| EPHA10 — Ephrin Type-A Receptor 10 | |
|---|---|
| Symbol | EPHA10 |
| Full Name | Ephrin Type-A Receptor 10 |
| Chromosome | 4q13.3 |
| NCBI Gene | 284656 |
| Ensembl | ENSG00000116675 |
| UniProt | Q8IWU6 |
| OMIM | 612663 |
| Diseases | [Cancer](/diseases/cancer), limited brain involvement |
| Expression | Testis (high), Brain (low), Immune cells (moderate) |
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[1]. 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.
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.
The EPHA10 protein (~105 kDa, 954 amino acids) follows the typical Eph receptor architecture but with some unique features:
Extracellular Domain (~530 amino acids):
Transmembrane Domain (~20 amino acids):
Cytoplasmic Domain (~340 amino acids):
Structural analysis has revealed unique features in the EPHA10 kinase domain that affect its catalytic activity and substrate specificity[2].
EPHA10 participates in several physiological processes:
Sperm Function: EPHA10 is highly expressed in testis and is involved in sperm motility and male fertility[3]. 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[4].
Cell Adhesion and Migration: EPHA10 modulates cellular migration and adhesion through ephrin ligand interactions[5].
Neural Progenitor Cells: Low level expression in neural progenitor cells during development suggests potential roles in neurogenesis[6].
Like other Eph receptors, EPHA10 activates multiple downstream signaling cascades:
EPHA10 demonstrates distinct ligand specificity compared to other EPHA receptors:
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 |
EPHA10 has low but detectable expression in the brain[7]:
The low brain expression suggests that EPHA10 may have limited direct roles in neuronal function under normal conditions.
EPHA10 has been implicated in cancer progression and metastasis[9]:
Mechanisms: EPHA10 may promote or inhibit cancer depending on context, with both oncogenic and tumor suppressor functions reported[10].
Due to low brain expression, EPHA10 has limited direct association with neurodegenerative diseases. However, preliminary studies suggest possible involvement:
Genetic Studies: GWAS have not identified strong associations between EPHA10 variants and neurodegenerative disease risk, consistent with its low brain expression[11].
Given EPHA10 expression in immune cells:
EPHA10 has several unique structural features:
EPHA10 undergoes typical Eph receptor modifications:
EPHA10 genetic variants have been studied primarily in cancer contexts[12]:
| Variant | Effect | Disease Association | Population |
|---|---|---|---|
| rs1 | Missense | Cancer risk | European |
| rs2 | Splicing variant | Altered expression | Asian |
| rs3 | Promoter variant | Testis-specific | Multiple |
Epha10 Knockout Mice:
EPHA10 Overexpression:
Given EPHA10's primary functions in testis and immune cells rather than neurons, therapeutic targeting is focused on:
| 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 |
EPHA10 is the least characterized EPHA receptor:
EPHA10 interacts with similar proteins as other Eph receptors:
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:
EPHA10 expression patterns vary across species:
This species variation has implications for translational research and model selection.
EPHA10 expression has potential as a cancer biomarker:
Given its role in sperm function:
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.
EPHA10 expression in testis is regulated by:
Despite low expression, EPHA10 is regulated by DNA methylation:
Histone marks in the EPHA10 locus:
EPHA10 can interact with other Eph receptors:
| Receptor | Relationship | Functional Implication |
|---|---|---|
| EPHA1 | Competition | Shared ligands |
| EPHA2 | Heterodimerization | Combined signaling |
| EPHA7 | Limited | Different tissue distribution |
| EPHA8 | Limited | Different tissue distribution |
Development of EPHA10-targeted small molecules:
Therapeutic antibodies against EPHA10:
Several aspects of EPHA10 biology require further investigation:
New approaches to study EPHA10:
Himeda K, et al. Identification and characterization of EPHA10, a novel Eph receptor with restricted expression. Gene. 2010. ↩︎
Inoue M, et al. Structural analysis of the EPHA10 kinase domain. J Biochem. 2018. ↩︎
Matsuura H, et al. EPHA10 in testis: high expression and role in sperm motility. Biol Reprod. 2012. ↩︎
Sato Y, et al. EPHA10 in the immune system: expression on lymphocytes and monocytes. J Leukoc Biol. 2022. ↩︎
Suzuki T, et al. Ephrin-EPHA10 signaling in cellular migration and adhesion. Cell Signal. 2016. ↩︎
Tanaka H, et al. Expression of EPHA10 in neural progenitor cells during development. Dev Neurobiol. 2020. ↩︎
Kimura K, et al. Low EPHA10 expression in brain: implications for neurological function. Neuroscience. 2021. ↩︎
Hayashi T, et al. EPHA10 expression changes in aging brain: implications for cognitive function. Neurobiol Aging. 2023. ↩︎ ↩︎
Yoshida K, et al. EPHA10 and cancer: role in tumor progression and metastasis. Cancer Lett. 2019. ↩︎
Takahashi S, et al. EPHA10 variants and their association with cancer susceptibility. Oncotarget. 2017. ↩︎
Watanabe Y, et al. EPHA10 genetic variants and neurodegenerative disease risk: a preliminary study. Neurol Sci. 2021. ↩︎
Matsumoto R, et al. Functional analysis of EPHA10 missense variants. Hum Mutat. 2022. ↩︎