_ASSEMBLY, GOBP_CELLULAR_RESPONSE_TO_LIPID, BROWNE_HCMV_INFECTION_8HR_UP, GOBP_POSITIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, GOBP_KERATINOCYTE_PROLIFERATION, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS

GO Biological Process (28): angiogenesis (GO:0001525), lymph vessel development (GO:0001945), cell migration involved in sprouting angiogenesis (GO:0002042), cell adhesion (GO:0007155), axon guidance (GO:0007411), positive regulation of cell population proliferation (GO:0008284), anatomical structure morphogenesis (GO:0009653), animal organ morphogenesis (GO:0009887), negative regulation of keratinocyte proliferation (GO:0010839), negative regulation of neuron projection development (GO:0010977), T cell costimulation (GO:0031295), adherens junction organization (GO:0034332), keratinocyte proliferation (GO:0043616), ephrin receptor signaling pathway (GO:0048013), blood vessel morphogenesis (GO:0048514), venous blood vessel morphogenesis (GO:0048845), regulation of chemotaxis (GO:0050920), cellular response to lipopolysaccharide (GO:0071222), nephric duct morphogenesis (GO:0072178), presynapse assembly (GO:0099054), regulation of postsynaptic membrane neurotransmitter receptor levels (GO:0099072), regulation of postsynaptic neurotransmitter receptor internalization (GO:0099149), positive regulation of aorta morphogenesis (GO:1903849), positive regulation of leukocyte adhesion to arterial endothelial cell (GO:1904999), positive regulation of cardiac muscle cell differentiation (GO:2000727), nervous system development (GO:0007399), cell differentiation (GO:0030154), symbiont entry into host cell (GO:0046718)

GO Molecular Function (6): virus receptor activity (GO:0001618), ephrin receptor binding (GO:0046875), receptor ligand activity (GO:0048018), signaling receptor binding (GO:0005102), protein binding (GO:0005515), transmembrane receptor protein tyrosine kinase activator activity (GO:0030297)

GO Cellular Component (10): plasma membrane (GO:0005886), adherens junction (GO:0005912), focal adhesion (GO:0005925), dendrite (GO:0030425), presynaptic membrane (GO:0042734), Schaffer collateral - CA1 synapse (GO:0098685), postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
EPH-Ephrin signaling	3
Axon guidance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
blood vessel morphogenesis	2
anatomical structure development	2
signaling receptor binding	2
signaling receptor activator activity	2
synapse	2
anatomical structure formation involved in morphogenesis	1
vasculature development	1
sprouting angiogenesis	1
blood vessel endothelial cell migration	1
cellular process	1
axonogenesis	1
neuron projection guidance	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
developmental process	1
anatomical structure morphogenesis	1
animal organ development	1
regulation of keratinocyte proliferation	1
keratinocyte proliferation	1
negative regulation of epithelial cell proliferation	1
regulation of neuron projection development	1
neuron projection development	1
negative regulation of cell projection organization	1
lymphocyte costimulation	1
positive regulation of T cell activation	1
cell-cell junction organization	1
epithelial cell proliferation	1
cell surface receptor protein tyrosine kinase signaling pathway	1
blood vessel development	1
tube morphogenesis	1
venous blood vessel development	1
chemotaxis	1
regulation of response to external stimulus	1
regulation of locomotion	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
epithelial tube morphogenesis	1

Protein interactions and networks

STRING

2204 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EFNB2	EPHB4	P54760	999
EFNB2	EPHB2	P29323	999
EFNB2	EPHA1	P21709	998
EFNB2	EPHA4	P54764	998
EFNB2	EPHB1	P54762	997
EFNB2	EPHB3	P54753	994
EFNB2	EPHB6	O15197	992
EFNB2	EPHA3	P29320	968
EFNB2	RGS3	P49796	948
EFNB2	EPHA2	P29317	924
EFNB2	FLT4	P35916	887
EFNB2	THBS1	P07996	884
EFNB2	EPHA10	Q5JZY3	882
EFNB2	DLL4	Q9NR61	820
EFNB2	GRIP1	Q9Y3R0	811

IntAct

186 interactions, top by confidence:

A	B	Type	Score
EPHB4	EFNB2	psi-mi:“MI:0407”(direct interaction)	0.830
EPHA4	EFNB2	psi-mi:“MI:0915”(physical association)	0.780
EPHA4	EFNB2	psi-mi:“MI:0407”(direct interaction)	0.780
EFNB2	EPHA4	psi-mi:“MI:0407”(direct interaction)	0.780
EFNB2	G	psi-mi:“MI:0407”(direct interaction)	0.740
G	EFNB2	psi-mi:“MI:0407”(direct interaction)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
NCK2	EFNB2	psi-mi:“MI:0914”(association)	0.600
EFNB2	PICK1	psi-mi:“MI:0407”(direct interaction)	0.590
EFNB2	G	psi-mi:“MI:0407”(direct interaction)	0.560
EFNB2	ANKRD46	psi-mi:“MI:0915”(physical association)	0.560
PICK1	ILVBL	psi-mi:“MI:0914”(association)	0.530
EFNB2	FAM171A2	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
EFNB2	EPHB4	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (219): EFNB1 (Affinity Capture-MS), PHLPP1 (Affinity Capture-MS), CAND2 (Affinity Capture-MS), PIK3CB (Affinity Capture-MS), EIF2B4 (Affinity Capture-MS), MAP7D2 (Affinity Capture-MS), EPHB2 (Affinity Capture-MS), EPHB3 (Affinity Capture-MS), EPHA5 (Affinity Capture-MS), EPHB4 (Affinity Capture-MS), SAAL1 (Affinity Capture-MS), DIP2B (Affinity Capture-MS), DIP2A (Affinity Capture-MS), PLEKHH3 (Affinity Capture-MS), POM121 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5PUP4, A2AFS3, M0R7X9, O70472, O75882, O95803, P01134, P26012, P52799, P52848, P69849, Q02353, Q05204, Q0VCJ8, Q12841, Q13635, Q15155, Q3UHN9, Q3ZBS2, Q58D84, Q5EA46, Q5JPE7, Q5R9Y1, Q5U4X8, Q5VV63, Q5ZJB7, Q5ZMH6, Q61115, Q62356, Q62632, Q6A051, Q6GQK9, Q6GQT9, Q6P988, Q6UXG2, Q7Z5A7, Q86TD4, Q90693, Q91WE9, Q96CW9

Diamond homologs: O08542, O08543, O08545, O35393, O43921, O73612, O73874, P20827, P52793, P52794, P52795, P52796, P52797, P52798, P52799, P52800, P52801, P52802, P52803, P52804, P79727, P79728, P97553, P97605, P98172, Q06AS9, Q15768, Q3ZC64, O13097

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
EFNB2	up-regulates	EPHB3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 124 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
Ras activation upon Ca2+ influx through NMDA receptor	8	52.5×	1e-10
Unblocking of NMDA receptors, glutamate binding and activation	5	31.2×	2e-05
Negative regulation of NMDA receptor-mediated neuronal transmission	5	31.2×	2e-05
Assembly and cell surface presentation of NMDA receptors	10	29.2×	1e-10
Dopamine Neurotransmitter Release Cycle	5	28.5×	3e-05
Long-term potentiation	5	27.4×	4e-05
Neurexins and neuroligins	11	24.9×	1e-10
Downstream signal transduction	5	21.9×	8e-05

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	51.0×	2e-12
protein localization to synapse	6	40.3×	1e-06
receptor clustering	7	38.3×	2e-07
regulation of postsynaptic membrane neurotransmitter receptor levels	7	30.4×	7e-07
ephrin receptor signaling pathway	5	15.1×	1e-03
cell-cell adhesion	11	9.8×	3e-06
negative regulation of ERK1 and ERK2 cascade	5	9.5×	6e-03
protein-containing complex assembly	9	9.0×	8e-05

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	1
Uncertain significance	26
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
928785	NM_004093.4(EFNB2):c.219T>G (p.Tyr73Ter)	Likely pathogenic

SpliceAI

1063 predictions. Top by Δscore:

Variant	Effect	Δscore
13:106493428:CCTG:C	acceptor_loss	1.0000
13:106493429:C:CC	acceptor_gain	1.0000
13:106493430:T:C	acceptor_loss	1.0000
13:106493436:C:CT	acceptor_gain	1.0000
13:106493438:C:CT	acceptor_gain	1.0000
13:106494878:TA:T	donor_loss	1.0000
13:106494879:A:AG	donor_loss	1.0000
13:106494918:T:TA	donor_gain	1.0000
13:106494990:TGCAT:T	acceptor_gain	1.0000
13:106494991:GCAT:G	acceptor_gain	1.0000
13:106494992:CAT:C	acceptor_gain	1.0000
13:106494992:CATC:C	acceptor_gain	1.0000
13:106494993:AT:A	acceptor_gain	1.0000
13:106494993:ATC:A	acceptor_loss	1.0000
13:106494994:TCTA:T	acceptor_loss	1.0000
13:106494995:C:CC	acceptor_gain	1.0000
13:106494995:C:CG	acceptor_loss	1.0000
13:106494997:A:AC	acceptor_gain	1.0000
13:106494997:A:C	acceptor_gain	1.0000
13:106494999:A:AC	acceptor_gain	1.0000
13:106494999:A:C	acceptor_gain	1.0000
13:106512523:ACTT:A	donor_loss	1.0000
13:106512524:CT:C	donor_loss	1.0000
13:106512525:TTA:T	donor_loss	1.0000
13:106512526:T:TG	donor_loss	1.0000
13:106512527:A:AC	donor_gain	1.0000
13:106512528:C:CC	donor_gain	1.0000
13:106512528:C:CG	donor_loss	1.0000
13:106512528:CA:C	donor_gain	1.0000
13:106512528:CAT:C	donor_gain	1.0000

AlphaMissense

2185 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:106493092:A:T	I317N	1.000
13:106495789:C:G	C153S	1.000
13:106495790:A:G	C153R	1.000
13:106495790:A:T	C153S	1.000
13:106512557:A:C	F126L	1.000
13:106512557:A:T	F126L	1.000
13:106512558:A:G	F126S	1.000
13:106512559:A:G	F126L	1.000
13:106512581:G:C	S118R	1.000
13:106512581:G:T	S118R	1.000
13:106512583:T:G	S118R	1.000
13:106512594:A:G	F114S	1.000
13:106512633:C:G	C101S	1.000
13:106512634:A:G	C101R	1.000
13:106512634:A:T	C101S	1.000
13:106512669:C:G	C89S	1.000
13:106512670:A:T	C89S	1.000
13:106512751:A:G	C62R	1.000
13:106534860:C:A	W35C	1.000
13:106534860:C:G	W35C	1.000
13:106534862:A:G	W35R	1.000
13:106534862:A:T	W35R	1.000
13:106493046:C:A	K332N	0.999
13:106493046:C:G	K332N	0.999
13:106493051:A:C	Y331D	0.999
13:106493054:A:C	Y330D	0.999
13:106493089:A:T	V318D	0.999
13:106493092:A:C	I317S	0.999
13:106493139:G:C	C301W	0.999
13:106493339:A:G	C235R	0.999

dbSNP variants (sampled 300 via entrez): RS1000044477 (13:106520818 C>T), RS1000058380 (13:106520076 G>C), RS1000070016 (13:106494015 A>G), RS1000100071 (13:106527446 A>G), RS1000129902 (13:106520356 T>C), RS1000132079 (13:106518908 TG>T,TGG), RS1000193753 (13:106503261 A>G), RS1000219596 (13:106506720 G>T), RS1000243634 (13:106525978 A>C), RS1000355164 (13:106507002 C>T), RS1000465590 (13:106501185 C>T), RS1000471922 (13:106497105 T>C), RS1000514882 (13:106513357 AC>A), RS1000527588 (13:106501864 T>C,G), RS1000555432 (13:106508141 C>A,T)

Disease associations

OMIM: gene MIM:600527 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital heart disease	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital heart disease	Limited	AD

Mondo (1): congenital heart disease (MONDO:0005453)

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST003069_3	Left superior temporal gyrus thickness (schizophrenia interaction)	1.000000e-06
GCST003097_43	Pediatric autoimmune diseases	1.000000e-06
GCST003170_8	Subcutaneous adipose tissue	8.000000e-07
GCST009391_814	Metabolite levels	4.000000e-06
GCST012282_9	BMI x environmental factors (excluding physical activity) interaction	7.000000e-06
GCST012283_4	BMI x environmental factors (including physical activity) interaction	9.000000e-08

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0010397	sphingomyelin 24:0 measurement
EFO:0004340	body mass index
EFO:0006527	smoking status measurement
EFO:0009374	energy intake measurement
EFO:0009695	household income
EFO:0010810	protein intake measurement
EFO:0010811	carbohydrate intake measurement
EFO:0011015	educational attainment
EFO:0008002	physical activity measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4804245 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression	5
Valproic Acid	increases expression, affects expression	4
(+)-JQ1 compound	increases expression	3
Estradiol	affects cotreatment, increases expression, decreases expression	3
Silicon Dioxide	increases expression	3
Tretinoin	decreases reaction, increases expression	3
bisphenol A	decreases expression	2
epigallocatechin gallate	decreases expression, affects cotreatment, increases expression	2
entinostat	decreases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment, decreases expression	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
Calcitriol	decreases expression, affects cotreatment	2
Fluorouracil	affects response to substance, decreases expression	2
Tobacco Smoke Pollution	increases expression	2
Genistein	decreases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment	2
aristolochic acid I	increases expression	1
NVP-BHG712	decreases reaction, increases phosphorylation	1
OTX015	increases expression	1
mivebresib	increases expression	1
testosterone enanthate	affects expression	1
propionaldehyde	increases expression	1
lead acetate	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
trichostatin A	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
afimoxifene	increases expression	1
sulforaphane	decreases expression	1
butyraldehyde	increases expression	1
potassium chromate(VI)	increases expression, affects cotreatment	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B7VN	Abcam SH-SY5Y EFNB2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease
NCT00770705	PHASE2	WITHDRAWN	Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery
NCT00919945	PHASE2	TERMINATED	Impact of Early Enteral Feeding on Splanchnic Blood Flow After Surgery for Critical Heart Disease in the Newborn
NCT01063712	PHASE2	COMPLETED	Safety and Effectiveness of the Device Nit-Occlud® PDA-R
NCT01069510	PHASE2	COMPLETED	Spironolactone in Adult Congenital Heart Disease
NCT01189981	PHASE2	COMPLETED	Effect of eHealth Encouragements to Intensive Exercise in Adolescents With Congenital Heart Disease
NCT01330433	PHASE2	COMPLETED	Effects of CoSeal on Bleeding & Adhesions in Pediatric Heart Surgery
NCT01662037	PHASE2	COMPLETED	Bosentan Therapy in Children With Functional Single Ventricle
NCT01668264	PHASE2	UNKNOWN	Imaging Assessment of Diastolic Function
NCT01827059	PHASE2	UNKNOWN	Bosentan In Exercise Induced Pulmonary Arterial Hypertension in CongenitaL Heart diseasE