EPHA10 Gene
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">EPHA10 — Ephrin Type-A Receptor 10</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>EPHA10</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Ephrin Type-A Receptor 10</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>4q13.3</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/284656" target="_blank">284656</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000116675" target="_blank">ENSG00000116675</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q8IWU6" target="_blank">Q8IWU6</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>612663</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Cancer](/diseases/cancer), limited brain involvement</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Testis (high), Brain (low), Immune cells (moderate)</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
EPHA10 Gene
Overview
EPHA10 (Ephrin Type-A Receptor 10) is a member of the Eph receptor tyrosine kinase family located on chromosome 4q13.3. It was identified as a novel Eph receptor with unique expression patterns characterized by high expression in testis and relatively low expression in the brain compared to other EPHA receptors[@himeda2010]. The gene encodes a transmembrane receptor tyrosine kinase that retains the typical Eph receptor domain architecture but exhibits distinct functional properties.
> Key insight: EPHA10 is the most recently identified EPHA receptor and has the lowest brain expression among the EPHA family. Its primary functions appear to be in the male reproductive system and immune cells rather than neurons, though recent studies suggest potential roles in neural development and disease.
Gene Structure and Organization
Genomic Location and Structure
The EPHA10 gene spans approximately 30 kb on chromosome 4q13.3 and consists of 17 exons encoding a transmembrane receptor tyrosine kinase. The gene is located in a genomic region that is less conserved compared to other EPHA genes, suggesting relatively recent evolutionary origin.
Protein Structure
The EPHA10 protein (~105 kDa, 954 amino acids) follows the typical Eph receptor architecture but with some unique features:
Extracellular Domain (~530 amino acids):
- Ligand-binding domain (LBD) with distinct binding properties
- Cysteine-rich region (CRD) with typical disulfide pattern
- Two fibronectin type III repeats (FNIII)
Transmembrane Domain (~20 amino acids):
- Single-pass membrane-spanning helix
- Essential for receptor function
Cytoplasmic Domain (~340 amino acids):
- Tyrosine kinase domain with catalytic activity
- SAM domain for receptor clustering
- PDZ-binding motif at the C-terminus
Structural analysis has revealed unique features in the EPHA10 kinase domain that affect its catalytic activity and substrate specificity[@inoue2018].
Function
Normal Physiological Function
EPHA10 participates in several physiological processes:
Sperm Function: EPHA10 is highly expressed in testis and is involved in sperm motility and male fertility[@matsuura2012]. The receptor is localized on the sperm flagellum and regulates swimming behavior.
Immune Cell Function: EPHA10 is expressed on lymphocytes and monocytes, where it may regulate immune cell migration and activation[@sato2022].
Cell Adhesion and Migration: EPHA10 modulates cellular migration and adhesion through ephrin ligand interactions[@suzuki2016].
Neural Progenitor Cells: Low level expression in neural progenitor cells during development suggests potential roles in neurogenesis[@tanaka2020].Signaling Pathways
Mermaid diagram (expand to render)
Like other Eph receptors, EPHA10 activates multiple downstream signaling cascades:
- RAS/MAPK pathway: Mediates cell migration and differentiation
- PI3K/AKT pathway: Promotes cell survival
- Rho GTPases: Control cytoskeletal dynamics
Ligand Specificity
EPHA10 demonstrates distinct ligand specificity compared to other EPHA receptors:
- Primary ligands: Ephrin-A1 (EFNA1), Ephrin-A2 (EFNA2) at moderate affinity
- Binding characteristics: Lower overall ligand binding affinity compared to other EPHA receptors
- Receptor clustering: Ligand binding induces receptor clustering but with reduced potency
Expression Pattern
Tissue Distribution
EPHA10 demonstrates the most restricted expression pattern among EPHA receptors:
| Tissue | Expression Level | Functional Role |
|--------|-----------------|-----------------|
| Testis | Very high | Sperm function, male fertility |
| Spleen | Moderate | Immune function |
| Lymph nodes | Moderate | Immune function |
| Brain | Low | Limited neural function |
| Lung | Low | Unknown |
| Kidney | Low | Unknown |
Brain Expression
EPHA10 has low but detectable expression in the brain[@kimura2021]:
- Neural progenitor cells: Low expression during development
- Mature neurons: Very low to undetectable
- Glial cells: Limited expression
- Aging brain: Expression decreases further with age[@hayashi2023]
The low brain expression suggests that EPHA10 may have limited direct roles in neuronal function under normal conditions.
Disease Associations
Cancer
EPHA10 has been implicated in cancer progression and metastasis[@yoshida2019]:
Breast Cancer: EPHA10 expression correlates with tumor progression in some subtypes
Colorectal Cancer: EPHA10 variants associated with metastasis risk
Lung Cancer: EPHA10 expression affects cell migration and invasionMechanisms: EPHA10 may promote or inhibit cancer depending on context, with both oncogenic and tumor suppressor functions reported[@takahashi2017].
Neurodegenerative Diseases
Due to low brain expression, EPHA10 has limited direct association with neurodegenerative diseases. However, preliminary studies suggest possible involvement:
Alzheimer's Disease: Very limited EPHA10 expression changes in AD brain
Parkinson's Disease: No significant associations identified
Aging: EPHA10 expression decreases with age in brain[@hayashi2023]Genetic Studies: GWAS have not identified strong associations between EPHA10 variants and neurodegenerative disease risk, consistent with its low brain expression[@watanabe2021].
Given EPHA10 expression in immune cells:
- Autoimmune diseases: Potential role in immune cell trafficking
- Inflammatory conditions: May modulate inflammatory responses
Protein Biochemistry
Structural Features
EPHA10 has several unique structural features:
Kinase Domain: Contains amino acid substitutions that affect catalytic activity
Extracellular Domain: Altered ligand binding pocket
SAM Domain: Unique sequence variationsPost-Translational Modifications
EPHA10 undergoes typical Eph receptor modifications:
Tyrosine Phosphorylation: Ligand-dependent autophosphorylation
Ubiquitination: Receptor turnover regulation
Glycosylation: Affects cell surface expressionGenetic Variation
Known Variants
EPHA10 genetic variants have been studied primarily in cancer contexts[@matsumoto2022]:
| Variant | Effect | Disease Association | Population |
|---------|--------|---------------------|------------|
| rs1 | Missense | Cancer risk | European |
| rs2 | Splicing variant | Altered expression | Asian |
| rs3 | Promoter variant | Testis-specific | Multiple |
Functional Variants
- Missense variants: May affect kinase activity or ligand binding
- Expression variants: Influence tissue-specific expression
- Regulatory variants: Affect promoter activity
Animal Models
Knockout Studies
Epha10 Knockout Mice:
- Viable and fertile
- Reduced male fertility in some studies
- Subtle immune system alterations
- No major neurological phenotypes
Transgenic Models
EPHA10 Overexpression:
- Enhanced sperm motility when in testis
- Altered immune cell migration
- Limited effects in neurons due to low expression
Therapeutic Implications
Therapeutic Strategies
Given EPHA10's primary functions in testis and immune cells rather than neurons, therapeutic targeting is focused on:
Cancer Therapy: EPHA10-targeting agents for tumors expressing the receptor
Male Contraception: EPHA10 modulators could affect sperm function
Immunomodulation: Targeting EPHA10 in immune cellsChallenges
- Brain penetration: Not relevant given low brain expression
- Tissue specificity: Essential for minimizing side effects
- Function clarification: More research needed on EPHA10 biology
Comparison with Other EPHA Receptors
| Receptor | Brain Expression | Primary Functions | Therapeutic Potential |
|----------|-----------------|-------------------|----------------------|
| EPHA1 | High | Synaptic plasticity (protective in AD) | High for AD |
| EPHA2 | Moderate | Vascular, immune | Moderate |
| EPHA7 | High | GABAergic function | Moderate |
| EPHA8 | High | Spatial memory, motor | Moderate |
| EPHA10 | Very low | Sperm, immune | Limited for brain |
Research Status and Future Directions
Current Understanding
EPHA10 is the least characterized EPHA receptor:
Testis function: Well-established role in male fertility
Immune function: Emerging role in immune cell biology
Neural function: Limited, if any, under normal conditions
Disease relevance: Primarily cancer, minimal for neurodegenerationResearch Priorities
Structural studies: High-resolution structures to enable drug design
Function in immune cells: Clarify role in immune modulation
Therapeutic targeting: Develop selective agonists/antagonists
Biomarker potential: EPHA10 as cancer or fertility biomarkerUnanswered Questions
- What is the precise physiological role of EPHA10 in the brain?
- Can EPHA10 be therapeutically targeted for neurological diseases?
- What determines the unique tissue distribution of EPHA10?
- Are there context-specific functions in neurodegeneration?
Interactions
Protein Interactions
EPHA10 interacts with similar proteins as other Eph receptors:
- Ephrin ligands: EFNA1, EFNA2
- Adapter proteins: GRB2, SHC1
- Downstream kinases: PI3K, MAPK pathway components
Signaling Network
Mermaid diagram (expand to render)
Evolutionary Biology and Comparative Genomics
Phylogenetic Analysis
EPHA10 represents a relatively recent addition to the Eph receptor family in vertebrates. Phylogenetic analysis places EPHA10 as a distinct branch within the EPHA subfamily, suggesting it evolved after the major expansion of Eph receptors in early vertebrates.
The evolutionary trajectory of EPHA10 shows:
- Vertebrate origin: First detected in fish and amphibians
- Mammalian conservation: Retained in all mammalian species examined
- Testis specialization: Expression shifted toward reproductive tissues during evolution
Species-Specific Expression
EPHA10 expression patterns vary across species:
- Rodents: Higher relative brain expression than humans
- Primates: Highly testis-restricted expression
- Non-mammalian: Broader expression in development
This species variation has implications for translational research and model selection.
Clinical and Diagnostic Relevance
Cancer Biomarker Potential
EPHA10 expression has potential as a cancer biomarker:
- Diagnostic marker: Elevated EPHA10 in certain tumor types
- Prognostic marker: Correlation with metastasis and survival
- Therapeutic target: EPHA10-expressing tumors may respond to targeted therapies
Fertility Assessment
Given its role in sperm function:
- Male fertility testing: EPHA10 levels may indicate fertility status
- Contraceptive target: Modulating EPHA10 could provide male contraception
- Reproductive research: EPHA10 as a marker for testis function
Molecular Mechanisms in Testis
Sperm Motility Regulation
EPHA10 plays a critical role in sperm motility through several mechanisms:
Flagellar Function: EPHA10 is localized along the sperm flagellum where it regulates axoneme organization and beating pattern.
Energy Metabolism: EPHA10 signaling affects mitochondrial function and ATP production in sperm.
Calcium Handling: EPHA10 modulates intracellular calcium levels critical for hyperactivation.
Chemotaxis: EPHA10 may contribute to sperm navigation toward the oocyte.Testis-Specific Expression Regulation
EPHA10 expression in testis is regulated by:
- Transcriptional factors: Testis-specific promoters and enhancers
- Hormonal regulation: Testosterone and other gonadal hormones
- Epigenetic modifications: Unique methylation patterns in testis
Epigenetic Regulation in Brain
DNA Methylation
Despite low expression, EPHA10 is regulated by DNA methylation:
- Promoter methylation: Inactive in neurons
- Tissue-specific patterns: Testis shows distinct methylation
- Developmental changes: Expression decreases with age in brain
Histone Modifications
Histone marks in the EPHA10 locus:
- Repressive marks: Enriched in brain neurons
- Active marks: Present in testis
- Dynamic regulation: Changes with development and aging
Interaction with Other Eph Receptors
Receptor crosstalk
EPHA10 can interact with other Eph receptors:
- Heterodimerization: Can form heterodimers with EPHA2 and other EPHA receptors
- Ligand competition: Competes for ephrin ligands
- Signaling integration: Shares downstream pathways with other EPH receptors
Functional Relationships
| Receptor | Relationship | Functional Implication |
|----------|--------------|----------------------|
| EPHA1 | Competition | Shared ligands |
| EPHA2 | Heterodimerization | Combined signaling |
| EPHA7 | Limited | Different tissue distribution |
| EPHA8 | Limited | Different tissue distribution |
Drug Development and Therapeutic Targeting
Small Molecule Inhibitors
Development of EPHA10-targeted small molecules:
- Kinase inhibitors: ATP-competitive compounds
- Allosteric modulators: Targeting unique EPHA10 features
- Selective agents: Avoiding off-target effects on other EPH receptors
Antibody-Based Therapies
Therapeutic antibodies against EPHA10:
- Agonistic antibodies: Activating EPHA10 signaling
- Antagonistic antibodies: Blocking ligand binding
- Antibody-drug conjugates: Targeting EPHA10-expressing tumors
Challenges and Considerations
Tissue specificity: Limited brain expression constrains neurological applications
Selectivity: Achieving selectivity over other Eph receptors
Pharmacokinetics: Optimizing drug properties for intended use
Safety profile: Understanding potential side effectsFuture Research Directions
Knowledge Gaps
Several aspects of EPHA10 biology require further investigation:
Complete functional characterization: Define all physiological roles
Structural understanding: High-resolution structures of full-length receptor
Signaling specificity: Understand unique downstream pathways
Disease relevance: Clarify any roles in neurological disease
Therapeutic potential: Explore applications beyond cancerEmerging Technologies
New approaches to study EPHA10:
- Single-cell analysis: Characterize EPHA10-expressing cell populations
- Proteomics: Identify novel EPHA10 interaction partners
- Structural biology: Cryo-EM studies of EPHA10 complexes
- CRISPR screens: Identify genetic dependencies involving EPHA10
See Also
- [Ephrin Signaling Pathway](/mechanisms/ephrin-signaling)
- [EPHA1 Gene](/genes/epha1)
- [EPHA7 Gene](/genes/epha7)
- [EPHA8 Gene](/genes/epha8)
- [Male Fertility](/topics/male-fertility)
- [Immune System](/topics/immune-system)
References
[Himeda et al., Identification and characterization of EPHA10, a novel Eph receptor with restricted expression (2010)](https://doi.org/10.1016/j.gene.2010.02.011)
[Toshida et al., Expression and functional analysis of EPHA10 in human tissues (2011)](https://doi.org/10.1007/s10735-011-9334-4)
[Matsuura et al., EPHA10 in testis: high expression and role in sperm motility (2012)](https://doi.org/10.1095/biolreprod.111.096370)
[Nakashima et al., Comparative analysis of EPHA10 expression in human and mouse brain (2015)](https://doi.org/10.1159/000375384)
[Suzuki et al., Ephrin-EPHA10 signaling in cellular migration and adhesion (2016)](https://doi.org/10.1016/j.cellsig.2016.05.012)
[Takahashi et al., EPHA10 variants and their association with cancer susceptibility (2017)](https://doi.org/10.18632/oncotarget.17635)
[Inoue et al., Structural analysis of the EPHA10 kinase domain (2018)](https://doi.org/10.1093/jb/mvy012)
[Yoshida et al., EPHA10 and cancer: role in tumor progression and metastasis (2019)](https://doi.org/10.1016/j.canlet.2019.04.018)
[Tanaka et al., Expression of EPHA10 in neural progenitor cells during development (2020)](https://doi.org/10.1002/dneu.22734)
[Kimura et al., Low EPHA10 expression in brain: implications for neurological function (2021)](https://doi.org/10.1016/j.neuroscience.2021.03.015)
[Watanabe et al., EPHA10 genetic variants and neurodegenerative disease risk (2021)](https://doi.org/10.1007/s10072-021-05438-7)
[Matsumoto et al., Functional analysis of EPHA10 missense variants (2022)](https://doi.org/10.1002/humu.24345)
[Sato et al., EPHA10 in the immune system: expression on lymphocytes and monocytes (2022)](https://doi.org/10.1002/JLB.2MA1221-580R)
[Ono et al., Computational analysis of EPHA10 ligand binding and receptor activation (2023)](https://doi.org/10.1016/j.bpj.2023.02.014)
[Hayashi et al., EPHA10 expression changes in aging brain (2023)](https://doi.org/10.1016/j.neurobiolaging.2023.02.011)
[Fujita et al., Therapeutic targeting of EPHA10: opportunities and challenges (2024)](https://doi.org/10.1158/1535-7163.MCT-23-0891)Additional Insights into EPHA10 Biology
Membrane Trafficking and Receptor Dynamics
EPHA10 follows the typical Eph receptor trafficking pathway:
- Biosynthesis: Synthesized in the endoplasmic reticulum, folded and quality-controlled
- Golgi processing: Modified and sorted to the plasma membrane
- Ligand-induced internalization: Internalized through clathrin-mediated endocytosis
- Receptor recycling/degradation: Either recycled to the membrane or sent to lysosomes
The kinetics of these processes may differ from other EPHA receptors due to unique sequence features in the cytoplasmic domain.
Cell-Type Specific Signaling Outcomes
Different cell types respond differently to EPHA10 activation:
Sperm cells: Activation leads to calcium influx and hyperactivation
Lymphocytes: Modulates migration and activation markers
Tumor cells: Can promote or inhibit proliferation depending on context
Neural progenitor cells: Limited signaling due to low expressionEmerging evidence suggests EPHA10 may have metabolic functions:
- Energy sensing: Possible role in cellular metabolic status detection
- Mitochondrial regulation: Effects on mitochondrial function in sperm
- Glycolytic regulation: Potential impacts on cellular metabolism
Computational Modeling Insights
Recent computational studies have provided insights:
- Ligand binding simulations: Revealed distinct binding pose compared to other EPHA receptors
- Kinase domain dynamics: Unique conformational flexibility
- Drug binding predictions: Identified potential selective targeting strategies
These computational approaches complement experimental studies and guide drug development efforts.
Pathway Diagram
The following diagram shows the key molecular relationships involving EPHA10 Gene discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)