EFNA2

Summary

EFNA2 (ephrin A2, HGNC:3222) is a protein-coding gene on chromosome 19p13.3, encoding Ephrin-A2 (O43921). Cell surface GPI-bound 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 family. The protein is composed of a signal sequence, a receptor-binding region, a spacer region, and a hydrophobic region. The EPH and EPH-related receptors comprise the largest subfamily of receptor protein-tyrosine kinases and have been implicated in mediating developmental events, particularly in the nervous system. 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. Posttranslational modifications determine whether this protein localizes to the nucleus or the cytoplasm.

Source: NCBI Gene 1943 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 37 total
• Druggable target: yes
• MANE Select transcript: NM_001405

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3222
Approved symbol	EFNA2
Name	ephrin A2
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	ELF-1, LERK6
Ensembl gene	ENSG00000099617
Ensembl biotype	protein_coding
OMIM	602756
Entrez	1943

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000215368

RefSeq mRNA: 1 — MANE Select: NM_001405 NM_001405

CCDS: CCDS12061

Canonical transcript exons

ENST00000215368 — 4 exons

Exon	Start	End
ENSE00000651415	1298551	1298616
ENSE00000651417	1295545	1295858
ENSE00000795141	1285873	1286308
ENSE00001305835	1299824	1301431

Expression profiles

Bgee: expression breadth ubiquitous, 101 present calls, max score 95.77.

FANTOM5 (CAGE): breadth broad, TPM avg 1.8316 / max 42.7640, expressed in 399 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
172943	1.0236	270
172945	0.6735	271
172944	0.1345	91

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	95.77	gold quality
mucosa of sigmoid colon	UBERON:0004993	93.48	gold quality
colonic mucosa	UBERON:0000317	93.27	gold quality
buccal mucosa cell	CL:0002336	89.53	silver quality
mucosa of transverse colon	UBERON:0004991	88.83	gold quality
pancreatic ductal cell	CL:0002079	88.69	silver quality
jejunal mucosa	UBERON:0000399	87.52	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.01	gold quality
cortical plate	UBERON:0005343	82.93	gold quality
duodenum	UBERON:0002114	81.13	gold quality
right lobe of liver	UBERON:0001114	79.44	gold quality
sural nerve	UBERON:0015488	78.31	gold quality
ganglionic eminence	UBERON:0004023	76.73	gold quality
transverse colon	UBERON:0001157	73.28	gold quality
liver	UBERON:0002107	72.38	gold quality
rectum	UBERON:0001052	72.31	gold quality
small intestine	UBERON:0002108	71.26	gold quality
small intestine Peyer’s patch	UBERON:0003454	71.16	gold quality
ventricular zone	UBERON:0003053	70.93	gold quality
gall bladder	UBERON:0002110	69.66	gold quality
pigmented layer of retina	UBERON:0001782	68.66	gold quality
esophagus squamous epithelium	UBERON:0006920	68.29	silver quality
secondary oocyte	CL:0000655	66.56	silver quality
jejunum	UBERON:0002115	66.43	gold quality
intestine	UBERON:0000160	65.76	gold quality
metanephric glomerulus	UBERON:0004736	64.37	gold quality
large intestine	UBERON:0000059	64.10	gold quality
colon	UBERON:0001155	63.58	gold quality
vermiform appendix	UBERON:0001154	62.65	gold quality
medial globus pallidus	UBERON:0002477	62.59	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.03

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOS, NFATC1, RBPJ

miRNA regulators (miRDB)

60 targeting EFNA2, 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-190A-3P	100.00	80.35	5520
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-3163	100.00	77.23	8605
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-4745-5P	99.98	65.95	1028
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-1296-3P	99.72	64.04	636
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-6848-3P	99.64	66.49	885
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-4797-5P	99.39	68.01	1354
HSA-MIR-5580-5P	99.38	66.96	1139
HSA-MIR-4999-5P	99.35	69.15	926
HSA-MIR-3678-3P	99.31	67.10	1432
HSA-MIR-6843-3P	99.26	66.42	915

Literature-anchored findings (GeneRIF, showing 12)

• Optic nerve section in adult rat differentially regulates the expression of ephrin-A2 in the superior colliculus(SC).At 1 month, levels were upregulated across the contralateral SC giving rise to an increasing rostro-caudal gradient. (PMID:11860487)
• Different forms of Elf-1 are the products of posttranslational modifications that determine its subcellular localization, activity, and metabolic degradation. (PMID:11884456)
• Abnormal posttranslational mechanisms of the Elf-1 protein result in defective expression of the functional 98-kDa form of Elf-1, and consequently, the transcriptional defect of TCR zeta-chain in patients with systemic lupus erythematosus. (PMID:12421992)
• There is a significant loss of ELF-1 and reduced Smad4 expression in gastrointestinal neoplasms. (PMID:16158060)
• Elf-1 represents the first transcription factor identified to be involved in the transcriptional regulation of Fc receptor gamma (PMID:17878388)
• The crystal structures of an A-class complex between EphA2 and ephrin-A1 and of unbound EphA2, are presented. (PMID:19525919)
• Implicate EphA2 as a novel proinflammatory mediator and potential regulator of atherosclerotic plaque development. (PMID:22247258)
• High EphA2 receptor expression in colorectal cancer was associated with a worse outcome in patients treated with cetuximab-based therapy (PMID:24050852)
• these studies suggested that Kaposi’s sarcoma-associated herpesvirus utilizes CIB1 as one of the key molecule(s) to coordinate and sustain the EphA2 mediated signaling involved in its entry (PMID:24550731)
• Ephrin-A2 expression was correlated with Ki-67 expression in PCa patients, both at the gene scale and protein level. Our data indicate that Ephrin-A2 is a potential diagnostic and prognostic biomarker and a promising molecular therapeutic target to attenuate prostate cancer progression (PMID:26561474)
• Ephrin-A2 promotes prostate cancer metastasis by enhancing angiogenesis and promoting EMT. (PMID:33772606)
• Genetic variation in genes regulating skeletal muscle regeneration and tissue remodelling associated with weight loss in chronic obstructive pulmonary disease. (PMID:34523824)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	efna2a	ENSDARG00000031372
danio_rerio	efna2b	ENSDARG00000079740
mus_musculus	Efna2	ENSMUSG00000003070
rattus_norvegicus	Efna2	ENSRNOG00000016203
drosophila_melanogaster	Ephrin	FBGN0040324
caenorhabditis_elegans		WBGENE00001163
caenorhabditis_elegans		WBGENE00001164
caenorhabditis_elegans		WBGENE00001165
caenorhabditis_elegans		WBGENE00006869

Paralogs (7): EFNB1 (ENSG00000090776), EFNB3 (ENSG00000108947), EFNB2 (ENSG00000125266), EFNA3 (ENSG00000143590), EFNA1 (ENSG00000169242), EFNA5 (ENSG00000184349), EFNA4 (ENSG00000243364)

Protein

Protein identifiers

Ephrin-A2 — O43921 (reviewed: O43921)

Alternative names: EPH-related receptor tyrosine kinase ligand 6, HEK7 ligand

All UniProt accessions (1): O43921

UniProt curated annotations — full annotation on UniProt →

Function. Cell surface GPI-bound 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. With the EPHA2 receptor may play a role in bone remodeling through regulation of osteoclastogenesis and osteoblastogenesis.

Subunit / interactions. Binds to the receptor tyrosine kinases EPHA3, EPHA4 and EPHA5. Interacts with EPHA8; activates EPHA8.

Subcellular location. Cell membrane.

Similarity. Belongs to the ephrin family.

RefSeq proteins (1): NP_001396* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001799	Ephrin_RBD	Domain
IPR008972	Cupredoxin	Homologous_superfamily
IPR019765	Ephrin_CS	Conserved_site
IPR031328	Ephrin	Family
IPR034252	Ephrin-A_Ecto	Domain

Pfam: PF00812

UniProt features (24 total): strand 9, sequence conflict 3, glycosylation site 3, helix 2, disulfide bond 2, signal peptide 1, chain 1, propeptide 1, domain 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2WO3	X-RAY DIFFRACTION	2.35

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43921-F1	81.00	0.60

Functional residue map

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

Post-translational modifications (1): 188

Disulfide bonds (2): 73–114, 102–163

Glycosylation sites (3): 42, 174, 188

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2682334	EPH-Ephrin signaling
R-HSA-3928663	EPHA-mediated growth cone collapse
R-HSA-3928665	EPH-ephrin mediated repulsion of cells

MSigDB gene sets: 128 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, MORF_RAGE, MODULE_52, MODULE_45, GOBP_NEUROGENESIS, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION, MODULE_16, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_CELL_CELL_SIGNALING, MODULE_66, VART_KSHV_INFECTION_ANGIOGENIC_MARKERS_UP, GOBP_EPHRIN_RECEPTOR_SIGNALING_PATHWAY, ABBUD_LIF_SIGNALING_1_DN, GOBP_HEAD_DEVELOPMENT, GOBP_OLFACTORY_LOBE_DEVELOPMENT

GO Biological Process (6): cell-cell signaling (GO:0007267), axon guidance (GO:0007411), olfactory bulb development (GO:0021772), osteoclast differentiation (GO:0030316), bone remodeling (GO:0046849), ephrin receptor signaling pathway (GO:0048013)

GO Molecular Function (2): ephrin receptor binding (GO:0046875), protein binding (GO:0005515)

GO Cellular Component (5): plasma membrane (GO:0005886), neuromuscular junction (GO:0031594), perikaryon (GO:0043204), side of membrane (GO:0098552), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
EPH-Ephrin signaling	2
Axon guidance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
membrane	2
cell communication	1
signaling	1
axonogenesis	1
neuron projection guidance	1
olfactory lobe development	1
anatomical structure development	1
myeloid leukocyte differentiation	1
tissue remodeling	1
cell surface receptor protein tyrosine kinase signaling pathway	1
signaling receptor binding	1
binding	1
cell periphery	1
synapse	1
neuronal cell body	1
leaflet of membrane bilayer	1

Protein interactions and networks

STRING

926 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EFNA2	EPHA2	P29317	998
EFNA2	EPHA4	P54764	998
EFNA2	EPHA1	P21709	997
EFNA2	EPHA3	P29320	979
EFNA2	EPHA5	P54756	951
EFNA2	EPHA8	P29322	925
EFNA2	EPHA10	Q5JZY3	919
EFNA2	EPHA7	Q15375	915
EFNA2	ADAM10	O14672	825
EFNA2	EPHB2	P29323	793
EFNA2	EPHB1	P54762	778
EFNA2	EPHB6	O15197	777
EFNA2	NGEF	Q8N5V2	757
EFNA2	EPHB4	P54760	747
EFNA2	EPHA6	Q9UF33	702

IntAct

10 interactions, top by confidence:

A	B	Type	Score
EPHA4	EFNA2	psi-mi:“MI:0407”(direct interaction)	0.650
EPHA4	EFNA2	psi-mi:“MI:0915”(physical association)	0.650
Chn2	EFNA2	psi-mi:“MI:0915”(physical association)	0.400
EFNA2	C1QL1	psi-mi:“MI:0914”(association)	0.350
EFNA2	MGST3	psi-mi:“MI:0914”(association)	0.350
Epha1	EFNA2	psi-mi:“MI:0914”(association)	0.350

BioGRID (67): EFNA2 (Two-hybrid), ADAM10 (Affinity Capture-Western), EPHA7 (Affinity Capture-Western), OAF (Affinity Capture-MS), DSTYK (Affinity Capture-MS), PDF (Affinity Capture-MS), TUBB1 (Affinity Capture-MS), ENDOG (Affinity Capture-MS), C1QL4 (Affinity Capture-MS), C1QL1 (Affinity Capture-MS), NPTX1 (Affinity Capture-MS), NGLY1 (Affinity Capture-MS), DHFRL1 (Affinity Capture-MS), GDF11 (Affinity Capture-MS), VEGFB (Affinity Capture-MS)

ESM2 similar proteins: A5A8Y8, A7MBM2, E9PY61, O08542, O08545, O08717, O43921, O75888, O77805, O77835, P04087, P05111, P07434, P07994, P17490, P34820, P43031, P52794, P52797, P52798, P52801, P55101, P58166, Q16586, Q24JP5, Q28686, Q5Q0T9, Q5RJL6, Q5SZI1, Q641Q3, Q6PGN1, Q6PRD1, Q6ZVN8, Q7TQ32, Q7Z5Y6, Q80WF4, Q8C1Q4, Q8K1S7, Q8N7M5, Q8NCW0

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, O44516

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
EFNA2	up-regulates	EPHA4	binding
EFNA2	up-regulates	EPHA7	binding
EFNA2	up-regulates	EPHA8	binding
EFNA2	up-regulates	EPHA2	binding
EFNA2	up-regulates	EPHA5	binding
EFNA2	up-regulates	EPHA6	binding

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	33
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1030 predictions. Top by Δscore:

Variant	Effect	Δscore
19:1286305:CCAGG:C	donor_loss	1.0000
19:1286306:CAGGT:C	donor_loss	1.0000
19:1286307:AGGTG:A	donor_loss	1.0000
19:1286309:G:GA	donor_loss	1.0000
19:1286309:G:GG	donor_gain	1.0000
19:1286310:T:A	donor_loss	1.0000
19:1295541:GCAG:G	acceptor_loss	1.0000
19:1295542:CA:C	acceptor_loss	1.0000
19:1295542:CAG:C	acceptor_loss	1.0000
19:1295543:A:C	acceptor_loss	1.0000
19:1295543:A:T	acceptor_loss	1.0000
19:1295543:AG:A	acceptor_gain	1.0000
19:1295544:GG:G	acceptor_gain	1.0000
19:1295854:CATCT:C	donor_gain	1.0000
19:1295855:ATCT:A	donor_gain	1.0000
19:1295856:TCT:T	donor_gain	1.0000
19:1295857:CT:C	donor_gain	1.0000
19:1295859:G:GG	donor_gain	1.0000
19:1298545:TTCTA:T	acceptor_loss	1.0000
19:1298546:TCTAG:T	acceptor_loss	1.0000
19:1298547:CTAG:C	acceptor_loss	1.0000
19:1298548:TA:T	acceptor_loss	1.0000
19:1298549:A:AG	acceptor_gain	1.0000
19:1298550:G:GA	acceptor_gain	1.0000
19:1298550:G:GG	acceptor_gain	1.0000
19:1298550:GC:G	acceptor_gain	1.0000
19:1298550:GCT:G	acceptor_gain	1.0000
19:1298550:GCTGC:G	acceptor_gain	1.0000
19:1298612:GACCA:G	donor_gain	1.0000
19:1298617:G:GG	donor_gain	1.0000

AlphaMissense

1370 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:1286291:G:C	W41C	1.000
19:1286291:G:T	W41C	1.000
19:1295604:A:T	D67V	1.000
19:1295610:T:C	L69P	1.000
19:1295621:T:A	C73S	1.000
19:1295621:T:C	C73R	1.000
19:1295622:G:A	C73Y	1.000
19:1295622:G:C	C73S	1.000
19:1295623:C:G	C73W	1.000
19:1295734:G:C	K110N	1.000
19:1295734:G:T	K110N	1.000
19:1295735:C:A	R111S	1.000
19:1295735:C:T	R111C	1.000
19:1295738:T:A	W112R	1.000
19:1295738:T:C	W112R	1.000
19:1295740:G:C	W112C	1.000
19:1295740:G:T	W112C	1.000
19:1295744:T:A	C114S	1.000
19:1295744:T:C	C114R	1.000
19:1295745:G:A	C114Y	1.000
19:1295745:G:C	C114S	1.000
19:1295746:C:G	C114W	1.000
19:1295780:T:C	F126L	1.000
19:1295781:T:C	F126S	1.000
19:1295781:T:G	F126C	1.000
19:1295782:C:A	F126L	1.000
19:1295782:C:G	F126L	1.000
19:1295788:G:C	E128D	1.000
19:1295788:G:T	E128D	1.000
19:1295789:A:G	K129E	1.000

dbSNP variants (sampled 300 via entrez): RS1000042799 (19:1288779 C>A,T), RS1000098646 (19:1292827 G>A), RS1000203327 (19:1301724 G>A), RS1000279026 (19:1286851 G>A), RS1000452244 (19:1283038 C>G,T), RS1000531145 (19:1292698 T>C,G), RS1000562341 (19:1288598 T>C), RS1000729323 (19:1286121 C>G,T), RS1000731087 (19:1296474 A>G), RS1000797274 (19:1287020 G>A), RS1000822123 (19:1283035 G>A), RS1000936165 (19:1282814 G>C), RS1000989767 (19:1298417 G>A), RS1001015227 (19:1285943 C>A,G), RS1001154503 (19:1293640 C>T)

Disease associations

OMIM: gene MIM:602756 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST012071_4	Response to selenium supplementation (change in plasma selenium concentration)	3.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0600021	response to dietary selenium supplementation

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1795109 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases methylation	4
S-(1,2-dichlorovinyl)cysteine	decreases expression, affects response to substance, increases expression, affects cotreatment	2
bisphenol F	affects cotreatment, decreases methylation	1
dicrotophos	increases expression	1
decabromobiphenyl ether	affects expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
sodium arsenite	increases expression	1
benzo(e)pyrene	decreases methylation	1
mercuric bromide	decreases expression	1
2-palmitoylglycerol	increases expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cisplatin	affects cotreatment, decreases expression	1
Diazinon	increases methylation	1
Estradiol	decreases expression	1
Lead	affects methylation	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment, decreases expression	1
Melphalan	increases expression	1
Methapyrilene	decreases methylation	1
Nicotine	increases expression	1
Phenylmercuric Acetate	decreases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	decreases expression	1
Cyclosporine	decreases methylation	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1806267	Binding	Inhibition of EPH A2 assessed as residual enzyme activity at 10 uM	A novel pyrazolo[1,5-a]pyrimidine is a potent inhibitor of cyclin-dependent protein kinases 1, 2, and 9, which demonstrates antitumor effects in human tumor xenografts following oral administration. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8KP	Ubigene HCT 116 EFNA2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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