Alternative titles; symbols
HGNC Approved Gene Symbol: EPHA2
Cytogenetic location: 1p36.13 Genomic coordinates (GRCh38): 1:16,124,337-16,156,069 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.13 | Cataract 6, multiple types | 116600 | Autosomal dominant | 3 |
See EPHA1 (179610) for background information on Eph receptors and their ligands, the ephrins.
By screening a HeLa cell cDNA library with degenerate oligonucleotides based on highly conserved regions of receptor protein-tyrosine kinases, Lindberg and Hunter (1990) isolated cDNAs encoding EPHA2, which they called ECK. The predicted 976-amino acid protein consists of a 534-amino acid external domain that includes a signal peptide; a 24-amino acid transmembrane domain; and a 418-amino acid cytoplasmic domain that contains a canonical protein-tyrosine kinase catalytic domain. Immunoprecipitated ECK from human cells migrated as an approximately 125- to 130-kD doublet by SDS-PAGE. Northern blot analysis detected an approximately 4.7-kb ECK transcript in human cells. Rat Eck mRNA was highly expressed in tissues containing a high proportion of epithelial cells, including lung, skin, small intestine, and ovary. Immunohistochemical analysis detected rat Eck protein in lung and kidney epithelial cells.
Using RT-PCR, Zhang et al. (2009) detected mRNA expression of the EPHA2 gene in a human lens epithelial cell line and human anterior lens capsule tissues.
By somatic cell hybrid analysis and fluorescence in situ hybridization, Sulman et al. (1997) mapped the EPHA2 gene to chromosome 1p36.1. They noted that there appears to be clusters of EPH genes on several chromosomes.
Ganju et al. (1994) mapped the mouse Epha2 gene to the distal region of chromosome 4, between the Akp2 (171760) and Gpd1 (138420) genes. They noted that this region shows homology of synteny with human chromosome 1p36-p34.
Jun et al. (2009) stated that EPHA2 was readily detectable in human lens fiber cells using immunoblot and immunohistochemistry.
Hiramoto-Yamaki et al. (2010) showed that EPHA2 interacted with ephexin-4 (ARHGEF16; 618871) in MDA-MB-231 human breast cancer cells, thereby promoting cell migration and invasion. The interaction was facilitated by the kinase domain of EPHA2 and the DBL (MCF2; 311030) homology (DH) domain of ephexin-4, but it was inhibited by the sterile-alpha motif (SAM) domain of EPHA2. Ephexin-4 acted as a GEF for RHOG (179505) downstream of EPHA2 and interacted with RHOG to activate it. Activated RHOG bound ELMO2 (606421) and recruited a ternary complex of ELMO2, DOCK4 (607679), and EPHA2 to the plasma membrane in MDA-MB-231 cells. DOCK4 promoted migration and invasion of MDA-MB-231 cells at tips of cortactin (CTTN; 164765)-rich protrusions through activation of RAC1 (602048).
Using a functional RNA interference kinase screen, Lupberger et al. (2011) identified EGFR (131550) and EPHA2 as host cofactors for hepatitis C virus (HCV; see 609532) entry into cells. Clinically approved receptor tyrosine kinase (RTK) inhibitors (erlotinib and dasatinib) or RTK-specific antibodies impaired infection by all major HCV genotypes and viral escape variants in cell culture and in a human liver chimeric mouse model. EGFR and EPHA2 mediated HCV entry by regulating CD81 (186845)-claudin-1 (CLDN1; 603718) coreceptor associations and viral glycoprotein-dependent membrane fusion. Lupberger et al. (2011) concluded that RTKs are HCV entry cofactors and that RTK inhibitors have substantial antiviral activity that may be useful for prevention and treatment of HCV infection.
Udayakumar et al. (2011) stated that EPHA2 is overexpressed in many cancer types and that it appears to participate in crosstalk between the RAS (190020)-PI3K (see 601232)-AKT (see 164730) and RAS-MAPK (see 176948) signaling pathways. They also stated that EPHA2 is an essential mediator of apoptosis in response to ultraviolet radiation, an important environmental carcinogen involved in melanoma formation. By characterizing a number of melanoma cell lines, they found that EPHA2 can function as either a prosurvival factor or as a proapoptotic factor depending on the cellular context. Knockdown of EPHA2 expression in high EPHA2-expressing cell lines resulted in profound loss of viability and tumorigenicity. However, overexpression of EPHA2 in low EPHA2-expressing cell lines elicited an apoptotic response.
Salaita et al. (2010) reconstituted the intermembrane signaling geometry between live EPHA2-expressing human breast cancer cells and supported membranes displaying laterally mobile ephrin-A1 (191164). Receptor-ligand binding, clustering, and subsequent lateral transport within this junction were observed. EPHA2 transport can be blocked by physical barriers nanofabricated onto the underlying substrate. This physical reorganization of EPHA2 alters the cellular response to ephrin-A1, as observed by changes in cytoskeleton morphology and recruitment of a disintegrin and metalloprotease-10 (MMP10; 185260). Quantitative analysis of receptor-ligand spatial organization across a library of 26 mammary epithelial cell lines revealed characteristic differences that strongly correlated with invasion potential.
Using an antibody array to assess the level of 28 receptors in the livers of 2 substrains of BALB/c mice, Kaushansky et al. (2015) determined that 9 receptors, including EphA2, were present at elevated levels in the substrain that is more susceptible to the murine malaria parasite, Plasmodium yoelii (see 611162). Infection of a murine hepatocyte line with P. yoelii showed that cells with the highest EphA2 levels also had the highest infection rate. Infection of mice revealed a strong preference for hepatocytes with high EphA2 levels. Infection was inhibited by antibody to the extracellular portion of EphA2 in a dose-dependent manner. EphA2 -/- mice had a lower liver-stage parasite burden and a delay in blood-stage infection compared with wildtype mice. Hepatocytes with high EphA2 levels also showed more effective parasitophorous vacuole membrane development, which is critical for liver-stage development. Further analysis showed that malaria sporozoite invasion involved interaction between EphA2 and parasite 6-cys proteins.
In a 4-generation Caucasian family with autosomal dominant posterior polar cataracts mapping to chromosome 1p36 (CTRCT6; 116600), Shiels et al. (2008) identified a heterozygous missense mutation in the EPHA2 gene (176946.0001) that segregated with disease and was not found in 192 controls.
In a 5-generation Han Chinese family with posterior polar cataracts, Zhang et al. (2009) identified a heterozygous mutation in the EPHA2 gene (T940I; 176946.0002) that segregated with disease and was not detected in 202 unrelated Chinese controls. Zhang et al. (2009) then sequenced the EPHA2 gene in a British and an Australian family with autosomal dominant cataract mapping to 1p, previously studied by Ionides et al. (1997) and McKay et al. (2005), respectively, and identified a heterozygous 2-bp deletion (176946.0003) and splice site mutation (176946.0004) that segregated with disease in the respective families.
In 3 independent Caucasian study populations from the United States, United Kingdom, and Australia, Jun et al. (2009) demonstrated significant association between SNPs in the EPHA2 gene and age-related cortical cataract, with the strongest association at rs6678616 in exon 3 (combined p = 10(-4)). In a large family with age-related cortical cataract, Jun et al. (2009) sequenced the EPHA2 gene and found that a nonsynonymous variant, R721Q (176946.0005), cosegregated with the phenotype; functional analysis demonstrated that R721Q significantly alters EPHA2 signaling and cellular regulation in vitro.
Khounlotham et al. (2009) observed increased granulomatous pathology, accumulation of Cd4 (186940)-positive and Cd8 (see 186910)-positive T cells and dendritic cells, and higher numbers of Tnf (191160)-, Ifng (147570)-, and Il4 (147780)-producing cells in the lungs of Epha2 -/- mice compared with wildtype mice following exposure to low-dose aerosol of Mycobacterium tuberculosis. RT-PCR analysis detected progressively increased expression of Epha1, Epha2, and ephrin A1 (EFNA1; 191164) in wildtype mice and increased expression of Epha1 and Efna1 in Epha2 -/- mice after infection. A small but statistically significant reduction in bacillary numbers was observed in chronically infected Epha2 -/- mice compared with wildtype mice. Khounlotham et al. (2009) proposed that EPHA2 inhibits the migration and accumulation of T cells and may be a mechanism exploited by M. tuberculosis to circumvent the host response.
Jun et al. (2009) generated 2 independent strains of Epha2-null mice and observed the development of significant lens opacity between 3 to 4 months, with mature cataracts including lens rupture occurring between 6 to 8 months. Cataract affected over 80% of homozygous knockout mice by 12 months. In wildtype mice, Jun et al. (2009) found that the level of expression of Epha2 decreased with age and was spatially and temporally regulated: immunofluorescence analysis revealed that Epha2 was low in anterior epithelial cells, upregulated as the cells entered differentiation at the equator, strongly expressed in the cortical fiber cells, but absent in the nuclei. In the lens of Epha2 null mice, Jun et al. (2009) observed overexpression of Hsp25 (mouse homolog of human HSP27, 602195) in an underphosphorylated form, suggestive of excessive cellular stress and protein misfolding.
In a 4-generation Caucasian family with autosomal dominant posterior polar cataracts mapping to chromosome 1p36 (CTRCT6; 116600), Shiels et al. (2008) identified heterozygosity for a 2842G-T transversion in exon 17 of the EPHA2 gene, resulting in a gly948-to-trp (G948W) substitution at a conserved residue in the cytoplasmic sterile-alpha-motif (SAM) domain. The mutation was not found in 192 controls.
In affected members of a 5-generation Han Chinese family with autosomal dominant posterior polar cataract mapping to chromosome 1p36 (CTRCT6; 116600), Zhang et al. (2009) identified heterozygosity for a 2819C-T transition in the EPHA2 gene, resulting in a thr940-to-ile (T940I) substitution at 1 of the 2 residues forming the oligomerization interface in the SAM domain of the receptor. The mutation was not found in unaffected family members or 202 unrelated Chinese controls.
In affected members of a British family with autosomal dominant posterior polar cataract mapping to chromosome 1p (CTRCT6; 116600), previously studied by Ionides et al. (1997), Zhang et al. (2009) identified heterozygosity for a 2-bp deletion (2915delTG) in exon 17 of the EPHA2 gene, causing a frameshift predicted to result in a mutant EPHA2 protein with a novel C-terminal polypeptide of 39 amino acid residues. Yeast 2-hybrid experiments using low molecular weight protein-tyrosine phosphate (LMW-PTP), which has been shown to associate with the C-terminal region of the EPHA2 receptor, negatively regulating EPHA2 signaling (Kikawa et al., 2002; Parri et al., 2005), suggested that enhanced recruitment or tighter binding of LMW-PTP to the mutant EPHA2 might exert a loss-of-function effect.
In an Australian family from Tasmania with autosomal dominant congenital total cataract mapping to chromosome 1p (CTRCT6; 116600), previously studied by McKay et al. (2005), Zhang et al. (2009) identified heterozygosity for a 2826-9G-A transition in IVS16 of the EPHA2 gene, creating a novel splice acceptor site that causes a 7-bp intronic sequence to be included in the processed transcript. The aberrant splicing was predicted to result in a novel C-terminal peptide of 71 amino acids, the last 39 of which are identical to that of the novel peptide produced by the 2-bp deletion in exon 17 (see 176946.0003). Yeast 2-hybrid experiments using low molecular weight protein-tyrosine phosphate (LMW-PTP), which has been shown to associate with the C-terminal region of the EPHA2 receptor, negatively regulating EPHA2 signaling (Kikawa et al., 2002; Parri et al., 2005), suggested that enhanced recruitment or tighter binding of LMW-PTP to the mutant EPHA2 might exert a loss-of-function effect.
In a family with autosomal dominant age-related cortical cataract (CTRCT6; 116600), Jun et al. (2009) identified a G-A variant in exon 13 of the EPHA2 gene, resulting in an arg721-to-gln (R721Q) substitution. The frequency of the rare 'A' allele in 3 independent study populations from the United States, United Kingdom, and Australia was 0.6%, 0%, and 0.2%, respectively; the authors stated that 0.1% to 0.2% probably represents a true population estimate for this rare variant. The risk allele had 78% penetrance in heterozygous individuals whose age was 70 years or more. When expressed in HEK293 cells, the mutant displayed significantly higher basal activation than wildtype in the absence of ligand stimulation, and this correlated with dramatically reduced basal ERK1/2 (see 176948) activity compared to wildtype, suggesting altered signaling by the mutant EPHA2. In a clonal growth assay, HEK293 cells expressing R721Q were significantly growth-inhibited by EPHA1, whereas wildtype-expressing cells were not. In addition, there was stochastic intracellular retention of the R721Q mutant EPHA2, but not wildtype EPHA2, when expressed in MEF cells derived from Epha2 -/- embryos, affecting about 40% of total cell populations. Jun et al. (2009) concluded that the R721Q mutation significantly alters EPHA2 signaling and cellular regulation in vitro.
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