EPHA10 Gene

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EPHA10 Gene

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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 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 invasion

Mechanisms: 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 variations

Post-Translational Modifications

EPHA10 undergoes typical Eph receptor modifications:

Tyrosine Phosphorylation: Ligand-dependent autophosphorylation

Ubiquitination: Receptor turnover regulation

Glycosylation: Affects cell surface expression

Genetic 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 cells

Challenges

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 neurodegeneration

Research 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 biomarker

Unanswered 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 effects

Future 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 cancer

Emerging 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

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 expression

Metabolic Functions

Emerging 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)

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Related Entities

EPHA10

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slug	genes-epha10
kg_node_id	EPHA10
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-5eb9e6f3dedb
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-epha10'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

55%

Debates

0

Incoming

11

Outgoing

21

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

EPHA10 Gene

EPHA10 Gene

EPHA10 Gene

Overview

EPHA10 Gene

EPHA10 Gene

Overview

Gene Structure and Organization

Genomic Location and Structure

Protein Structure

Function

Normal Physiological Function

Signaling Pathways

Ligand Specificity

Expression Pattern

Tissue Distribution

Brain Expression

Disease Associations

Cancer

Neurodegenerative Diseases

Immune-Related Conditions

Protein Biochemistry

Structural Features

Post-Translational Modifications

Genetic Variation

Known Variants

Functional Variants

Animal Models

Knockout Studies

Transgenic Models

Therapeutic Implications

Therapeutic Strategies

Challenges

Comparison with Other EPHA Receptors

Research Status and Future Directions

Current Understanding

Research Priorities

Unanswered Questions

Interactions

Protein Interactions

Signaling Network

Evolutionary Biology and Comparative Genomics

Phylogenetic Analysis

Species-Specific Expression

Clinical and Diagnostic Relevance

Cancer Biomarker Potential

Fertility Assessment

Molecular Mechanisms in Testis

Sperm Motility Regulation

Testis-Specific Expression Regulation

Epigenetic Regulation in Brain

DNA Methylation

Histone Modifications

Interaction with Other Eph Receptors

Receptor crosstalk

Functional Relationships

Drug Development and Therapeutic Targeting

Small Molecule Inhibitors

Antibody-Based Therapies

Challenges and Considerations

Future Research Directions

Knowledge Gaps

Emerging Technologies

See Also

References

Additional Insights into EPHA10 Biology

Membrane Trafficking and Receptor Dynamics

Cell-Type Specific Signaling Outcomes

Metabolic Functions

Computational Modeling Insights

Pathway Diagram

💬 Discussion