EPHA2 (EPH receptor A2)

2012-03-01   Elisavet T Gatzidou , Stamatios Theocharis , Constantinos Giaginis 




Atlas Image
EPHA2 gene structure. This diagram presents exon as blue boxes, introns as connecting lines with bp, codons are numbered in pink boxes and the location of structural motifs of EPHA2 protein as yellow boxes.


The EPHA2 is composed of 17 exons and 16 intervening introns spanning in a region of 31,73 kb.


The transcribed mRNA was 3970 bp (NM_004431).


Atlas Image
Structure of EPHA2 protein.


EPHA2 receptor is a transmembrane glycoprotein composed of 976 amino acid residues, with a calculated molecular mass of 130 kDa and an isoelectric point 6.1398. It is one member of the largest EPH (erythropoietin-producing hepatoma amplified sequence) family receptor tyrosine kinases. The family of Eph kinases binds ligands (known as ephrins) that are anchored to the membrane adjacent cells and consists of 16 known members across species, 14 of which are found in mammals and characterized by shared features in both the extracellular and intracellular domains.
EPH class receptors contain a single transmembrane spanning domain. Like other receptor tyrosine kinases, the extracellular domain of EPHA2 mediates ligand binding whereas the intacellular domain possesses intrinsic enzymatic activity.
The extracellular domain is glycosylated and is composed of globular, amino terminal domain followed by a cysteine-rich region with an epidermal growth factor-like motif and two fibronectin III-type repeats. The globular, amino-terminal domain contains immunoglobulin-like motifs and is both necessary and sufficient for ephrin-binding.
The intracellular domain includes a juxtamembrane region, a tyrosine kinase domain, a sterile alpha motif (SAM) and a PDZ-binding motif in the carboxy terminal end. The kinase domain and juxtamembrane region contain tyrosine residues and phosphorylation of these tyrosine residues creates docking sites for interaction with signalling proteins containing SH2/SH3 (Src - homology - 2/3) domains. SAM domain forms homodimers and may regulate receptor dimerization. The PDZ-binding motif binds to PDZ domain-containing proteins, which are though to serve as scaffolds for the assembly of multi-protein signalling complexes at the membrane.
EPHA2 shows 25-35% sequence homologies with other EPH receptors, and the tyrosine residues are conserved within the juxtamembrane and kinase domain.


EPHA2 is largely restricted at low levels on adult proliferating epithelial cells and enriched within sites of cell-cell adhesion in normal epithelial cells. EPHA2 expression has been detected in the brain, skin, bone marrow, lung, thymus, small intestine, colon, urinary bladder, kidney, liver, spleen, uterus, testis and prostate. EPHA2 expression levels in the colon, skin, kidney and lung were over 10-fold compared to those of the bone marrow. EPHA2 is also expressed during gastrulation in the ectodermal cells and early embryogenesis in the developing hind brain. In the skin, EphA2 is present in keratinocytes of epidermis and hair follicles but not in dermal cells, such as fibroblasts, vascular cells and inflammatory cells. EPHA2 has also been detected in proliferating mammary glands in female mice at puberty and differentially expressed during the estrous cycle. EPHA2 is widely unregulated and functionally altered in a variety of carcinomas and is implicated in cell transformation, primary tumor initiation, angiogenesis and metastasis in advanced cancer models. Overexpression has been shown both at the mRNA and protein level in established cell lines and human clinical specimens. Consistent findings indicate the prevalence of EPHA2 overexpression in many cancers, including glioblastoma, colorectal, gastric, esophageal, breast, thyroid, ovarian, endometrial, cervical, pancreatic, prostate, melanoma, bladder, renal cell, lung and hepatocellular carcinoma.


The EPHA2 is localized to the cell membrane.


The ligands for the EPH receptors are ephrins, which are 9 members and also fall into 2 subclasses: the GPI (glycosylphosphatidylinositol) anchored A-class of ligands (Ephrin A1-6) and the transmembrane B-class of ligands (B1-3).
EPH receptors interact with their cognate membrane anchored ligands at cell-cell contact sites to activate bidirectional signaling pathways effecting diverse physiologic processes including cell adhesion, repulsion, morphology, migration, differentiation and proliferation. Specifically, EPHA2 is activated by the ligand ephrin A1/EFNA1 and regulates migration, proliferation, integrin-mediated adhesion and differentiation of cells.
EPH receptor signaling has been implicated in many biological processes such as axon guidance and fasciculation, tissue border formation, neuronal targeting and angiogenesis during embryonic development. Especially, EPHA2 is involved in angiogenesis, in early hindbrain development and epithelial proliferation and branching morphogenesis during mammary gland development. EPHA2 with ephrin A2/EFNA2 may play a role in bone remodeling through regulation of osteoclastogenesis and osteoblastogenesis. It also engaged with the ephrin A5/EFNA5 and may regulate lens fiber cells shape and interactions and be critical for lens transparency development and maintenance.
Emerging evidence implicates EPHA2 overexpression in cell transformation, primary tumor initiation, progression, angiogenesis and metastasis in a variety of cancer models.


Human EPHA2 shares 96% amino acid identity with the chimpanzee, 95% amino acid identity with dogs, 94% with cows, 93% with mouse, 92% with rats and 56% amino acid identity with zebrafish.



Congenital cataract (CC) is one of the most significant causes of visual impairment and blidness in childhood. Approximately, up to 25% of all CC could be inherited, most often transmitting as an autosomal dominant trait and showing considerable inter- and intra-familial phenotypic variation.


Loci for autosomal dominant posterior polar CC and total CC have both been mapped to chromosom 1p36 harboring the EPHA2 gene. Two missense mutations and one frameshift in the EPHA2 gene have been linked with posterior polar CC and one splicing mutation have been associated with total CC.
The c.2819 C>T (p.T940I) missense mutation changes an oligomerization interface of the SAM domain, most likely inactivating the EPHA2 signalling function by destroying its SAM domain.
The c.2842 G>T (p.G648W) missense mutation identified in exon 17 and occured at the first base of codon 948 and was predicted to result in substitution of glycine to tryptophan at the level of translation, placing it in the cytoplasmic SAM domain of EPHA2 gene.
The c.2915_2916delTG deletion of 2 bp discovered in exon 7 of EPHA2 gene and was predicted to result in a frameshift mutation creating a mutant protein with a novel C-terminal polypeptide of 39 amino acid residues.
The c.2826-9G>A is a splicing mutation with a single base substitution in intron 16 which creates a novel splice acceptor site causing an intronic sequence of 7 bp to be included in the processed transcript. This aberrant splicing is predicted to result in translational of a novel C-terminal polypeptide of 71 amino acid residues of which the last 39 are identical to that of the nove polypeptide produced bt the c.2915_2916delTG.

Implicated in

Entity name
Various cancers
EphA2 has been reported to be overexpressed in several cancers and a high level of EphA2 has been detected in malignant cancer-derived cell lines and advanced forms of cancer.
Eph-A2 overexpression was significantly associated with poor prognosis in several types of malignant tumors, including oral tongue, oesophageal, lung, renal, ovarian, cervical and endometrial carcinoma, as well as glioblastoma and melanoma. In human epidermal growth factor receptor 2 (Her2) positive breast cancer patients, increased levels of EphA2 mRNA were correlated to a decreased potential for overall and disease-free survival.
Entity name
Epithelial ovarian carcinoma
High EphA2 expression was evident in clinical specimens of invasive ovarian tumors, while little or no staining was observed in normal ovaries. Moreover, EphA2 overexpression was significantly associated with higher grade, advanced disease stage and with factors involved in invasion and angiogenesis. A relationship between EphA2 overexpression and the status of tumor suppressor p53 was noted. High EphA2 expressing tumors exhibited increased microvessel density when stained for CD31 as a measure of angiogenesis. In addition, the matrix metalloproteinase expression, which degrades the extracellular matrix during cancer progression, was also associated with EphA2 expression.
Entity name
Prostate cancer
In clinical prostate carcinoma specimens, EphA2 immunoreactivity was increased with a positive staining in 60-100% of cells. EphA2 was overexpressed more in metastatic cells compared to non-invasive prostatic epithelial cells and its levels as increased as prostatic epithelial cells moved toward a more aggressive phenotype.
Entity name
Breast cancer
In breast carcinoma specimens, 92% of the cases showed moderate to high staining for EphA2. EphA2 overexpression in breast cancer was negatively associated with estrogen receptor expression. In clinical specimens of benign mammary epithelia, 75% of the specimens were negative, while 25% were weak positive.
Entity name
Pancreatic carcinoma
EphA2 was overexpressed in about 95% of pancreatic cancer specimens, being associated with metastatic disease, increased cellular invasiveness and patients age.
Entity name
Lung cancers
In non-small cell lung cancer specimens, moderate to high EphA2 immunostaining was observed in the membrane and cytoplasm in more than 70% of the examined carcinomas. This increase was comparable in adenocarcinoma, squamous cell carcinoma and large cell carcinomas. EphA2 was also associated with clinically advanced stages of disease, the presence of brain metastasis and smoking status.
Entity name
Brain cancers
EphA2 was found to be overexpressed but not to be tyrosine phosphorylated in glioblastoma multiforme cells or tumors. In surgically resected human malignant glioma tissues, a heterogeneous and variable EphA2 staining pattern was observed. Although normal brain tissues exhibited minimal EphA2 staining, the cases of anaplastic astrocytoma and glioblastoma multiforme exhibited variable staining patterns. In astrocytic tumors, EphA2 overexpression was also correlated with the pathological grade and the proliferation status of tumors.
Entity name
Urinary bladder carcinoma
Clinical specimens of urinary bladder carcinoma when examined by a semi-quantitative immunostaining showed a differential staining pattern than normal specimens. Of all urinary bladder specimens with Ta grade lesions, 30% showed moderately strong staining, while in the T3 and T4 lesions, 75% and 90% of the samples showed strong staining, respectively. In sharp contrast, 85% of normal tissues showed weak staining, while the remaining 15% showed moderate staining for EphA2. Notably, EphA2 staining intensity was associated with advanced stage of urothelial carcinoma.
Entity name
EphA2 was found to be phosphorylated in aggressive melanoma-derived cells and was associated with vasculogenic mimicry, i.e. the formation of endothelial cell-like network. In a tissue microarray of melanomas, strong cytoplasmic EphA2 staining was present in 16% of the cases, being associated with histological thickness of melanomas and tumors proliferation status. A correlation of metastatic potential and high EphA2 expression was also observed in human melanoma cell lines derived from patients, while EphA2 overexpression changed cellular migration from the mesenchymal- to the amoeboid-type.
Entity name
Oesophageal squamous cell carcinoma
EphA2 overexpression was detected in esophageal carcinoma-derived cells and in 50% of clinical specimens. EphA2 expression was correlated with lymph node metastases, whereas no significant association with patients age, tumour location, tumour size, histological differentiation and clinical stage was noted.
Entity name
Colorectal carcinoma
Increased expression of EphA2 was observed in over 59% of clinical specimens from colorectal cancer patients. EphA2 expression was increased in early-stage tumors compared to those of advanced stage, as well as in smaller tumors than large tumors. Microvessel count was also correlated with overexpression of EphA2. In human colon cancer-derived HCT116 cells, a dose and time-dependent upregulation of EphA2 was noticed after treatment with deoxycholic acid, a component of bile acids and promoter of colon cancer. The upregulation of EphA2 was p53-independent, but it was linked to the activation of MAP kinase pathway.
Entity name
Renal cell carcinoma
Higher levels of EphA2 expression were correlated with tumors that were of higher grade, larger and more highly vascularized in patients with renal cell carcinoma.
Entity name
Vulvar carcinoma
In vulvar cancers, more than 50% of vulvar squamous cell carcinomas expressed elevated levels of EphA2.
Entity name
Malignant and benign thyroid malignancies
Eph-A2 receptor was associated with increased proliferative activity of malignant thyroid lesions. Eph-A2 was significantly overexpressed in malignant compared to benign thyroid lesions. Papillary carcinoma cases also presented significantly increased Eph-A2 expression compared to those with hyperplasia nodules.
Entity name
Squamous cell cervical carcinomas
In early squamous cell cervical carcinomas, EphA2 expression was classified as negative in 21 tumors (10%), weak positive in 108 tumors (50%), moderate positive in 69 (32%) and strong positive in 19 tumors (9%).
Entity name
Oral tongue squamous cell carcinoma
In oral tongue SCC specimens, Eph-A2 expression was significantly correlated with tumor size, clinical stage, lymph invasion, recurrence and distant metastasis.


Pubmed IDLast YearTitleAuthors
164284722006Expression of EphA2 and Ephrin A-1 in carcinoma of the urinary bladder.Abraham S et al
184980772008EPH receptors in cancer.Castaño J et al
196421432010EFNA1 ligand and its receptor EphA2: potential biomarkers for hepatocellular carcinoma.Cui XD et al
151479542004Invasiveness of breast carcinoma cells and transcript profile: Eph receptors and ephrin ligands as molecular markers of potential diagnostic and prognostic application.Fox BP et al
199499122010Clinical significance of ephrin (eph)-A1, -A2, -a4, -a5 and -a7 receptors in pancreatic ductal adenocarcinoma.Giaginis C et al
160612792005The clinical significance of EphA2 and Ephrin A-1 in epithelial ovarian carcinomas.Han L et al
156715502005Expression of EphA2 is prognostic of disease-free interval and overall survival in surgically treated patients with renal cell carcinoma.Herrem CJ et al
171586422007Expression of EphA2 and EphrinA-1 in vulvar carcinomas and its relation to prognosis.Holm R et al
185666742008Expressions of EphA2 and EphrinA-1 in early squamous cell cervical carcinomas and their relation to prognosis.Holm R et al
222368652012Higher expression of EphA2 and ephrin-A1 is related to favorable clinicopathological features in pathological stage I non-small cell lung carcinoma.Ishikawa M et al
193968182009EphA2 overexpression is associated with lack of hormone receptor expression and poor outcome in endometrial cancer.Kamat AA et al
218739382011Eph-A2 and Eph-A4 expression in human benign and malignant thyroid lesions: an immunohistochemical study.Karidis NP et al
149653632004Correlation of EPHA2 overexpression with high microvessel count in human primary colorectal cancer.Kataoka H et al
126506082003Overexpression and functional alterations of the EphA2 tyrosine kinase in cancer.Kinch MS et al
125764262003Predictive value of the EphA2 receptor tyrosine kinase in lung cancer recurrence and survival.Kinch MS et al
163004692005EphA2 as a target for ovarian cancer therapy.Landen CN et al
21741051990cDNA cloning and characterization of eck, an epithelial cell receptor protein-tyrosine kinase in the eph/elk family of protein kinases.Lindberg RA et al
124944752003EphA2 overexpression correlates with poor prognosis in esophageal squamous cell carcinoma.Miyazaki T et al
171466152006Patterns of EphA2 protein expression in primary and metastatic pancreatic carcinoma and correlation with genetic status.Mudali SV et al
122426972002Diverse roles for the Eph family of receptor tyrosine kinases in carcinogenesis.Nakamoto M et al
156492542005EPHA2/EFNA1 expression in human gastric cancer.Nakamura R et al
192441302009EphA2 reexpression prompts invasion of melanoma cells shifting from mesenchymal to amoeboid-like motility style.Parri M et al
159287102005Eph receptor signalling casts a wide net on cell behaviour.Pasquale EB et al
79181001994The expression of the receptor-protein tyrosine kinase gene, eck, is highly restricted during early mouse development.Ruiz JC et al
184857992008Expression of EphA2 and VEGF in squamous cell carcinoma of the tongue: correlation with the angiogenesis and clinical outcome.Shao Z et al
190055742008The EPHA2 gene is associated with cataracts linked to chromosome 1p.Shiels A et al
192649062009Kinase-dependent and -independent roles of EphA2 in the regulation of prostate cancer invasion and metastasis.Taddei ML et al
211428022011Emerging strategies for EphA2 receptor targeting for cancer therapeutics.Tandon M et al
152974182004EphA2 expression is associated with aggressive features in ovarian carcinoma.Thaker PH et al
191442112008Eph receptors in breast cancer: roles in tumor promotion and tumor suppression.Vaught D et al
180975892008Increased expression of EphA2 correlates with adverse outcome in primary and recurrent glioblastoma multiforme patients.Wang LF et al
190748252008The EphA2 receptor and ephrinA1 ligand in solid tumors: function and therapeutic targeting.Wykosky J et al
162541882005EphA2 as a novel molecular marker and target in glioblastoma multiforme.Wykosky J et al
193063282009Mutations of the EPHA2 receptor tyrosine kinase gene cause autosomal dominant congenital cataract.Zhang T et al

Other Information

Locus ID:

NCBI: 1969
MIM: 176946
HGNC: 3386
Ensembl: ENSG00000142627


dbSNP: 1969
ClinVar: 1969
TCGA: ENSG00000142627


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Axon guidanceKEGGko04360
Axon guidanceKEGGhsa04360
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Ras signaling pathwayKEGGhsa04014
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
EPH-Ephrin signalingREACTOMER-HSA-2682334
EPHA-mediated growth cone collapseREACTOMER-HSA-3928663
EPH-ephrin mediated repulsion of cellsREACTOMER-HSA-3928665


Pubmed IDYearTitleCitations
215160872011EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy.287
202239872010Restriction of receptor movement alters cellular response: physical force sensing by EphA2.136
190748252008The EphA2 receptor and ephrinA1 ligand in solid tumors: function and therapeutic targeting.114
180799692008The receptor tyrosine kinase EphA2 promotes mammary adenocarcinoma tumorigenesis and metastatic progression in mice by amplifying ErbB2 signaling.110
123708232002Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo.101
160984642005A conditional feedback loop regulates Ras activity through EphA2.94
202288012010An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly.89
124963642002Blockade of EphA receptor tyrosine kinase activation inhibits vascular endothelial cell growth factor-induced angiogenesis.85
198984822009Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy.84
125764262003Predictive value of the EphA2 receptor tyrosine kinase in lung cancer recurrence and survival.80


Elisavet T Gatzidou ; Stamatios Theocharis ; Constantinos Giaginis

EPHA2 (EPH receptor A2)

Atlas Genet Cytogenet Oncol Haematol. 2012-03-01

Online version: http://atlasgeneticsoncology.org/gene/40462/epha2